Sample records for epigenetic cell memory
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The contribution of epigenetic memory to immunologic memory.
Zediak, Valerie P; Wherry, E John; Berger, Shelley L
2011-04-01
Memory T lymphocytes are distinct from antigen-inexperienced naïve T cells in that memory T cells can respond more rapidly when they re-encounter a pathogen. Work over the past decade has begun to define the epigenetic underpinnings of the transcriptional component of the memory T cell response. An emerging theme is the persistence of an active chromatin signature at relevant gene loci in resting memory T cells, even when those genes are transcriptionally inactive. This gives strength to the concept of gene poising, and has shown that memory T lymphocytes are an ideal model in which to further define various mechanisms of epigenetic poising. Copyright © 2011 Elsevier Ltd. All rights reserved.
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Multi-layered epigenetic mechanisms contribute to transcriptional memory in T lymphocytes.
Dunn, Jennifer; McCuaig, Robert; Tu, Wen Juan; Hardy, Kristine; Rao, Sudha
2015-05-06
Immunological memory is the ability of the immune system to respond more rapidly and effectively to previously encountered pathogens, a key feature of adaptive immunity. The capacity of memory T cells to "remember" previous cellular responses to specific antigens ultimately resides in their unique patterns of gene expression. Following re-exposure to an antigen, previously activated genes are transcribed more rapidly and robustly in memory T cells compared to their naïve counterparts. The ability for cells to remember past transcriptional responses is termed "adaptive transcriptional memory". Recent global epigenome studies suggest that epigenetic mechanisms are central to establishing and maintaining transcriptional memory, with elegant studies in model organisms providing tantalizing insights into the epigenetic programs that contribute to adaptive immunity. These epigenetic mechanisms are diverse, and include not only classical acetylation and methylation events, but also exciting and less well-known mechanisms involving histone structure, upstream signalling pathways, and nuclear localisation of genomic regions. Current global health challenges in areas such as tuberculosis and influenza demand not only more effective and safer vaccines, but also vaccines for a wider range of health priorities, including HIV, cancer, and emerging pathogens such as Ebola. Understanding the multi-layered epigenetic mechanisms that underpin the rapid recall responses of memory T cells following reactivation is a critical component of this development pathway.
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Epigenetic Regulation of Myeloid Cells
IVASHKIV, LIONEL B.; PARK, SUNG HO
2017-01-01
Epigenetic regulation in myeloid cells is crucial for cell differentiation and activation in response to developmental and environmental cues. Epigenetic control involves posttranslational modification of DNA or chromatin, and is also coupled to upstream signaling pathways and transcription factors. In this review, we summarize key epigenetic events and how dynamics in the epigenetic landscape of myeloid cells shape the development, immune activation, and innate immune memory. PMID:27337441
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Engrampigenetics: Epigenetics of engram memory cells.
Ripoli, Cristian
2017-05-15
For long time, the epidemiology of late-onset sporadic Alzheimer's disease (AD) risk factors has centered on adult life-style. Recent studies have, instead, focused on the role of early life experiences in progression of such disease especially in the context of prenatal and postnatal life. Although no single unfavorable environmental event has been shown to be neither necessary nor sufficient for AD development, it is possible that the sum of several environmentally induced effects, over time, contribute to its pathophysiology through epigenetic mechanisms. Indeed, epigenetic changes are influenced by environmental factors and have been proposed to play a role in multifactorial pathologies such as AD. At the same time, recent findings suggest that epigenetic mechanisms are one method that neurons use to translate transient stimuli into stable memories. Thus, the characteristics of epigenetics being a critical link between the environment and genes and playing a crucial role in memory formation make candidate epigenetic mechanisms a natural substrate for AD research. Indeed, independent groups have reported several epigenetically dysregulated genes in AD models; however, the role of epigenetic mechanisms in AD has remained elusive owing to contradictory results. Here, I propose that restricting the analysis of epigenetic changes specifically to subpopulations of neurons (namely, engram memory cells) might be helpful in understanding the role of the epigenetic process in the memory-related specific epigenetic code and might constitute a new template for therapeutic interventions against AD. Copyright © 2016. Published by Elsevier B.V.
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The epigenetic basis of memory formation and storage.
Jarome, Timothy J; Thomas, Jasmyne S; Lubin, Farah D
2014-01-01
The formation of long-term memory requires a series of cellular and molecular changes that involve transcriptional regulation of gene expression. While these changes in gene transcription were initially thought to be largely regulated by the activation of transcription factors by intracellular signaling molecules, epigenetic mechanisms have emerged as an important regulator of transcriptional processes across multiple brain regions to form a memory circuit for a learned event or experience. Due to their self-perpetuating nature and ability to bidirectionally control gene expression, these epigenetic mechanisms have the potential to not only regulate initial memory formation but also modify and update memory over time. This chapter focuses on the established, but poorly understood, role for epigenetic mechanisms such as posttranslational modifications of histone proteins and DNA methylation at the different stages of memory storage. Additionally, this chapter emphasizes how these mechanisms interact to control the ideal epigenetic environment for memory formation and modification in neurons. The reader will gain insights into the limitations in our current understanding of epigenetic regulation of memory storage, especially in terms of their cell-type specificity and the lack of understanding in the interactions of various epigenetic modifiers to one another to impact gene expression changes during memory formation.
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Szilagyi, B A; Triebus, J; Kressler, C; de Almeida, M; Tierling, S; Durek, P; Mardahl, M; Szilagyi, A; Floess, S; Huehn, J; Syrbe, U; Walter, J; Polansky, J K; Hamann, A
2017-11-01
The concept of a "topographical memory" in lymphocytes implies a stable expression of homing receptors mediating trafficking of lymphocytes back to the tissue of initial activation. However, a significant plasticity of the gut-homing receptor α 4 β 7 was found in CD8 + T cells, questioning the concept. We now demonstrate that α 4 β 7 expression in murine CD4 + memory T cells is, in contrast, imprinted and remains stable in the absence of the inducing factor retinoic acid (RA) or other stimuli from mucosal environments. Repetitive rounds of RA treatment enhanced the stability of de novo induced α 4 β 7 . A novel enhancer element in the murine Itga4 locus was identified that showed, correlating to stability, selective DNA demethylation in mucosa-seeking memory cells and methylation-dependent transcriptional activity in a reporter gene assay. This implies that epigenetic mechanisms contribute to the stabilization of α 4 β 7 expression. Analogous DNA methylation patterns could be observed in the human ITGA4 locus, suggesting that its epigenetic regulation is conserved between mice and men. These data prove that mucosa-specific homing mediated by α 4 β 7 is imprinted in CD4 + memory T cells, reinstating the validity of the concept of "topographical memory" for mucosal tissues, and imply a critical role of epigenetic mechanisms.
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Dynamic and static maintenance of epigenetic memory in pluripotent and somatic cells.
Shipony, Zohar; Mukamel, Zohar; Cohen, Netta Mendelson; Landan, Gilad; Chomsky, Elad; Zeliger, Shlomit Reich; Fried, Yael Chagit; Ainbinder, Elena; Friedman, Nir; Tanay, Amos
2014-09-04
Stable maintenance of gene regulatory programs is essential for normal function in multicellular organisms. Epigenetic mechanisms, and DNA methylation in particular, are hypothesized to facilitate such maintenance by creating cellular memory that can be written during embryonic development and then guide cell-type-specific gene expression. Here we develop new methods for quantitative inference of DNA methylation turnover rates, and show that human embryonic stem cells preserve their epigenetic state by balancing antagonistic processes that add and remove methylation marks rather than by copying epigenetic information from mother to daughter cells. In contrast, somatic cells transmit considerable epigenetic information to progenies. Paradoxically, the persistence of the somatic epigenome makes it more vulnerable to noise, since random epimutations can accumulate to massively perturb the epigenomic ground state. The rate of epigenetic perturbation depends on the genomic context, and, in particular, DNA methylation loss is coupled to late DNA replication dynamics. Epigenetic perturbation is not observed in the pluripotent state, because the rapid turnover-based equilibrium continuously reinforces the canonical state. This dynamic epigenetic equilibrium also explains how the epigenome can be reprogrammed quickly and to near perfection after induced pluripotency.
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He, Shan; Liu, Yongnian; Meng, Lijun; Sun, Hongxing; Wang, Ying; Ji, Yun; Purushe, Janaki; Chen, Pan; Li, Changhong; Madzo, Jozef; Issa, Jean-Pierre; Soboloff, Jonathan; Reshef, Ran; Moore, Bethany; Gattinoni, Luca; Zhang, Yi
2017-12-14
Memory T cells sustain effector T-cell production while self-renewing in reaction to persistent antigen; yet, excessive expansion reduces memory potential and impairs antitumor immunity. Epigenetic mechanisms are thought to be important for balancing effector and memory differentiation; however, the epigenetic regulator(s) underpinning this process remains unknown. Herein, we show that the histone methyltransferase Ezh2 controls CD8 + T memory precursor formation and antitumor activity. Ezh2 activates Id3 while silencing Id2, Prdm1 and Eomes, promoting the expansion of memory precursor cells and their differentiation into functional memory cells. Akt activation phosphorylates Ezh2 and decreases its control of these transcriptional programs, causing enhanced effector differentiation at the expense of T memory precursors. Engineering T cells with an Akt-insensitive Ezh2 mutant markedly improves their memory potential and capability of controlling tumor growth compared to transiently inhibiting Akt. These findings establish Akt-mediated phosphorylation of Ezh2 as a critical target to potentiate antitumor immunotherapeutic strategies.
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Effector CD8 T cells dedifferentiate into long-lived memory cells.
Youngblood, Ben; Hale, J Scott; Kissick, Haydn T; Ahn, Eunseon; Xu, Xiaojin; Wieland, Andreas; Araki, Koichi; West, Erin E; Ghoneim, Hazem E; Fan, Yiping; Dogra, Pranay; Davis, Carl W; Konieczny, Bogumila T; Antia, Rustom; Cheng, Xiaodong; Ahmed, Rafi
2017-12-21
Memory CD8 T cells that circulate in the blood and are present in lymphoid organs are an essential component of long-lived T cell immunity. These memory CD8 T cells remain poised to rapidly elaborate effector functions upon re-exposure to pathogens, but also have many properties in common with naive cells, including pluripotency and the ability to migrate to the lymph nodes and spleen. Thus, memory cells embody features of both naive and effector cells, fuelling a long-standing debate centred on whether memory T cells develop from effector cells or directly from naive cells. Here we show that long-lived memory CD8 T cells are derived from a subset of effector T cells through a process of dedifferentiation. To assess the developmental origin of memory CD8 T cells, we investigated changes in DNA methylation programming at naive and effector cell-associated genes in virus-specific CD8 T cells during acute lymphocytic choriomeningitis virus infection in mice. Methylation profiling of terminal effector versus memory-precursor CD8 T cell subsets showed that, rather than retaining a naive epigenetic state, the subset of cells that gives rise to memory cells acquired de novo DNA methylation programs at naive-associated genes and became demethylated at the loci of classically defined effector molecules. Conditional deletion of the de novo methyltransferase Dnmt3a at an early stage of effector differentiation resulted in reduced methylation and faster re-expression of naive-associated genes, thereby accelerating the development of memory cells. Longitudinal phenotypic and epigenetic characterization of the memory-precursor effector subset of virus-specific CD8 T cells transferred into antigen-free mice revealed that differentiation to memory cells was coupled to erasure of de novo methylation programs and re-expression of naive-associated genes. Thus, epigenetic repression of naive-associated genes in effector CD8 T cells can be reversed in cells that develop into long-lived memory CD8 T cells while key effector genes remain demethylated, demonstrating that memory T cells arise from a subset of fate-permissive effector T cells.
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Human memory CD8 T cell effector potential is epigenetically preserved during in vivo homeostasis.
Abdelsamed, Hossam A; Moustaki, Ardiana; Fan, Yiping; Dogra, Pranay; Ghoneim, Hazem E; Zebley, Caitlin C; Triplett, Brandon M; Sekaly, Rafick-Pierre; Youngblood, Ben
2017-06-05
Antigen-independent homeostasis of memory CD8 T cells is vital for sustaining long-lived T cell-mediated immunity. In this study, we report that maintenance of human memory CD8 T cell effector potential during in vitro and in vivo homeostatic proliferation is coupled to preservation of acquired DNA methylation programs. Whole-genome bisulfite sequencing of primary human naive, short-lived effector memory (T EM ), and longer-lived central memory (T CM ) and stem cell memory (T SCM ) CD8 T cells identified effector molecules with demethylated promoters and poised for expression. Effector-loci demethylation was heritably preserved during IL-7- and IL-15-mediated in vitro cell proliferation. Conversely, cytokine-driven proliferation of T CM and T SCM memory cells resulted in phenotypic conversion into T EM cells and was coupled to increased methylation of the CCR7 and Tcf7 loci. Furthermore, haploidentical donor memory CD8 T cells undergoing in vivo proliferation in lymphodepleted recipients also maintained their effector-associated demethylated status but acquired T EM -associated programs. These data demonstrate that effector-associated epigenetic programs are preserved during cytokine-driven subset interconversion of human memory CD8 T cells. © 2017 Abdelsamed et al.
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Rodriguez, Ramon M; Suarez-Alvarez, Beatriz; Lavín, José L; Mosén-Ansorena, David; Baragaño Raneros, Aroa; Márquez-Kisinousky, Leonardo; Aransay, Ana M; Lopez-Larrea, Carlos
2017-01-15
Epigenetic mechanisms play a critical role during differentiation of T cells by contributing to the formation of stable and heritable transcriptional patterns. To better understand the mechanisms of memory maintenance in CD8 + T cells, we performed genome-wide analysis of DNA methylation, histone marking (acetylated lysine 9 in histone H3 and trimethylated lysine 9 in histone), and gene-expression profiles in naive, effector memory (EM), and terminally differentiated EM (TEMRA) cells. Our results indicate that DNA demethylation and histone acetylation are coordinated to generate the transcriptional program associated with memory cells. Conversely, EM and TEMRA cells share a very similar epigenetic landscape. Nonetheless, the TEMRA transcriptional program predicts an innate immunity phenotype associated with genes never reported in these cells, including several mediators of NK cell activation (VAV3 and LYN) and a large array of NK receptors (e.g., KIR2DL3, KIR2DL4, KIR2DL1, KIR3DL1, KIR2DS5). In addition, we identified up to 161 genes that encode transcriptional regulators, some of unknown function in CD8 + T cells, and that were differentially expressed in the course of differentiation. Overall, these results provide new insights into the regulatory networks involved in memory CD8 + T cell maintenance and T cell terminal differentiation. Copyright © 2017 by The American Association of Immunologists, Inc.
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Does stress remove the HDAC brakes for the formation and persistence of long-term memory?
White, André O; Wood, Marcelo A
2014-07-01
It has been known for numerous decades that gene expression is required for long-lasting forms of memory. In the past decade, the study of epigenetic mechanisms in memory processes has revealed yet another layer of complexity in the regulation of gene expression. Epigenetic mechanisms do not only provide complexity in the protein regulatory complexes that control coordinate transcription for specific cell function, but the epigenome encodes critical information that integrates experience and cellular history for specific cell functions as well. Thus, epigenetic mechanisms provide a unique mechanism of gene expression regulation for memory processes. This may be why critical negative regulators of gene expression, such as histone deacetylases (HDACs), have powerful effects on the formation and persistence of memory. For example, HDAC inhibition has been shown to transform a subthreshold learning event into robust long-term memory and also generate a form of long-term memory that persists beyond the point at which normal long-term memory fails. A key question that is explored in this review, from a learning and memory perspective, is whether stress-dependent signaling drives the formation and persistence of long-term memory via HDAC-dependent mechanisms. Copyright © 2013 Elsevier Inc. All rights reserved.
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Does stress remove the HDAC brakes for the formation and persistence of long-term memory?
White, André O.; Wood, Marcelo A.
2013-01-01
It has been known for numerous decades that gene expression is required for long-lasting forms of memory. In the past decade, the study of epigenetic mechanisms in memory processes has revealed yet another layer of complexity in the regulation of gene expression. Epigenetic mechanisms do not only provide complexity in the protein regulatory complexes that control coordinate transcription for specific cell function, but the epigenome encodes critical information that integrates experience and cellular history for specific cell functions as well. Thus, epigenetic mechanisms provide a unique mechanism of gene expression regulation for memory processes. This may be why critical negative regulators of gene expression, such as histone deacetylases (HDACs), have powerful effects on the formation and persistence of memory. For example, HDAC inhibition has been shown to transform a subthreshold learning event into robust long-term memory and also generate a form of long-term memory that persists beyond the point at which normal long-term memory fails. A key question that is explored in this review, from a learning and memory perspective, is whether stress-dependent signaling drives the formation and persistence of long-term memory via HDAC-dependent mechanisms. PMID:24149059
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Epigenetic control of CD8+ T cell differentiation.
Henning, Amanda N; Roychoudhuri, Rahul; Restifo, Nicholas P
2018-05-01
Upon stimulation, small numbers of naive CD8 + T cells proliferate and differentiate into a variety of memory and effector cell types. CD8 + T cells can persist for years and kill tumour cells and virally infected cells. The functional and phenotypic changes that occur during CD8 + T cell differentiation are well characterized, but the epigenetic states that underlie these changes are incompletely understood. Here, we review the epigenetic processes that direct CD8 + T cell differentiation and function. We focus on epigenetic modification of DNA and associated histones at genes and their regulatory elements. We also describe structural changes in chromatin organization that affect gene expression. Finally, we examine the translational potential of epigenetic interventions to improve CD8 + T cell function in individuals with chronic infections and cancer.
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Complex multicellular functions at a unicellular eukaryote level: Learning, memory, and immunity.
Csaba, György
2017-06-01
According to experimental data, eukaryote unicellulars are able to learn, have immunity and memory. Learning is carried out in a very primitive form, and the memory is not neural but an epigenetic one. However, this epigenetic memory, which is well justified by the presence and manifestation of hormonal imprinting, is strong and permanent in the life of cell and also in its progenies. This memory is epigenetically executed by the alteration and fixation of methylation pattern of genes without changes in base sequences. The immunity of unicellulars is based on self/non-self discrimination, which leads to the destruction of non-self invaders and utilization of them as nourishment (by phagocytosis). The tools of learning, memory, and immunity of unicellulars are uniformly found in plasma membrane receptors, which formed under the effect of dynamic receptor pattern generation, suggested by Koch et al., and this is the basis of hormonal imprinting, by which the encounter between a chemical substance and the cell is specifically memorized. The receptors and imprinting are also used in the later steps of evolution up to mammals (including man) in each mentioned functions. This means that learning, memory, and immunity can be deduced to a unicellular eukaryote level.
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Trans-differentiation via Epigenetics: A New Paradigm in the Bone Regeneration.
Cho, Young-Dan; Ryoo, Hyun-Mo
2018-02-01
In regenerative medicine, growing cells or tissues in the laboratory is necessary when damaged cells can not heal by themselves. Acquisition of the required cells from the patient's own cells or tissues is an ideal option without additive side effects. In this context, cell reprogramming methods, including the use of induced pluripotent stem cells (iPSCs) and trans-differentiation, have been widely studied in regenerative research. Both approaches have advantages and disadvantages, and the possibility of de-differentiation because of the epigenetic memory of iPSCs has strengthened the need for controlling the epigenetic background for successful cell reprogramming. Therefore, interest in epigenetics has increased in the field of regenerative medicine. Herein, we outline in detail the cell trans-differentiation method using epigenetic modification for bone regeneration in comparison to the use of iPSCs.
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Origin and differentiation of human memory CD8 T cells after vaccination.
Akondy, Rama S; Fitch, Mark; Edupuganti, Srilatha; Yang, Shu; Kissick, Haydn T; Li, Kelvin W; Youngblood, Ben A; Abdelsamed, Hossam A; McGuire, Donald J; Cohen, Kristen W; Alexe, Gabriela; Nagar, Shashi; McCausland, Megan M; Gupta, Satish; Tata, Pramila; Haining, W Nicholas; McElrath, M Juliana; Zhang, David; Hu, Bin; Greenleaf, William J; Goronzy, Jorg J; Mulligan, Mark J; Hellerstein, Marc; Ahmed, Rafi
2017-12-21
The differentiation of human memory CD8 T cells is not well understood. Here we address this issue using the live yellow fever virus (YFV) vaccine, which induces long-term immunity in humans. We used in vivo deuterium labelling to mark CD8 T cells that proliferated in response to the virus and then assessed cellular turnover and longevity by quantifying deuterium dilution kinetics in YFV-specific CD8 T cells using mass spectrometry. This longitudinal analysis showed that the memory pool originates from CD8 T cells that divided extensively during the first two weeks after infection and is maintained by quiescent cells that divide less than once every year (doubling time of over 450 days). Although these long-lived YFV-specific memory CD8 T cells did not express effector molecules, their epigenetic landscape resembled that of effector CD8 T cells. This open chromatin profile at effector genes was maintained in memory CD8 T cells isolated even a decade after vaccination, indicating that these cells retain an epigenetic fingerprint of their effector history and remain poised to respond rapidly upon re-exposure to the pathogen.
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Oct1 and OCA-B are selectively required for CD4 memory T cell function.
Shakya, Arvind; Goren, Alon; Shalek, Alex; German, Cody N; Snook, Jeremy; Kuchroo, Vijay K; Yosef, Nir; Chan, Raymond C; Regev, Aviv; Williams, Matthew A; Tantin, Dean
2015-11-16
Epigenetic changes are crucial for the generation of immunological memory. Failure to generate or maintain these changes will result in poor memory responses. Similarly, augmenting or stabilizing the correct epigenetic states offers a potential method of enhancing memory. Yet the transcription factors that regulate these processes are poorly defined. We find that the transcription factor Oct1 and its cofactor OCA-B are selectively required for the in vivo generation of CD4(+) memory T cells. More importantly, the memory cells that are formed do not respond properly to antigen reencounter. In vitro, both proteins are required to maintain a poised state at the Il2 target locus in resting but previously stimulated CD4(+) T cells. OCA-B is also required for the robust reexpression of multiple other genes including Ifng. ChIPseq identifies ∼50 differentially expressed direct Oct1 and OCA-B targets. We identify an underlying mechanism involving OCA-B recruitment of the histone lysine demethylase Jmjd1a to targets such as Il2, Ifng, and Zbtb32. The findings pinpoint Oct1 and OCA-B as central mediators of CD4(+) T cell memory. © 2015 Shakya et al.
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Oct1 and OCA-B are selectively required for CD4 memory T cell function
Shakya, Arvind; Goren, Alon; Shalek, Alex; German, Cody N.; Snook, Jeremy; Kuchroo, Vijay K.; Yosef, Nir; Chan, Raymond C.; Regev, Aviv
2015-01-01
Epigenetic changes are crucial for the generation of immunological memory. Failure to generate or maintain these changes will result in poor memory responses. Similarly, augmenting or stabilizing the correct epigenetic states offers a potential method of enhancing memory. Yet the transcription factors that regulate these processes are poorly defined. We find that the transcription factor Oct1 and its cofactor OCA-B are selectively required for the in vivo generation of CD4+ memory T cells. More importantly, the memory cells that are formed do not respond properly to antigen reencounter. In vitro, both proteins are required to maintain a poised state at the Il2 target locus in resting but previously stimulated CD4+ T cells. OCA-B is also required for the robust reexpression of multiple other genes including Ifng. ChIPseq identifies ∼50 differentially expressed direct Oct1 and OCA-B targets. We identify an underlying mechanism involving OCA-B recruitment of the histone lysine demethylase Jmjd1a to targets such as Il2, Ifng, and Zbtb32. The findings pinpoint Oct1 and OCA-B as central mediators of CD4+ T cell memory. PMID:26481684
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Epigenetics of Peripheral B-Cell Differentiation and the Antibody Response
Zan, Hong; Casali, Paolo
2015-01-01
Epigenetic modifications, such as histone post-translational modifications, DNA methylation, and alteration of gene expression by non-coding RNAs, including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), are heritable changes that are independent from the genomic DNA sequence. These regulate gene activities and, therefore, cellular functions. Epigenetic modifications act in concert with transcription factors and play critical roles in B cell development and differentiation, thereby modulating antibody responses to foreign- and self-antigens. Upon antigen encounter by mature B cells in the periphery, alterations of these lymphocytes epigenetic landscape are induced by the same stimuli that drive the antibody response. Such alterations instruct B cells to undergo immunoglobulin (Ig) class switch DNA recombination (CSR) and somatic hypermutation (SHM), as well as differentiation to memory B cells or long-lived plasma cells for the immune memory. Inducible histone modifications, together with DNA methylation and miRNAs modulate the transcriptome, particularly the expression of activation-induced cytidine deaminase, which is essential for CSR and SHM, and factors central to plasma cell differentiation, such as B lymphocyte-induced maturation protein-1. These inducible B cell-intrinsic epigenetic marks guide the maturation of antibody responses. Combinatorial histone modifications also function as histone codes to target CSR and, possibly, SHM machinery to the Ig loci by recruiting specific adaptors that can stabilize CSR/SHM factors. In addition, lncRNAs, such as recently reported lncRNA-CSR and an lncRNA generated through transcription of the S region that form G-quadruplex structures, are also important for CSR targeting. Epigenetic dysregulation in B cells, including the aberrant expression of non-coding RNAs and alterations of histone modifications and DNA methylation, can result in aberrant antibody responses to foreign antigens, such as those on microbial pathogens, and generation of pathogenic autoantibodies, IgE in allergic reactions, as well as B cell neoplasia. Epigenetic marks would be attractive targets for new therapeutics for autoimmune and allergic diseases, and B cell malignancies. PMID:26697022
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Rosales-Reynoso, M A; Ochoa-Hernández, A B; Juárez-Vázquez, C I; Barros-Núñez, P
Today, scientists accept that the central nervous system of an adult possesses considerable morphological and functional flexibility, allowing it to perform structural remodelling processes even after the individual is fully developed and mature. In addition to the vast number of genes participating in the development of memory, different known epigenetic mechanisms are involved in normal and pathological modifications to neurons and therefore also affect the mechanisms of memory development. This study entailed a systematic review of biomedical article databases in search of genetic and epigenetic factors that participate in synaptic function and memory. The activation of gene expression in response to external stimuli also occurs in differentiated nerve cells. Neural activity induces specific forms of synaptic plasticity that permit the creation and storage of long-term memory. Epigenetic mechanisms play a key role in synaptic modification processes and in the creation and development of memory. Changes in these mechanisms result in the cognitive and memory impairment seen in neurodegenerative diseases (Alzheimer disease, Huntington disease) and in neurodevelopmental disorders (Rett syndrome, fragile X, and schizophrenia). Nevertheless, results obtained from different models are promising and point to potential treatments for some of these diseases. Copyright © 2013 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.
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Sharples, Adam P; Stewart, Claire E; Seaborne, Robert A
2016-08-01
Skeletal muscle mass, quality and adaptability are fundamental in promoting muscle performance, maintaining metabolic function and supporting longevity and healthspan. Skeletal muscle is programmable and can 'remember' early-life metabolic stimuli affecting its function in adult life. In this review, the authors pose the question as to whether skeletal muscle has an 'epi'-memory? Following an initial encounter with an environmental stimulus, we discuss the underlying molecular and epigenetic mechanisms enabling skeletal muscle to adapt, should it re-encounter the stimulus in later life. We also define skeletal muscle memory and outline the scientific literature contributing to this field. Furthermore, we review the evidence for early-life nutrient stress and low birth weight in animals and human cohort studies, respectively, and discuss the underlying molecular mechanisms culminating in skeletal muscle dysfunction, metabolic disease and loss of skeletal muscle mass across the lifespan. We also summarize and discuss studies that isolate muscle stem cells from different environmental niches in vivo (physically active, diabetic, cachectic, aged) and how they reportedly remember this environment once isolated in vitro. Finally, we will outline the molecular and epigenetic mechanisms underlying skeletal muscle memory and review the epigenetic regulation of exercise-induced skeletal muscle adaptation, highlighting exercise interventions as suitable models to investigate skeletal muscle memory in humans. We believe that understanding the 'epi'-memory of skeletal muscle will enable the next generation of targeted therapies to promote muscle growth and reduce muscle loss to enable healthy aging. © 2016 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.
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Epigenetic Memory Underlies Cell-Autonomous Heterogeneous Behavior of Hematopoietic Stem Cells.
Yu, Vionnie W C; Yusuf, Rushdia Z; Oki, Toshihiko; Wu, Juwell; Saez, Borja; Wang, Xin; Cook, Colleen; Baryawno, Ninib; Ziller, Michael J; Lee, Eunjung; Gu, Hongcang; Meissner, Alexander; Lin, Charles P; Kharchenko, Peter V; Scadden, David T
2016-11-17
Stem cells determine homeostasis and repair of many tissues and are increasingly recognized as functionally heterogeneous. To define the extent of-and molecular basis for-heterogeneity, we overlaid functional, transcriptional, and epigenetic attributes of hematopoietic stem cells (HSCs) at a clonal level using endogenous fluorescent tagging. Endogenous HSC had clone-specific functional attributes over time in vivo. The intra-clonal behaviors were highly stereotypic, conserved under the stress of transplantation, inflammation, and genotoxic injury, and associated with distinctive transcriptional, DNA methylation, and chromatin accessibility patterns. Further, HSC function corresponded to epigenetic configuration but not always to transcriptional state. Therefore, hematopoiesis under homeostatic and stress conditions represents the integrated action of highly heterogeneous clones of HSC with epigenetically scripted behaviors. This high degree of epigenetically driven cell autonomy among HSCs implies that refinement of the concepts of stem cell plasticity and of the stem cell niche is warranted. Copyright © 2016 Elsevier Inc. All rights reserved.
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Understanding Neurological Disease Mechanisms in the Era of Epigenetics
Qureshi, Irfan A.; Mehler, Mark F.
2015-01-01
The burgeoning field of epigenetics is making a significant impact on our understanding of brain evolution, development, and function. In fact, it is now clear that epigenetic mechanisms promote seminal neurobiological processes, ranging from neural stem cell maintenance and differentiation to learning and memory. At the molecular level, epigenetic mechanisms regulate the structure and activity of the genome in response to intracellular and environmental cues, including the deployment of cell type–specific gene networks and those underlying synaptic plasticity. Pharmacological and genetic manipulation of epigenetic factors can, in turn, induce remarkable changes in neural cell identity and cognitive and behavioral phenotypes. Not surprisingly, it is also becoming apparent that epigenetics is intimately involved in neurological disease pathogenesis. Herein, we highlight emerging paradigms for linking epigenetic machinery and processes with neurological disease states, including how (1) mutations in genes encoding epigenetic factors cause disease, (2) genetic variation in genes encoding epigenetic factors modify disease risk, (3) abnormalities in epigenetic factor expression, localization, or function are involved in disease pathophysiology, (4) epigenetic mechanisms regulate disease-associated genomic loci, gene products, and cellular pathways, and (5) differential epigenetic profiles are present in patient-derived central and peripheral tissues. PMID:23571666
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Epigenetic memory in response to environmental stressors.
Vineis, Paolo; Chatziioannou, Aristotelis; Cunliffe, Vincent T; Flanagan, James M; Hanson, Mark; Kirsch-Volders, Micheline; Kyrtopoulos, Soterios
2017-06-01
Exposure to environmental stressors, toxicants, and nutrient deficiencies can affect DNA in several ways. Some exposures cause damage and alter the structure of DNA, but there is increasing evidence that the same or other environmental exposures, including those that occur during fetal development in utero , can cause epigenetic effects that modulate DNA function and gene expression. Some epigenetic changes to DNA that affect gene transcription are at least partially reversible ( i.e., they can be enzymatically reversed after cessation of exposure to environmental agents), but some epigenetic modifications seem to persist, even for decades. To explain the effects of early life experiences (such as famine and exposures to other stressors) on the long-term persistence of specific patterns of epigenetic modifications, such as DNA methylation, we propose an analogy with immune memory. We propose that an epigenetic memory can be established and maintained in self-renewing stem cell compartments. We suggest that the observations on early life effects on adult diseases and the persistence of methylation changes in smokers support our hypothesis, for which a mechanistic basis, however, needs to be further clarified. We outline a new model based on methylation changes. Although these changes seem to be mainly adaptive, they are also implicated in the pathogenesis and onset of diseases, depending on individual genotypic background and types of subsequent exposures. Elucidating the relationships between the adaptive and maladaptive consequences of the epigenetic modifications that result from complex environmental exposures is a major challenge for current and future research in epigenetics.-Vineis, P., Chatziioannou, A., Cunliffe, V. T., Flanagan, J. M., Hanson, M., Kirsch-Volders, M., Kyrtopoulos, S. Epigenetic memory in response to environmental stressors. © FASEB.
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Connections Between Metabolism and Epigenetics in Programming Cellular Differentiation.
Chisolm, Danielle A; Weinmann, Amy S
2018-04-26
Researchers are intensifying efforts to understand the mechanisms by which changes in metabolic states influence differentiation programs. An emerging objective is to define how fluctuations in metabolites influence the epigenetic states that contribute to differentiation programs. This is because metabolites such as S-adenosylmethionine, acetyl-CoA, α-ketoglutarate, 2-hydroxyglutarate, and butyrate are donors, substrates, cofactors, and antagonists for the activities of epigenetic-modifying complexes and for epigenetic modifications. We discuss this topic from the perspective of specialized CD4 + T cells as well as effector and memory T cell differentiation programs. We also highlight findings from embryonic stem cells that give mechanistic insight into how nutrients processed through pathways such as glycolysis, glutaminolysis, and one-carbon metabolism regulate metabolite levels to influence epigenetic events and discuss similar mechanistic principles in T cells. Finally, we highlight how dysregulated environments, such as the tumor microenvironment, might alter programming events.
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The Dynamic Epigenetic Landscape of the Retina During Development, Reprogramming, and Tumorigenesis
Aldiri, Issam; Xu, Beisi; Wang, Lu; Chen, Xiang; Hiler, Daniel; Griffiths, Lyra; Valentine, Marc; Shirinifard, Abbas; Thiagarajan, Suresh; Sablauer, Andras; Barabas, Marie-Elizabeth; Zhang, Jiakun; Johnson, Dianna; Frase, Sharon; Zhou, Xin; Easton, John; Zhang, Jinghui; Mardis, Elaine R.; Wilson, Richard K.; Downing, James R.; Dyer, Michael A.
2017-01-01
SUMMARY In the developing retina, multipotent neural progenitors undergo unidirectional differentiation in a precise spatiotemporal order. Here we profile the epigenetic and transcriptional changes that occur during retinogenesis in mice and humans. Although some progenitor genes and cell cycle genes were epigenetically silenced during retinogenesis, the most dramatic change was derepression of cell type–specific differentiation programs. We identified developmental stage–specific super-enhancers and showed that most epigenetic changes are conserved in humans and mice. To determine how the epigenome changes during tumorigenesis and reprogramming, we performed integrated epigenetic analysis of murine and human retinoblastomas and induced pluripotent stem cells (iPSCs) derived from murine rod photoreceptors. The retinoblastoma epigenome mapped to the developmental stage when retinal progenitors switch from neurogenic to a terminal patterns of cell division. The epigenome of retinoblastomas was more similar to that of normal retina than was that of retina-derived iPSCs, and we identified retina-specific epigenetic memory. PMID:28472656
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Set1/COMPASS and Mediator are repurposed to promote epigenetic transcriptional memory.
D'Urso, Agustina; Takahashi, Yoh-Hei; Xiong, Bin; Marone, Jessica; Coukos, Robert; Randise-Hinchliff, Carlo; Wang, Ji-Ping; Shilatifard, Ali; Brickner, Jason H
2016-06-23
In yeast and humans, previous experiences can lead to epigenetic transcriptional memory: repressed genes that exhibit mitotically heritable changes in chromatin structure and promoter recruitment of poised RNA polymerase II preinitiation complex (RNAPII PIC), which enhances future reactivation. Here, we show that INO1 memory in yeast is initiated by binding of the Sfl1 transcription factor to the cis-acting Memory Recruitment Sequence, targeting INO1 to the nuclear periphery. Memory requires a remodeled form of the Set1/COMPASS methyltransferase lacking Spp1, which dimethylates histone H3 lysine 4 (H3K4me2). H3K4me2 recruits the SET3C complex, which plays an essential role in maintaining this mark. Finally, while active INO1 is associated with Cdk8(-) Mediator, during memory, Cdk8(+) Mediator recruits poised RNAPII PIC lacking the Kin28 CTD kinase. Aspects of this mechanism are generalizable to yeast and conserved in human cells. Thus, COMPASS and Mediator are repurposed to promote epigenetic transcriptional poising by a highly conserved mechanism.
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Where Environment Meets Cognition: A Focus on Two Developmental Intellectual Disability Disorders
Ossowski, S.
2016-01-01
One of the most challenging questions in neuroscience is to dissect how learning and memory, the foundational pillars of cognition, are grounded in stable, yet plastic, gene expression states. All known epigenetic mechanisms such as DNA methylation and hydroxymethylation, histone modifications, chromatin remodelling, and noncoding RNAs regulate brain gene expression, both during neurodevelopment and in the adult brain in processes related to cognition. On the other hand, alterations in the various components of the epigenetic machinery have been linked to well-known causes of intellectual disability disorders (IDDs). Two examples are Down Syndrome (DS) and Fragile X Syndrome (FXS), where global and local epigenetic alterations lead to impairments in synaptic plasticity, memory, and learning. Since epigenetic modifications are reversible, it is theoretically possible to use epigenetic drugs as cognitive enhancers for the treatment of IDDs. Epigenetic treatments act in a context specific manner, targeting different regions based on cell and state specific chromatin accessibility, facilitating the establishment of the lost balance. Here, we discuss epigenetic studies of IDDs, focusing on DS and FXS, and the use of epidrugs in combinatorial therapies for IDDs. PMID:27547454
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Where Environment Meets Cognition: A Focus on Two Developmental Intellectual Disability Disorders.
Toma, I De; Gil, L Manubens; Ossowski, S; Dierssen, M
2016-01-01
One of the most challenging questions in neuroscience is to dissect how learning and memory, the foundational pillars of cognition, are grounded in stable, yet plastic, gene expression states. All known epigenetic mechanisms such as DNA methylation and hydroxymethylation, histone modifications, chromatin remodelling, and noncoding RNAs regulate brain gene expression, both during neurodevelopment and in the adult brain in processes related to cognition. On the other hand, alterations in the various components of the epigenetic machinery have been linked to well-known causes of intellectual disability disorders (IDDs). Two examples are Down Syndrome (DS) and Fragile X Syndrome (FXS), where global and local epigenetic alterations lead to impairments in synaptic plasticity, memory, and learning. Since epigenetic modifications are reversible, it is theoretically possible to use epigenetic drugs as cognitive enhancers for the treatment of IDDs. Epigenetic treatments act in a context specific manner, targeting different regions based on cell and state specific chromatin accessibility, facilitating the establishment of the lost balance. Here, we discuss epigenetic studies of IDDs, focusing on DS and FXS, and the use of epidrugs in combinatorial therapies for IDDs.
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Dorn, Isabel; Klich, Katharina; Arauzo-Bravo, Marcos J; Radstaak, Martina; Santourlidis, Simeon; Ghanjati, Foued; Radke, Teja F; Psathaki, Olympia E; Hargus, Gunnar; Kramer, Jan; Einhaus, Martin; Kim, Jeong Beom; Kögler, Gesine; Wernet, Peter; Schöler, Hans R; Schlenke, Peter; Zaehres, Holm
2015-01-01
Epigenetic memory in induced pluripotent stem cells, which is related to the somatic cell type of origin of the stem cells, might lead to variations in the differentiation capacities of the pluripotent stem cells. In this context, induced pluripotent stem cells from human CD34(+) hematopoietic stem cells might be more suitable for hematopoietic differentiation than the commonly used fibroblast-derived induced pluripotent stem cells. To investigate the influence of an epigenetic memory on the ex vivo expansion of induced pluripotent stem cells into erythroid cells, we compared induced pluripotent stem cells from human neural stem cells and human cord blood-derived CD34(+) hematopoietic stem cells and evaluated their potential for differentiation into hematopoietic progenitor and mature red blood cells. Although genome-wide DNA methylation profiling at all promoter regions demonstrates that the epigenetic memory of induced pluripotent stem cells is influenced by the somatic cell type of origin of the stem cells, we found a similar hematopoietic induction potential and erythroid differentiation pattern of induced pluripotent stem cells of different somatic cell origin. All human induced pluripotent stem cell lines showed terminal maturation into normoblasts and enucleated reticulocytes, producing predominantly fetal hemoglobin. Differences were only observed in the growth rate of erythroid cells, which was slightly higher in the induced pluripotent stem cells derived from CD34(+) hematopoietic stem cells. More detailed methylation analysis of the hematopoietic and erythroid promoters identified similar CpG methylation levels in the induced pluripotent stem cell lines derived from CD34(+) cells and those derived from neural stem cells, which confirms their comparable erythroid differentiation potential. Copyright© Ferrata Storti Foundation.
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Manukyan, Maria; Singh, Prim B
2012-05-01
Induced pluripotent stem (iPS) cells have provided a rational means of obtaining histo-compatible tissues for 'patient-specific' regenerative therapies (Hanna et al. 2010; Yamanaka & Blau 2010). Despite the obvious potential of iPS cell-based therapies, there are certain problems that must be overcome before these therapies can become safe and routine (Ohi et al. 2011; Pera 2011). As an alternative, we have recently explored the possibility of using 'epigenetic rejuvenation', where the specialized functions of an old cell are rejuvenated in the absence of any change in its differentiated state (Singh & Zacouto 2010). The mechanism(s) that underpin 'epigenetic rejuvenation' are unknown and here we discuss model systems, using key epigenetic modifiers, which might shed light on the processes involved. Epigenetic rejuvenation has advantages over iPS cell techniques that are currently being pursued. First, the genetic and epigenetic abnormalities that arise through the cycle of dedifferentiation of somatic cells to iPS cells followed by redifferentiation of iPS cells into the desired cell type are avoided (Gore et al. 2011; Hussein et al. 2011; Pera 2011): epigenetic rejuvenation does not require passage through the de-/redifferentiation cycle. Second, because the aim of epigenetic rejuvenation is to ensure that the differentiated cell type retains its specialized function it makes redundant the question of transcriptional memory that is inimical to iPS cell-based therapies (Ohi et al. 2011). Third, to produce unrelated cell types using the iPS technology takes a long time, around three weeks, whereas epigenetic rejuvenation of old cells will take only a matter of days. Epigenetic rejuvenation provides the most safe, rapid and cheap route to successful regenerative medicine. © 2012 The Authors. Journal compilation © 2012 by the Molecular Biology Society of Japan/Blackwell Publishing Ltd.
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Epigenetic memory loss in aging oligodendrocytes in the corpus callosum
Siming, Shen; Aixiao, Liu; Jiadong, Li; Candy, Wolubah; Patrizia, Casaccia-Bonnefil
2008-01-01
In this study we address the hypothesis that aging modifies the intrinsic properties of oligodendrocytes, the myelin-forming cells of the brain. According to our model, an “epigenetic memory” is stored in the chromatin of the oligodendrocyte lineage cells and is responsible for the maintenance of a mature phenotype, characterized by low levels of expression of transcriptional inhibitors. We report here an age-related decline of histone deacetylation and methylation, the molecular mechanisms responsible for the establishment and maintenance of this “epigenetic memory” of the differentiated state. We further show that lack of histone methylation and increased acetylation in mature oligodendrocytes are associated with global changes in gene expression, that include the re-expression of bHLH inhibitors (i.e. Hes5 and Id4) and precursor markers (i.e. Sox2). These changes characteristic of the “aging” oligodendrocytes can be recapitulated in vitro, by treating primary oligodendrocyte cultures with histone deacetylase inhibitors. Thus, we conclude that the “epigenetic memory loss” detected in white matter tracts of older mice induces global changes of gene expression that modify the intrinsic properties of aged oligodendrocytes and may functionally modulate the responsiveness of these cells to external stimuli. PMID:17182153
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Epigenetic memory for stress response and adaptation in plants.
Kinoshita, Tetsu; Seki, Motoaki
2014-11-01
In contrast to the majority of animal species, plants are sessile organisms and are, therefore, constantly challenged by environmental perturbations. Over the past few decades, our knowledge of how plants perceive environmental stimuli has increased considerably, e.g. the mechanisms for transducing environmental stress stimuli into cellular signaling cascades and gene transcription networks. In addition, it has recently been shown that plants can remember past environmental events and can use these memories to aid responses when these events recur. In this mini review, we focus on recent progress in determination of the epigenetic mechanisms used by plants under various environmental stresses. Epigenetic mechanisms are now known to play a vital role in the control of gene expression through small RNAs, histone modifications and DNA methylation. These are inherited through mitotic cell divisions and, in some cases, can be transmitted to the next generation. They therefore offer a possible mechanism for stress memories in plants. Recent studies have yielded evidence indicating that epigenetic mechanisms are indeed essential for stress memories and adaptation in plants. © The Author 2014. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please email: journals.permissions@oup.com.
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Conine, Colin C.; Moresco, James J.; Gu, Weifeng; Shirayama, Masaki; Conte, Darryl; Yates, John R.; Mello, Craig C.
2014-01-01
SUMMARY During each life cycle germ cells preserve and pass on both genetic and epigenetic information. In C. elegans, the ALG-3/4 Argonaute proteins are expressed during male gametogenesis and promote male fertility. Here we show that the CSR-1 Argonaute functions with ALG-3/4 to positively regulate target genes required for spermiogenesis. Our findings suggest that ALG-3/4 functions during spermatogenesis to amplify a small-RNA signal that represents an epigenetic memory of male-specific gene expression. CSR-1, which is abundant in mature sperm, appears to transmit this memory to offspring. Surprisingly, in addition to small RNAs targeting male-specific genes, we show that males also harbor an extensive repertoire of CSR-1 small RNAs targeting oogenesis-specific mRNAs. Together these findings suggest that C. elegans sperm transmit not only the genome but also epigenetic binary signals in the form of Argonaute/small-RNA complexes that constitute a memory of gene expression in preceding generations. PMID:24360276
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Rodríguez-Cortez, Virginia C.; del Pino-Molina, Lucia; Rodríguez-Ubreva, Javier; Ciudad, Laura; Gómez-Cabrero, David; Company, Carlos; Urquiza, José M.; Tegnér, Jesper; Rodríguez-Gallego, Carlos; López-Granados, Eduardo; Ballestar, Esteban
2015-01-01
Common variable immunodeficiency (CVID), the most frequent primary immunodeficiency characterized by loss of B-cell function, depends partly on genetic defects, and epigenetic changes are thought to contribute to its aetiology. Here we perform a high-throughput DNA methylation analysis of this disorder using a pair of CVID-discordant MZ twins and show predominant gain of DNA methylation in CVID B cells with respect to those from the healthy sibling in critical B lymphocyte genes, such as PIK3CD, BCL2L1, RPS6KB2, TCF3 and KCNN4. Individual analysis confirms hypermethylation of these genes. Analysis in naive, unswitched and switched memory B cells in a CVID patient cohort shows impaired ability to demethylate and upregulate these genes in transitioning from naive to memory cells in CVID. Our results not only indicate a role for epigenetic alterations in CVID but also identify relevant DNA methylation changes in B cells that could explain the clinical manifestations of CVID individuals. PMID:26081581
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Inserra, Antonio
2018-01-01
Ayahuasca ingestion modulates brain activity, neurotransmission, gene expression and epigenetic regulation. N,N -Dimethyltryptamine (DMT, one of the alkaloids in Ayahuasca) activates sigma 1 receptor (SIGMAR1) and others. SIGMAR1 is a multi-faceted stress-responsive receptor which promotes cell survival, neuroprotection, neuroplasticity, and neuroimmunomodulation. Simultaneously, monoamine oxidase inhibitors (MAOIs) also present in Ayahuasca prevent the degradation of DMT. One peculiarity of SIGMAR1 activation and MAOI activity is the reversal of mnemonic deficits in pre-clinical models. Since traumatic memories in post-traumatic stress disorder (PTSD) are often characterised by "repression" and PTSD patients ingesting Ayahuasca report the retrieval of such memories, it cannot be excluded that DMT-mediated SIGMAR1 activation and the concomitant MAOIs effects during Ayahuasca ingestion might mediate such "anti-amnesic" process. Here I hypothesise that Ayahuasca, via hyperactivation of trauma and emotional memory-related centres, and via its concomitant SIGMAR1- and MAOIs- induced anti-amnesic effects, facilitates the retrieval of traumatic memories, in turn making them labile (destabilised). As Ayahuasca alkaloids enhance synaptic plasticity, increase neurogenesis and boost dopaminergic neurotransmission, and those processes are involved in memory reconsolidation and fear extinction, the fear response triggered by the memory can be reprogramed and/or extinguished. Subsequently, the memory is stored with this updated significance. To date, it is unclear if new memories replace, co-exist with or bypass old ones. Although the mechanisms involved in memory are still debated, they seem to require the involvement of cellular and molecular events, such as reorganisation of homo and heteroreceptor complexes at the synapse, synaptic plasticity, and epigenetic re-modulation of gene expression. Since SIGMAR1 mobilises synaptic receptor, boosts synaptic plasticity and modulates epigenetic processes, such effects might be involved in the reported healing of traumatic memories in PTSD patients. If this theory proves to be true, Ayahuasca could come to represent the only standing pharmacological treatment which targets traumatic memories in PTSD. Lastly, since SIGMAR1 activation triggers both epigenetic and immunomodulatory programmes, the mechanism here presented could help understanding and treating other conditions in which the cellular memory is dysregulated, such as cancer, diabetes, autoimmune and neurodegenerative pathologies and substance addiction.
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Metabolic memory and chronic diabetes complications: potential role for epigenetic mechanisms.
Intine, Robert V; Sarras, Michael P
2012-10-01
Recent estimates indicate that diabetes mellitus currently affects more than 10 % of the world's population. Evidence from both the laboratory and large scale clinical trials has revealed that prolonged hyperglycemia induces chronic complications which persist and progress unimpeded even when glycemic control is pharmaceutically achieved via the phenomenon of metabolic memory. The epigenome is comprised of all chromatin modifications including post translational histone modification, expression control via miRNAs and the methylation of cytosine within DNA. Modifications of these epigenetic marks not only allow cells and organisms to quickly respond to changing environmental stimuli but also confer the ability of the cell to "memorize" these encounters. As such, these processes have gained much attention as potential molecular mechanisms underlying metabolic memory and chronic diabetic complications. Here we present a review of the very recent literature published pertaining to this subject.
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Cell of Origin and Cancer Stem Cell Phenotype in Medulloblastomas
2015-07-01
dominant role over some oncogene function.In addition, we recently reported that cancer stem cells (CSCs)- stem cell like cells in tumors that have stem ... cell properties and tumor initiating ability- retain epigenetic memories of their cells of origin (Chow et al., 2014). We showed that CSCs derived from
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Epigenetic mechanisms of memory formation and reconsolidation.
Jarome, Timothy J; Lubin, Farah D
2014-11-01
Memory consolidation involves transcriptional control of genes in neurons to stabilize a newly formed memory. Following retrieval, a once consolidated memory destabilizes and again requires gene transcription changes in order to restabilize, a process referred to as reconsolidation. Understanding the molecular mechanisms of gene transcription during the consolidation and reconsolidation processes could provide crucial insights into normal memory formation and memory dysfunction associated with psychiatric disorders. In the past decade, modifications of epigenetic markers such as DNA methylation and posttranslational modifications of histone proteins have emerged as critical transcriptional regulators of gene expression during initial memory formation and after retrieval. In light of the rapidly growing literature in this exciting area of research, we here examine the most recent and latest evidence demonstrating how memory acquisition and retrieval trigger epigenetic changes during the consolidation and reconsolidation phases to impact behavior. In particular we focus on the reconsolidation process, where we discuss the already identified epigenetic regulators of gene transcription during memory reconsolidation, while exploring other potential epigenetic modifications that may also be involved, and expand on how these epigenetic modifications may be precisely and temporally controlled by important signaling cascades critical to the reconsolidation process. Finally, we explore the possibility that epigenetic mechanisms may serve to regulate a system or circuit level reconsolidation process and may be involved in retrieval-dependent memory updating. Hence, we propose that epigenetic mechanisms coordinate changes in neuronal gene transcription, not only during the initial memory consolidation phase, but are triggered by retrieval to regulate molecular and cellular processes during memory reconsolidation. Copyright © 2014 Elsevier Inc. All rights reserved.
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Epigenetic Mechanisms of Memory Formation and Reconsolidation
Jarome, Timothy J.; Lubin, Farah D.
2014-01-01
Memory consolidation involves transcriptional control of genes in neurons to stabilize a newly formed memory. Following retrieval, a once consolidated memory destabilizes and again requires gene transcription changes in order to restabilize, a process referred to as reconsolidation. Understanding the molecular mechanisms of gene transcription during the consolidation and reconsolidation processes could provide crucial insights into normal memory formation and memory dysfunction associated with psychiatric disorders. In the past decade, modifications of epigenetic markers such as DNA methylation and posttranslational modifications of histone proteins have emerged as critical transcriptional regulators of gene expression during initial memory formation and after retrieval. In light of the rapidly growing literature in this exciting area of research, we here examine the most recent and latest evidence demonstrating how memory acquisition and retrieval trigger epigenetic changes during the consolidation and reconsolidation phases to impact behavior. In particular we focus on the reconsolidation process, where we discuss the already identified epigenetic regulators of gene transcription during memory reconsolidation, while exploring other potential epigenetic modifications that may also be involved, and expand on how these epigenetic modifications may be precisely and temporally controlled by important signaling cascades critical to the reconsolidation process. Finally, we explore the possibility that epigenetic mechanisms may serve to regulate a system or circuit level reconsolidation process and may be involved in retrieval-dependent memory updating. Hence, we propose that epigenetic mechanisms coordinate changes in neuronal gene transcription, not only during the initial memory consolidation phase, but are triggered by retrieval to regulate molecular and cellular processes during memory reconsolidation. PMID:25130533
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Smith, E N; Ghia, E M; DeBoever, C M; Rassenti, L Z; Jepsen, K; Yoon, K-A; Matsui, H; Rozenzhak, S; Alakus, H; Shepard, P J; Dai, Y; Khosroheidari, M; Bina, M; Gunderson, K L; Messer, K; Muthuswamy, L; Hudson, T J; Harismendy, O; Barrett, C L; Jamieson, C H M; Carson, D A; Kipps, T J; Frazer, K A
2015-04-10
We examined genetic and epigenetic changes that occur during disease progression from indolent to aggressive forms of chronic lymphocytic leukemia (CLL) using serial samples from 27 patients. Analysis of DNA mutations grouped the leukemia cases into three categories: evolving (26%), expanding (26%) and static (47%). Thus, approximately three-quarters of the CLL cases had little to no genetic subclonal evolution. However, we identified significant recurrent DNA methylation changes during progression at 4752 CpGs enriched for regions near Polycomb 2 repressive complex (PRC2) targets. Progression-associated CpGs near the PRC2 targets undergo methylation changes in the same direction during disease progression as during normal development from naive to memory B cells. Our study shows that CLL progression does not typically occur via subclonal evolution, but that certain CpG sites undergo recurrent methylation changes. Our results suggest CLL progression may involve developmental processes shared in common with the generation of normal memory B cells.
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Activity-induced histone modifications govern Neurexin-1 mRNA splicing and memory preservation.
Ding, Xinlu; Liu, Sanxiong; Tian, Miaomiao; Zhang, Wenhao; Zhu, Tao; Li, Dongdong; Wu, Jiawei; Deng, HaiTeng; Jia, Yichang; Xie, Wei; Xie, Hong; Guan, Ji-Song
2017-05-01
Epigenetic mechanisms regulate the formation, consolidation and reconsolidation of memories. However, the signaling path from neuronal activation to epigenetic modifications within the memory-related brain circuit remains unknown. We report that learning induces long-lasting histone modifications in hippocampal memory-activated neurons to regulate memory stability. Neuronal activity triggers a late-onset shift in Nrxn1 splice isoform choice at splicing site 4 by accumulating a repressive histone marker, H3K9me3, to modulate the splicing process. Activity-dependent phosphorylation of p66α via AMP-activated protein kinase recruits HDAC2 and Suv39h1 to establish repressive histone markers and changes the connectivity of the activated neurons. Removal of Suv39h1 abolished the activity-dependent shift in Nrxn1 splice isoform choice and reduced the stability of established memories. We uncover a cell-autonomous process for memory preservation in which memory-related neurons initiate a late-onset reduction of their rewiring capacities through activity-induced histone modifications.
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Epigenetics of the antibody response
Li, Guideng; Zan, Hong; Xu, Zhenming; Casali, Paolo
2013-01-01
Epigenetic marks, such as DNA methylation, histone posttranslational modifications and microRNAs, are induced in B cells by the same stimuli that drive the antibody response. They play major roles in regulating somatic hypermutation (SHM), class switch DNA recombination (CSR) and differentiation to plasma cells or long-lived memory B cells. Histone modifications target the CSR and, possibly, SHM machinery to the immunoglobulin locus; they together with DNA methylation and microRNAs modulate the expression of critical elements of that machinery, such as AID, as well as factors central to plasma cell differentiation, such as Blimp-1. These inducible B cell-intrinsic epigenetic marks instruct the maturation of antibody responses. Their dysregulation plays an important role in aberrant antibody responses to foreign antigens, such as those of microbial pathogens, and self-antigens, such those targeted in autoimmunity, and B cell neoplasias. PMID:23643790
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Epigenetic regulation of estrogen-dependent memory
Fortress, Ashley M.; Frick, Karyn M.
2014-01-01
Hippocampal memory formation is highly regulated by post-translational histone modifications and DNA methylation. Accordingly, these epigenetic processes play a major role in the effects of modulatory factors, such as sex steroid hormones, on hippocampal memory. Our laboratory recently demonstrated that the ability of the potent estrogen 17β-estradiol (E2) to enhance hippocampal-dependent novel object recognition memory in ovariectomized female mice requires ERK-dependent histone H3 acetylation and DNA methylation in the dorsal hippocampus. Although these data provide valuable insight into the chromatin modifications that mediate the memory-enhancing effects of E2, epigenetic regulation of gene expression is enormously complex. Therefore, more research is needed to fully understand how E2 and other hormones employ epigenetic alterations to shape behavior. This review discusses the epigenetic alterations shown thus far to regulate hippocampal memory, briefly reviews the effects of E2 on hippocampal function, and describes in detail our work on epigenetic regulation of estrogenic memory enhancement. PMID:24878494
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Epigenetic regulation of estrogen-dependent memory.
Fortress, Ashley M; Frick, Karyn M
2014-10-01
Hippocampal memory formation is highly regulated by post-translational histone modifications and DNA methylation. Accordingly, these epigenetic processes play a major role in the effects of modulatory factors, such as sex steroid hormones, on hippocampal memory. Our laboratory recently demonstrated that the ability of the potent estrogen 17β-estradiol (E2) to enhance hippocampal-dependent novel object recognition memory in ovariectomized female mice requires ERK-dependent histone H3 acetylation and DNA methylation in the dorsal hippocampus. Although these data provide valuable insight into the chromatin modifications that mediate the memory-enhancing effects of E2, epigenetic regulation of gene expression is enormously complex. Therefore, more research is needed to fully understand how E2 and other hormones employ epigenetic alterations to shape behavior. This review discusses the epigenetic alterations shown thus far to regulate hippocampal memory, briefly reviews the effects of E2 on hippocampal function, and describes in detail our work on epigenetic regulation of estrogenic memory enhancement. Copyright © 2014 Elsevier Inc. All rights reserved.
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Epigenetics and Cellular Metabolism
Xu, Wenyi; Wang, Fengzhong; Yu, Zhongsheng; Xin, Fengjiao
2016-01-01
Living eukaryotic systems evolve delicate cellular mechanisms for responding to various environmental signals. Among them, epigenetic machinery (DNA methylation, histone modifications, microRNAs, etc.) is the hub in transducing external stimuli into transcriptional response. Emerging evidence reveals the concept that epigenetic signatures are essential for the proper maintenance of cellular metabolism. On the other hand, the metabolite, a main environmental input, can also influence the processing of epigenetic memory. Here, we summarize the recent research progress in the epigenetic regulation of cellular metabolism and discuss how the dysfunction of epigenetic machineries influences the development of metabolic disorders such as diabetes and obesity; then, we focus on discussing the notion that manipulating metabolites, the fuel of cell metabolism, can function as a strategy for interfering epigenetic machinery and its related disease progression as well. PMID:27695375
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Inserra, Antonio
2018-01-01
Ayahuasca ingestion modulates brain activity, neurotransmission, gene expression and epigenetic regulation. N,N-Dimethyltryptamine (DMT, one of the alkaloids in Ayahuasca) activates sigma 1 receptor (SIGMAR1) and others. SIGMAR1 is a multi-faceted stress-responsive receptor which promotes cell survival, neuroprotection, neuroplasticity, and neuroimmunomodulation. Simultaneously, monoamine oxidase inhibitors (MAOIs) also present in Ayahuasca prevent the degradation of DMT. One peculiarity of SIGMAR1 activation and MAOI activity is the reversal of mnemonic deficits in pre-clinical models. Since traumatic memories in post-traumatic stress disorder (PTSD) are often characterised by “repression” and PTSD patients ingesting Ayahuasca report the retrieval of such memories, it cannot be excluded that DMT-mediated SIGMAR1 activation and the concomitant MAOIs effects during Ayahuasca ingestion might mediate such “anti-amnesic” process. Here I hypothesise that Ayahuasca, via hyperactivation of trauma and emotional memory-related centres, and via its concomitant SIGMAR1- and MAOIs- induced anti-amnesic effects, facilitates the retrieval of traumatic memories, in turn making them labile (destabilised). As Ayahuasca alkaloids enhance synaptic plasticity, increase neurogenesis and boost dopaminergic neurotransmission, and those processes are involved in memory reconsolidation and fear extinction, the fear response triggered by the memory can be reprogramed and/or extinguished. Subsequently, the memory is stored with this updated significance. To date, it is unclear if new memories replace, co-exist with or bypass old ones. Although the mechanisms involved in memory are still debated, they seem to require the involvement of cellular and molecular events, such as reorganisation of homo and heteroreceptor complexes at the synapse, synaptic plasticity, and epigenetic re-modulation of gene expression. Since SIGMAR1 mobilises synaptic receptor, boosts synaptic plasticity and modulates epigenetic processes, such effects might be involved in the reported healing of traumatic memories in PTSD patients. If this theory proves to be true, Ayahuasca could come to represent the only standing pharmacological treatment which targets traumatic memories in PTSD. Lastly, since SIGMAR1 activation triggers both epigenetic and immunomodulatory programmes, the mechanism here presented could help understanding and treating other conditions in which the cellular memory is dysregulated, such as cancer, diabetes, autoimmune and neurodegenerative pathologies and substance addiction. PMID:29674970
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Yakovlev, Igor A; Carneros, Elena; Lee, YeonKyeong; Olsen, Jorunn E; Fossdal, Carl Gunnar
2016-05-01
A significant number of epigenetic regulators were differentially expressed during embryogenesis at different epitype-inducing conditions. Our results support that methylation of DNA and histones, as well as sRNAs, are pivotal for the establishment of the epigenetic memory. As a forest tree species with long generation times, Norway spruce is remarkably well adapted to local environmental conditions despite having recently, from an evolutionary perspective, recolonized large areas following the last glaciation. In this species, there is an enigmatic epigenetic memory of the temperature conditions during embryogenesis that allows rapid adaptation to changing environment. We used a transcriptomic approach to investigate the molecular mechanisms underlying the formation of the epigenetic memory during somatic embryogenesis in Norway spruce. Nine mRNA libraries were prepared from three epitypes of the same genotype resulting from exposure to epitype-inducing temperatures of 18, 23 and 28 °C. RNA-Seq analysis revealed more than 10,000 differentially expressed genes (DEGs). The epitype-inducing conditions during SE were accompanied by marked transcriptomic changes for multiple gene models related to the epigenetic machinery. Out of 735 putative orthologs of epigenetic regulators, 329 were affected by the epitype-inducing temperatures and differentially expressed. The majority of DEGs among the epigenetic regulators was related to DNA and histone methylation, along with sRNA pathways and a range of putative thermosensing and signaling genes. These genes could be the main epigenetic regulators involved in formation of the epigenetic memory. We suggest considerable expansion of gene families of epigenetic regulators in Norway spruce compared to orthologous gene families in Populus and Arabidopsis. Obtained results provide a solid basis for further genome annotation and studies focusing on the importance of these candidate genes for the epigenetic memory formation.
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Epigenetic memory: the Lamarckian brain
Fischer, Andre
2014-01-01
Recent data support the view that epigenetic processes play a role in memory consolidation and help to transmit acquired memories even across generations in a Lamarckian manner. Drugs that target the epigenetic machinery were found to enhance memory function in rodents and ameliorate disease phenotypes in models for brain diseases such as Alzheimer's disease, Chorea Huntington, Depression or Schizophrenia. In this review, I will give an overview on the current knowledge of epigenetic processes in memory function and brain disease with a focus on Morbus Alzheimer as the most common neurodegenerative disease. I will address the question whether an epigenetic therapy could indeed be a suitable therapeutic avenue to treat brain diseases and discuss the necessary steps that should help to take neuroepigenetic research to the next level. PMID:24719207
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Epigenetic control of learning and memory in Drosophila by Tip60 HAT action.
Xu, Songjun; Wilf, Rona; Menon, Trisha; Panikker, Priyalakshmi; Sarthi, Jessica; Elefant, Felice
2014-12-01
Disruption of epigenetic gene control mechanisms in the brain causes significant cognitive impairment that is a debilitating hallmark of most neurodegenerative disorders, including Alzheimer's disease (AD). Histone acetylation is one of the best characterized of these epigenetic mechanisms that is critical for regulating learning- and memory- associated gene expression profiles, yet the specific histone acetyltransferases (HATs) that mediate these effects have yet to be fully characterized. Here, we investigate an epigenetic role for the HAT Tip60 in learning and memory formation using the Drosophila CNS mushroom body (MB) as a well-characterized cognition model. We show that Tip60 is endogenously expressed in the Kenyon cells, the intrinsic neurons of the MB, and in the MB axonal lobes. Targeted loss of Tip60 HAT activity in the MB causes thinner and shorter axonal lobes while increasing Tip60 HAT levels cause no morphological defects. Functional consequences of both loss and gain of Tip60 HAT levels in the MB are evidenced by defects in immediate-recall memory. Our ChIP-Seq analysis reveals that Tip60 target genes are enriched for functions in cognitive processes, and, accordingly, key genes representing these pathways are misregulated in the Tip60 HAT mutant fly brain. Remarkably, we find that both learning and immediate-recall memory deficits that occur under AD-associated, amyloid precursor protein (APP)-induced neurodegenerative conditions can be effectively rescued by increasing Tip60 HAT levels specifically in the MB. Together, our findings uncover an epigenetic transcriptional regulatory role for Tip60 in cognitive function and highlight the potential of HAT activators as a therapeutic option for neurodegenerative disorders. Copyright © 2014 by the Genetics Society of America.
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Innate immune memory in the brain shapes neurological disease hallmarks.
Wendeln, Ann-Christin; Degenhardt, Karoline; Kaurani, Lalit; Gertig, Michael; Ulas, Thomas; Jain, Gaurav; Wagner, Jessica; Häsler, Lisa M; Wild, Katleen; Skodras, Angelos; Blank, Thomas; Staszewski, Ori; Datta, Moumita; Centeno, Tonatiuh Pena; Capece, Vincenzo; Islam, Md Rezaul; Kerimoglu, Cemil; Staufenbiel, Matthias; Schultze, Joachim L; Beyer, Marc; Prinz, Marco; Jucker, Mathias; Fischer, André; Neher, Jonas J
2018-04-01
Innate immune memory is a vital mechanism of myeloid cell plasticity that occurs in response to environmental stimuli and alters subsequent immune responses. Two types of immunological imprinting can be distinguished-training and tolerance. These are epigenetically mediated and enhance or suppress subsequent inflammation, respectively. Whether immune memory occurs in tissue-resident macrophages in vivo and how it may affect pathology remains largely unknown. Here we demonstrate that peripherally applied inflammatory stimuli induce acute immune training and tolerance in the brain and lead to differential epigenetic reprogramming of brain-resident macrophages (microglia) that persists for at least six months. Strikingly, in a mouse model of Alzheimer's pathology, immune training exacerbates cerebral β-amyloidosis and immune tolerance alleviates it; similarly, peripheral immune stimulation modifies pathological features after stroke. Our results identify immune memory in the brain as an important modifier of neuropathology.
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Epigenetic mechanisms in memory and synaptic function
Sultan, Faraz A; Day, Jeremy J
2011-01-01
Although the term ‘epigenetics’ was coined nearly seventy years ago, its critical function in memory processing by the adult CNS has only recently been appreciated. The hypothesis that epigenetic mechanisms regulate memory and behavior was motivated by the need for stable molecular processes that evade turnover of the neuronal proteome. In this article, we discuss evidence that supports a role for neural epigenetic modifications in the formation, consolidation and storage of memory. In addition, we will review the evidence that epigenetic mechanisms regulate synaptic plasticity, a cellular correlate of memory. We will also examine how the concerted action of multiple epigenetic mechanisms with varying spatiotemporal profiles influence selective gene expression in response to behavioral experience. Finally, we will suggest key areas for future research that will help elucidate the complex, vital and still mysterious, role of epigenetic mechanisms in neural function and behavior. PMID:22122279
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Single-cell epigenomics: techniques and emerging applications.
Schwartzman, Omer; Tanay, Amos
2015-12-01
Epigenomics is the study of the physical modifications, associations and conformations of genomic DNA sequences, with the aim of linking these with epigenetic memory, cellular identity and tissue-specific functions. While current techniques in the field are characterizing the average epigenomic features across large cell ensembles, the increasing interest in the epigenetics within complex and heterogeneous tissues is driving the development of single-cell epigenomics. We review emerging single-cell methods for capturing DNA methylation, chromatin accessibility, histone modifications, chromosome conformation and replication dynamics. Together, these techniques are rapidly becoming a powerful tool in studies of cellular plasticity and diversity, as seen in stem cells and cancer.
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Deibel, Scott H.; Zelinski, Erin L.; Keeley, Robin J.; Kovalchuk, Olga; McDonald, Robert J.
2015-01-01
Circadian rhythm dysfunction and cognitive decline, specifically memory loss, frequently accompany natural aging. Circadian rhythms and memory are intertwined, as circadian rhythms influence memory formation and recall in young and old rodents. Although, the precise relationship between circadian rhythms and memory is still largely unknown, it is hypothesized that circadian rhythm disruption, which occurs during aging, contributes to age-associated cognitive decline, specifically memory loss. While there are a variety of mechanisms that could mediate this effect, changes in the epigenome that occur during aging has been proposed as a potential candidate. Interestingly, epigenetic mechanisms, such as DNA methylation and sirtuin1 (SIRT1) are necessary for both circadian rhythms and memory. During aging, similar alterations of epigenetic mechanisms occur in the suprachiasmatic nucleus (SCN) and hippocampus, which are necessary for circadian rhythm generation and memory, respectively. Recently, circadian rhythms have been linked to epigenetic function in the hippocampus, as some of these epigenetic mechanisms oscillate in the hippocampus and are disrupted by clock gene deletion. The current paper will review how circadian rhythms and memory change with age, and will suggest how epigenetic changes in these processes might contribute to age-related cognitive decline. PMID:26252151
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HDACis (class I), cancer stem cell, and phytochemicals: Cancer therapy and prevention implications.
Bayat, Sahar; Shekari Khaniani, Mahmoud; Choupani, Jalal; Alivand, Mohammad Reza; Mansoori Derakhshan, Sima
2018-01-01
Epigenetics is independent of the sequence events that physically affect the condensing of chromatin and genes expression. The unique epigenetic memories of various cells trigger exclusive gene expression profiling. According to different studies, the aberrant epigenetic signatures and impaired gene expression profiles are master occurrences in cancer cells in which oncogene and tumor suppressor genes are affected. Owing to the facts that epigenetic modifications are performed earlier than expression and are reversible, the epigenetic reprogramming of cancer cells could be applied potentially for their prevention, control, and therapy. The disruption of the acetylation signature, as a master epigenetic change in cancers, is related to the expression and the activity of HDACs. In this context, class I HDACs play a significant role in the regulation of cell proliferation and cancer. More recently, cancer stem cell (CSC) has been introduced as a minority population of tumor that is responsible for invasiveness, drug resistance, and relapse of cancers. It is now believed that controlling CSC via epigenetic reprogramming such as targeting HDACs could be helpful in regulating the acetylation pattern of chromatin. Recently, a number of reports have introduced some phytochemicals as HDAC inhibitors. The use of phytochemicals with the HDAC inhibition property could be potentially efficient in overcoming the mentioned problems of CSCs. This review presents a perspective concerning HDAC-targeted phytochemicals to control CSC in tumors. Hopefully, this new route would have more advantages in therapeutic applications and prevention against cancer. Copyright © 2017. Published by Elsevier Masson SAS.
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Epigenetic mechanisms in fear conditioning: Implications for treating post-traumatic stress disorder
Kwapis, Janine L.; Wood, Marcelo A.
2014-01-01
Post-traumatic stress disorder (PTSD) and other anxiety disorders stemming from dysregulated fear memory are problematic and costly. Understanding the molecular mechanisms that contribute to the formation and maintenance of these persistent fear associations is critical to developing treatments for PTSD. Epigenetic mechanisms, which control gene expression to produce long-lasting changes in cellular function, may support the formation of fear memory underlying PTSD. Here, we address the role of epigenetic mechanisms in the formation, storage, updating, and extinction of fear memories and discuss methods of targeting these epigenetic mechanisms to reduce the initial formation of fear memory or to enhance its extinction. Epigenetic mechanisms may provide a novel target for pharmaceutical and other treatments to reduce aversive memory contributing to PTSD. PMID:25220045
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Epigenetic mechanisms: critical contributors to long-term memory formation.
Lubin, Farah D; Gupta, Swati; Parrish, R Ryley; Grissom, Nicola M; Davis, Robin L
2011-12-01
Recent advances in chromatin biology have identified a role for epigenetic mechanisms in the regulation of neuronal gene expression changes, a necessary process for proper synaptic plasticity and memory formation. Experimental evidence for dynamic chromatin remodeling influencing gene transcription in postmitotic neurons grew from initial reports describing posttranslational modifications of histones, including phosphorylation and acetylation occurring in various brain regions during memory consolidation. An accumulation of recent studies, however, has also highlighted the importance of other epigenetic modifications, such as DNA methylation and histone methylation, as playing a role in memory formation. This present review examines learning-induced gene transcription by chromatin remodeling underlying long-lasting changes in neurons, with direct implications for the study of epigenetic mechanisms in long-term memory formation and behavior. Furthermore, the study of epigenetic gene regulation, in conjunction with transcription factor activation, can provide complementary lines of evidence to further understanding transcriptional mechanisms subserving memory storage.
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Ahmad Ganai, Shabir; Ramadoss, Mahalakshmi; Mahadevan, Vijayalakshmi
2016-01-01
Epigenetic regulation of neuronal signalling through histone acetylation dictates transcription programs that govern neuronal memory, plasticity and learning paradigms. Histone Acetyl Transferases (HATs) and Histone Deacetylases (HDACs) are antagonistic enzymes that regulate gene expression through acetylation and deacetylation of histone proteins around which DNA is wrapped inside a eukaryotic cell nucleus. The epigenetic control of HDACs and the cellular imbalance between HATs and HDACs dictate disease states and have been implicated in muscular dystrophy, loss of memory, neurodegeneration and autistic disorders. Altering gene expression profiles through inhibition of HDACs is now emerging as a powerful technique in therapy. This review presents evolving applications of HDAC inhibitors as potential drugs in neurological research and therapy. Mechanisms that govern their expression profiles in neuronal signalling, plasticity and learning will be covered. Promising and exciting possibilities of HDAC inhibitors in memory formation, fear conditioning, ischemic stroke and neural regeneration have been detailed. PMID:26487502
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Centeno, Tonatiuh Pena; Shomroni, Orr; Hennion, Magali; Halder, Rashi; Vidal, Ramon; Rahman, Raza-Ur; Bonn, Stefan
2016-10-11
Recent evidence suggests that the formation and maintenance of memory requires epigenetic changes. In an effort to understand the spatio-temporal extent of learning and memory-related epigenetic changes we have charted genome-wide histone and DNA methylation profiles, in two different brain regions, two cell types, and three time-points, before and after learning. In this data descriptor we provide detailed information on data generation, give insights into the rationale of experiments, highlight necessary steps to assess data quality, offer guidelines for future use of the data and supply ready-to-use code to replicate the analysis results. The data provides a blueprint of the gene regulatory network underlying short- and long-term memory formation and maintenance. This 'healthy' gene regulatory network of learning can now be compared to changes in neurological or psychiatric diseases, providing mechanistic insights into brain disorders and highlighting potential therapeutic avenues.
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Ganai, Shabir Ahmad; Ramadoss, Mahalakshmi; Mahadevan, Vijayalakshmi
2016-01-01
Epigenetic regulation of neuronal signalling through histone acetylation dictates transcription programs that govern neuronal memory, plasticity and learning paradigms. Histone Acetyl Transferases (HATs) and Histone Deacetylases (HDACs) are antagonistic enzymes that regulate gene expression through acetylation and deacetylation of histone proteins around which DNA is wrapped inside a eukaryotic cell nucleus. The epigenetic control of HDACs and the cellular imbalance between HATs and HDACs dictate disease states and have been implicated in muscular dystrophy, loss of memory, neurodegeneration and autistic disorders. Altering gene expression profiles through inhibition of HDACs is now emerging as a powerful technique in therapy. This review presents evolving applications of HDAC inhibitors as potential drugs in neurological research and therapy. Mechanisms that govern their expression profiles in neuronal signalling, plasticity and learning will be covered. Promising and exciting possibilities of HDAC inhibitors in memory formation, fear conditioning, ischemic stroke and neural regeneration have been detailed.
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Epigenetic Regulation of Learning and Memory by Drosophila EHMT/G9a
Kramer, Jamie M.; Kochinke, Korinna; Oortveld, Merel A. W.; Marks, Hendrik; Kramer, Daniela; de Jong, Eiko K.; Asztalos, Zoltan; Westwood, J. Timothy; Stunnenberg, Hendrik G.; Sokolowski, Marla B.; Keleman, Krystyna; Zhou, Huiqing; van Bokhoven, Hans; Schenck, Annette
2011-01-01
The epigenetic modification of chromatin structure and its effect on complex neuronal processes like learning and memory is an emerging field in neuroscience. However, little is known about the “writers” of the neuronal epigenome and how they lay down the basis for proper cognition. Here, we have dissected the neuronal function of the Drosophila euchromatin histone methyltransferase (EHMT), a member of a conserved protein family that methylates histone 3 at lysine 9 (H3K9). EHMT is widely expressed in the nervous system and other tissues, yet EHMT mutant flies are viable. Neurodevelopmental and behavioral analyses identified EHMT as a regulator of peripheral dendrite development, larval locomotor behavior, non-associative learning, and courtship memory. The requirement for EHMT in memory was mapped to 7B-Gal4 positive cells, which are, in adult brains, predominantly mushroom body neurons. Moreover, memory was restored by EHMT re-expression during adulthood, indicating that cognitive defects are reversible in EHMT mutants. To uncover the underlying molecular mechanisms, we generated genome-wide H3K9 dimethylation profiles by ChIP-seq. Loss of H3K9 dimethylation in EHMT mutants occurs at 5% of the euchromatic genome and is enriched at the 5′ and 3′ ends of distinct classes of genes that control neuronal and behavioral processes that are corrupted in EHMT mutants. Our study identifies Drosophila EHMT as a key regulator of cognition that orchestrates an epigenetic program featuring classic learning and memory genes. Our findings are relevant to the pathophysiological mechanisms underlying Kleefstra Syndrome, a severe form of intellectual disability caused by mutations in human EHMT1, and have potential therapeutic implications. Our work thus provides novel insights into the epigenetic control of cognition in health and disease. PMID:21245904
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A Myc-driven self-reinforcing regulatory network maintains mouse embryonic stem cell identity
Fagnocchi, Luca; Cherubini, Alessandro; Hatsuda, Hiroshi; Fasciani, Alessandra; Mazzoleni, Stefania; Poli, Vittoria; Berno, Valeria; Rossi, Riccardo L.; Reinbold, Rolland; Endele, Max; Schroeder, Timm; Rocchigiani, Marina; Szkarłat, Żaneta; Oliviero, Salvatore; Dalton, Stephen; Zippo, Alessio
2016-01-01
Stem cell identity depends on the integration of extrinsic and intrinsic signals, which directly influence the maintenance of their epigenetic state. Although Myc transcription factors play a major role in stem cell self-renewal and pluripotency, their integration with signalling pathways and epigenetic regulators remains poorly defined. We addressed this point by profiling the gene expression and epigenetic pattern in ESCs whose growth depends on conditional Myc activity. Here we show that Myc potentiates the Wnt/β-catenin signalling pathway, which cooperates with the transcriptional regulatory network in sustaining ESC self-renewal. Myc activation results in the transcriptional repression of Wnt antagonists through the direct recruitment of PRC2 on these targets. The consequent potentiation of the autocrine Wnt/β-catenin signalling induces the transcriptional activation of the endogenous Myc family members, which in turn activates a Myc-driven self-reinforcing circuit. Thus, our data unravel a Myc-dependent self-propagating epigenetic memory in the maintenance of ESC self-renewal capacity. PMID:27301576
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A Myc-driven self-reinforcing regulatory network maintains mouse embryonic stem cell identity.
Fagnocchi, Luca; Cherubini, Alessandro; Hatsuda, Hiroshi; Fasciani, Alessandra; Mazzoleni, Stefania; Poli, Vittoria; Berno, Valeria; Rossi, Riccardo L; Reinbold, Rolland; Endele, Max; Schroeder, Timm; Rocchigiani, Marina; Szkarłat, Żaneta; Oliviero, Salvatore; Dalton, Stephen; Zippo, Alessio
2016-06-15
Stem cell identity depends on the integration of extrinsic and intrinsic signals, which directly influence the maintenance of their epigenetic state. Although Myc transcription factors play a major role in stem cell self-renewal and pluripotency, their integration with signalling pathways and epigenetic regulators remains poorly defined. We addressed this point by profiling the gene expression and epigenetic pattern in ESCs whose growth depends on conditional Myc activity. Here we show that Myc potentiates the Wnt/β-catenin signalling pathway, which cooperates with the transcriptional regulatory network in sustaining ESC self-renewal. Myc activation results in the transcriptional repression of Wnt antagonists through the direct recruitment of PRC2 on these targets. The consequent potentiation of the autocrine Wnt/β-catenin signalling induces the transcriptional activation of the endogenous Myc family members, which in turn activates a Myc-driven self-reinforcing circuit. Thus, our data unravel a Myc-dependent self-propagating epigenetic memory in the maintenance of ESC self-renewal capacity.
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Epigenetic regulation and chromatin remodeling in learning and memory.
Kim, Somi; Kaang, Bong-Kiun
2017-01-13
Understanding the underlying mechanisms of memory formation and maintenance has been a major goal in the field of neuroscience. Memory formation and maintenance are tightly controlled complex processes. Among the various processes occurring at different levels, gene expression regulation is especially crucial for proper memory processing, as some genes need to be activated while some genes must be suppressed. Epigenetic regulation of the genome involves processes such as DNA methylation and histone post-translational modifications. These processes edit genomic properties or the interactions between the genome and histone cores. They then induce structural changes in the chromatin and lead to transcriptional changes of different genes. Recent studies have focused on the concept of chromatin remodeling, which consists of 3D structural changes in chromatin in relation to gene regulation, and is an important process in learning and memory. In this review, we will introduce three major epigenetic processes involved in memory regulation: DNA methylation, histone methylation and histone acetylation. We will also discuss general mechanisms of long-term memory storage and relate the epigenetic control of learning and memory to chromatin remodeling. Finally, we will discuss how epigenetic mechanisms can contribute to the pathologies of neurological disorders and cause memory-related symptoms.
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Characterization of the Epigenetic Changes During Human Gonadal Primordial Germ Cells Reprogramming.
Eguizabal, C; Herrera, L; De Oñate, L; Montserrat, N; Hajkova, P; Izpisua Belmonte, J C
2016-09-01
Epigenetic reprogramming is a central process during mammalian germline development. Genome-wide DNA demethylation in primordial germ cells (PGCs) is a prerequisite for the erasure of epigenetic memory, preventing the transmission of epimutations to the next generation. Apart from DNA demethylation, germline reprogramming has been shown to entail reprogramming of histone marks and chromatin remodelling. Contrary to other animal models, there is limited information about the epigenetic dynamics during early germ cell development in humans. Here, we provide further characterization of the epigenetic configuration of the early human gonadal PGCs. We show that early gonadal human PGCs are DNA hypomethylated and their chromatin is characterized by low H3K9me2 and high H3K27me3 marks. Similarly to previous observations in mice, human gonadal PGCs undergo dynamic chromatin changes concomitant with the erasure of genomic imprints. Interestingly, and contrary to mouse early germ cells, expression of BLIMP1/PRDM1 persists in through all gestational stages in human gonadal PGCs and is associated with nuclear lysine-specific demethylase-1. Our work provides important additional information regarding the chromatin changes associated with human PGCs development between 6 and 13 weeks of gestation in male and female gonads. Stem Cells 2016;34:2418-2428. © 2016 AlphaMed Press.
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Infectious Agents as Stimuli of Trained Innate Immunity.
Rusek, Paulina; Wala, Mateusz; Druszczyńska, Magdalena; Fol, Marek
2018-02-03
The discoveries made over the past few years have modified the current immunological paradigm. It turns out that innate immunity cells can mount some kind of immunological memory, similar to that observed in the acquired immunity and corresponding to the defense mechanisms of lower organisms, which increases their resistance to reinfection. This phenomenon is termed trained innate immunity. It is based on epigenetic changes in innate immune cells (monocytes/macrophages, NK cells) after their stimulation with various infectious or non-infectious agents. Many infectious stimuli, including bacterial or fungal cells and their components (LPS, β-glucan, chitin) as well as viruses or even parasites are considered potent inducers of innate immune memory. Epigenetic cell reprogramming occurring at the heart of the phenomenon may provide a useful basis for designing novel prophylactic and therapeutic strategies to prevent and protect against multiple diseases. In this article, we present the current state of art on trained innate immunity occurring as a result of infectious agent induction. Additionally, we discuss the mechanisms of cell reprogramming and the implications for immune response stimulation/manipulation.
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Elements of the cellular metabolic structure
De la Fuente, Ildefonso M.
2015-01-01
A large number of studies have demonstrated the existence of metabolic covalent modifications in different molecular structures, which are able to store biochemical information that is not encoded by DNA. Some of these covalent mark patterns can be transmitted across generations (epigenetic changes). Recently, the emergence of Hopfield-like attractor dynamics has been observed in self-organized enzymatic networks, which have the capacity to store functional catalytic patterns that can be correctly recovered by specific input stimuli. Hopfield-like metabolic dynamics are stable and can be maintained as a long-term biochemical memory. In addition, specific molecular information can be transferred from the functional dynamics of the metabolic networks to the enzymatic activity involved in covalent post-translational modulation, so that determined functional memory can be embedded in multiple stable molecular marks. The metabolic dynamics governed by Hopfield-type attractors (functional processes), as well as the enzymatic covalent modifications of specific molecules (structural dynamic processes) seem to represent the two stages of the dynamical memory of cellular metabolism (metabolic memory). Epigenetic processes appear to be the structural manifestation of this cellular metabolic memory. Here, a new framework for molecular information storage in the cell is presented, which is characterized by two functionally and molecularly interrelated systems: a dynamic, flexible and adaptive system (metabolic memory) and an essentially conservative system (genetic memory). The molecular information of both systems seems to coordinate the physiological development of the whole cell. PMID:25988183
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A zebrafish model of diabetes mellitus and metabolic memory.
Intine, Robert V; Olsen, Ansgar S; Sarras, Michael P
2013-02-28
Diabetes mellitus currently affects 346 million individuals and this is projected to increase to 400 million by 2030. Evidence from both the laboratory and large scale clinical trials has revealed that diabetic complications progress unimpeded via the phenomenon of metabolic memory even when glycemic control is pharmaceutically achieved. Gene expression can be stably altered through epigenetic changes which not only allow cells and organisms to quickly respond to changing environmental stimuli but also confer the ability of the cell to "memorize" these encounters once the stimulus is removed. As such, the roles that these mechanisms play in the metabolic memory phenomenon are currently being examined. We have recently reported the development of a zebrafish model of type I diabetes mellitus and characterized this model to show that diabetic zebrafish not only display the known secondary complications including the changes associated with diabetic retinopathy, diabetic nephropathy and impaired wound healing but also exhibit impaired caudal fin regeneration. This model is unique in that the zebrafish is capable to regenerate its damaged pancreas and restore a euglycemic state similar to what would be expected in post-transplant human patients. Moreover, multiple rounds of caudal fin amputation allow for the separation and study of pure epigenetic effects in an in vivo system without potential complicating factors from the previous diabetic state. Although euglycemia is achieved following pancreatic regeneration, the diabetic secondary complication of fin regeneration and skin wound healing persists indefinitely. In the case of impaired fin regeneration, this pathology is retained even after multiple rounds of fin regeneration in the daughter fin tissues. These observations point to an underlying epigenetic process existing in the metabolic memory state. Here we present the methods needed to successfully generate the diabetic and metabolic memory groups of fish and discuss the advantages of this model.
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The secret language of destiny: stress imprinting and transgenerational origins of disease
Zucchi, Fabiola C. R.; Yao, Youli; Metz, Gerlinde A.
2012-01-01
Epigenetic regulation modulates gene expression without altering the DNA sequence to facilitate rapid adjustments to dynamically changing environmental conditions. The formation of an epigenetic memory allows passing on this information to subsequent generations. Here we propose that epigenetic memories formed by adverse environmental conditions and stress represent a critical determinant of health and disease in the F3 generation and beyond. Transgenerational programming of epigenetic regulation may represent a key to understand adult-onset complex disease pathogenesis and cumulative effects of life span and familial disease etiology. Ultimately, the mechanisms of generating an epigenetic memory may become of potentially promising diagnostic and therapeutic relevance due to their reversible nature. Exploring the role of environmental factors, such as stress, in causing variations in epigenetic profiles may lead to new avenues of personalized, preventive medicine based on epigenetic signatures and interventions. PMID:22675331
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Tip off the HAT– Epigenetic control of learning and memory by Drosophila Tip60
Xu, Songjun; Elefant, Felice
2015-01-01
Disruption of epigenetic gene control mechanisms involving histone acetylation in the brain causes cognitive impairment, a debilitating hallmark of most neurodegenerative disorders. Histone acetylation regulates cognitive gene expression via chromatin packaging control in neurons. Unfortunately, the histone acetyltransferases (HATs) that generate such neural epigenetic signatures and their mechanisms of action remain unclear. Our recent findings provide insight into this question by demonstrating that Tip60 HAT action is critical for morphology and function of the mushroom body (MB), the learning and memory center in the Drosophila brain. We show that Tip60 is robustly produced in MB Kenyon cells and extending axonal lobes and that targeted MB Tip60 HAT loss results in axonal outgrowth disruption. Functional consequences of loss and gain of Tip60 HAT levels in the MB are evidenced by defects in memory. Tip60 ChIP-Seq analysis reveals enrichment for genes that function in cognitive processes and accordingly, key genes representing these pathways are misregulated in the Tip60 HAT mutant fly brain. Remarkably, increasing levels of Tip60 in the MB rescues learning and memory deficits resulting from Alzheimer's disease associated amyloid precursor protein (APP) induced neurodegeneration. Our studies highlight the potential of HAT activators as a therapeutic option for cognitive disorders. PMID:26327426
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Sexual dimorphism in epigenomicresponses of stem cells to extreme fetal growth
Delahaye, Fabien; Wijetunga, N. Ari; Heo, Hye J.; Tozour, Jessica N.; Zhao, Yong Mei; Greally, John M.; Einstein, Francine H.
2014-01-01
Extreme fetal growth is associated with increased susceptibility to a range of adult diseases through an unknown mechanism of cellular memory. We tested whether heritable epigenetic processes in long-lived CD34+ hematopoietic stem/progenitor cells (HSPCs) showed evidence for re-programming associated with the extremes of fetal growth. Here we show that both fetal growth restriction and over-growth are associated with global shifts towards DNA hypermethylation, targeting cis-regulatory elements in proximity to genes involved in glucose homeostasis and stem cell function. We find a sexually dimorphic response; intrauterine growth restriction (IUGR) is associated with substantially greater epigenetic dysregulation in males, whereas large for gestational age (LGA) growth predominantly affects females. The findings are consistent with extreme fetal growth interacting with variable fetal susceptibility to influence cellular aging and metabolic characteristics through epigenetic mechanisms, potentially generating biomarkers that could identify infants at higher risk for chronic disease later in life. PMID:25300954
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Sexual dimorphism in epigenomic responses of stem cells to extreme fetal growth.
Delahaye, Fabien; Wijetunga, N Ari; Heo, Hye J; Tozour, Jessica N; Zhao, Yong Mei; Greally, John M; Einstein, Francine H
2014-10-10
Extreme fetal growth is associated with increased susceptibility to a range of adult diseases through an unknown mechanism of cellular memory. We tested whether heritable epigenetic processes in long-lived CD34(+) haematopoietic stem/progenitor cells showed evidence for re-programming associated with the extremes of fetal growth. Here we show that both fetal growth restriction and over-growth are associated with global shifts towards DNA hypermethylation, targeting cis-regulatory elements in proximity to genes involved in glucose homeostasis and stem cell function. We find a sexually dimorphic response; intrauterine growth restriction is associated with substantially greater epigenetic dysregulation in males, whereas large for gestational age growth predominantly affects females. The findings are consistent with extreme fetal growth interacting with variable fetal susceptibility to influence cellular ageing and metabolic characteristics through epigenetic mechanisms, potentially generating biomarkers that could identify infants at higher risk for chronic disease later in life.
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Sensory Cortical Plasticity Participates in the Epigenetic Regulation of Robust Memory Formation
Phan, Mimi L.; Bieszczad, Kasia M.
2016-01-01
Neuroplasticity remodels sensory cortex across the lifespan. A function of adult sensory cortical plasticity may be capturing available information during perception for memory formation. The degree of experience-dependent remodeling in sensory cortex appears to determine memory strength and specificity for important sensory signals. A key open question is how plasticity is engaged to induce different degrees of sensory cortical remodeling. Neural plasticity for long-term memory requires the expression of genes underlying stable changes in neuronal function, structure, connectivity, and, ultimately, behavior. Lasting changes in transcriptional activity may depend on epigenetic mechanisms; some of the best studied in behavioral neuroscience are DNA methylation and histone acetylation and deacetylation, which, respectively, promote and repress gene expression. One purpose of this review is to propose epigenetic regulation of sensory cortical remodeling as a mechanism enabling the transformation of significant information from experiences into content-rich memories of those experiences. Recent evidence suggests how epigenetic mechanisms regulate highly specific reorganization of sensory cortical representations that establish a widespread network for memory. Thus, epigenetic mechanisms could initiate events to establish exceptionally persistent and robust memories at a systems-wide level by engaging sensory cortical plasticity for gating what and how much information becomes encoded. PMID:26881129
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Kagoya, Yuki; Nakatsugawa, Munehide; Yamashita, Yuki; Ochi, Toshiki; Guo, Tingxi; Anczurowski, Mark; Saso, Kayoko; Butler, Marcus O; Arrowsmith, Cheryl H; Hirano, Naoto
2016-09-01
Adoptive immunotherapy is a potentially curative therapeutic approach for patients with advanced cancer. However, the in vitro expansion of antitumor T cells prior to infusion inevitably incurs differentiation towards effector T cells and impairs persistence following adoptive transfer. Epigenetic profiles regulate gene expression of key transcription factors over the course of immune cell differentiation, proliferation, and function. Using comprehensive screening of chemical probes with defined epigenetic targets, we found that JQ1, an inhibitor of bromodomain and extra-terminal motif (BET) proteins, maintained CD8+ T cells with functional properties of stem cell-like and central memory T cells. Mechanistically, the BET protein BRD4 directly regulated expression of the transcription factor BATF in CD8+ T cells, which was associated with differentiation of T cells into an effector memory phenotype. JQ1-treated T cells showed enhanced persistence and antitumor effects in murine T cell receptor and chimeric antigen receptor gene therapy models. Furthermore, we found that histone acetyltransferase p300 supported the recruitment of BRD4 to the BATF promoter region, and p300 inhibition similarly augmented antitumor effects of the adoptively transferred T cells. These results demonstrate that targeting the BRD4-p300 signaling cascade supports the generation of superior antitumor T cell grafts for adoptive immunotherapy.
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Chronic exposure to water pollutant trichloroethylene increased epigenetic drift in CD4(+) T cells.
Gilbert, Kathleen M; Blossom, Sarah J; Erickson, Stephen W; Reisfeld, Brad; Zurlinden, Todd J; Broadfoot, Brannon; West, Kirk; Bai, Shasha; Cooney, Craig A
2016-05-01
Autoimmune disease and CD4(+) T-cell alterations are induced in mice exposed to the water pollutant trichloroethylene (TCE). We examined here whether TCE altered gene-specific DNA methylation in CD4(+) T cells as a possible mechanism of immunotoxicity. Naive and effector/memory CD4(+) T cells from mice exposed to TCE (0.5 mg/ml in drinking water) for 40 weeks were examined by bisulfite next-generation DNA sequencing. A probabilistic model calculated from multiple genes showed that TCE decreased methylation control in CD4(+) T cells. Data from individual genes fitted to a quadratic regression model showed that TCE increased gene-specific methylation variance in both CD4 subsets. TCE increased epigenetic drift of specific CpG sites in CD4(+) T cells.
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Kakaradov, Boyko; Arsenio, Janilyn; Widjaja, Christella E.; He, Zhaoren; Aigner, Stefan; Metz, Patrick J.; Yu, Bingfei; Wehrens, Ellen J.; Lopez, Justine; Kim, Stephanie H.; Zuniga, Elina I.; Goldrath, Ananda W.; Chang, John T.; Yeo, Gene W.
2017-01-01
SUMMARY During microbial infection, responding CD8+ T lymphocytes differentiate into heterogeneous subsets that together provide immediate and durable protection. To elucidate the dynamic transcriptional changes that underlie this process, we applied a single-cell RNA sequencing approach and analyzed individual CD8+ T lymphocytes sequentially throughout the course of a viral infection in vivo. Our analyses revealed a striking transcriptional divergence among cells that had undergone their first division and identified previously unknown molecular determinants controlling CD8+ T lymphocyte fate specification. These findings suggest a model of terminal effector cell differentiation initiated by an early burst of transcriptional activity and subsequently refined by epigenetic silencing of transcripts associated with memory lymphocytes, highlighting the power and necessity of single-cell approaches. PMID:28218746
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I Remember You: Epigenetic Priming in Epithelial Stem Cells.
Novakovic, Boris; Stunnenberg, Hendrik G
2017-12-19
Exposure to inflammatory stimuli can remodel immune cells in a way that alters their response to future insults. In a landmark paper in Nature, Elaine Fuchs and colleagues show that memory of inflammation is not restricted to the hematopoietic lineage (Naik et al., 2017). Copyright © 2017 Elsevier Inc. All rights reserved.
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Goodson, Jamie; Al-Azzawi, Haneen; Allain, Shannon Q.; Simon, Noah; Palasek, Stan; Miller, Daniel G.; Johnson, Winslow C.; Laird, Charles D.
2017-01-01
In storing and transmitting epigenetic information, organisms must balance the need to maintain information about past conditions with the capacity to respond to information in their current and future environments. Some of this information is encoded by DNA methylation, which can be transmitted with variable fidelity from parent to daughter strand. High fidelity confers strong pattern matching between the strands of individual DNA molecules and thus pattern stability over rounds of DNA replication; lower fidelity confers reduced pattern matching, and thus greater flexibility. Here, we present a new conceptual framework, Ratio of Concordance Preference (RCP), that uses double-stranded methylation data to quantify the flexibility and stability of the system that gave rise to a given set of patterns. We find that differentiated mammalian cells operate with high DNA methylation stability, consistent with earlier reports. Stem cells in culture and in embryos, in contrast, operate with reduced, albeit significant, methylation stability. We conclude that preference for concordant DNA methylation is a consistent mode of information transfer, and thus provides epigenetic stability across cell divisions, even in stem cells and those undergoing developmental transitions. Broader application of our RCP framework will permit comparison of epigenetic-information systems across cells, developmental stages, and organisms whose methylation machineries differ substantially or are not yet well understood. PMID:29107996
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Reprogramming T cell Lymphocytes to Induced Pluripotent Stem Cells
NASA Astrophysics Data System (ADS)
Bared, Kalia
The discovery of induced pluripotent stem cells (iPSC) provided a novel technology for the study of development and pharmacology and complement embryonic stem cells (ES) for cell therapy applications. Though iPSC are derived from adult tissue they are comparable to ES cells in their behavior; multi-lineage differentiation and self-renewal. This makes iPSC research appealing because they can be studied in great detail and expanded in culture broadly. Fibroblasts were the first cell type reprogrammed to an iPSC using a retrovirus vector, since then alternative cell types including lymphocytes have been used to generate iPSC. Different types of vectors have also been developed to enhance iPSC formation and quality. However, specific T lymphocyte subsets have not been shown to reprogram to a pluripotent state to date. Here, we proposed to derive iPSC from peripheral blood effector and central memory T cells, reasoning that the resultant iPSC will maintain the epigenetic memory of a T lymphocyte, including the T cell receptor (TCR) gene rearrangement. This epigenetic memory will enable the differentiation and expansion of T cell iPSC into professional T cells containing a specific TCR. These could then be used for cell therapy to target specific antigens, as well as to improve culture techniques to expand T cells
in vitro . We studied different gene delivery methods to derive iPSC from different types of T lymphocytes. We assessed the viability of viral transduction using flow cytometry to detect green fluorescent marker contained in the viral construct and quantitative real time polymerase chain reaction (qRT-PCR) to detect Oct4, Klf4, Sox2, and c-Myc gene expression. Our results demonstrate that the Sendai virus construct is the most feasible platform to reprogram T lymphocytes. We anticipate that this platform will provide an efficient and safe approach to derive iPSC from different T cell subsets, including memory T cells.
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The potential of epigenetics in stress-enhanced fear learning models of PTSD
Blouin, Ashley M.; Sillivan, Stephanie E.; Joseph, Nadine F.
2016-01-01
Prolonged distress and dysregulated memory processes are the core features of post-traumatic stress disorder (PTSD) and represent the debilitating, persistent nature of the illness. However, the neurobiological mechanisms underlying the expression of these symptoms are challenging to study in human patients. Stress-enhanced fear learning (SEFL) paradigms, which encompass both stress and memory components in rodents, are emerging as valuable preclinical models of PTSD. Rodent models designed to study the long-term mechanisms of either stress or fear memory alone have identified a critical role for numerous epigenetic modifications to DNA and histone proteins. However, the epigenetic modifications underlying SEFL remain largely unknown. This review will provide a brief overview of the epigenetic modifications implicated in stress and fear memory independently, followed by a description of existing SEFL models and the few epigenetic mechanisms found to date to underlie SEFL. The results of the animal studies discussed here highlight neuroepigenetics as an essential area for future research in the context of PTSD through SEFL studies, because of its potential to identify novel candidates for neurotherapeutics targeting stress-induced pathogenic memories. PMID:27634148
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Epigenetic mechanisms and memory strength: a comparative study.
Federman, Noel; Zalcman, Gisela; de la Fuente, Verónica; Fustiñana, Maria Sol; Romano, Arturo
2014-01-01
Memory consolidation requires de novo mRNA and protein synthesis. Transcriptional activation is controlled by transcription factors, their cofactors and repressors. Cofactors and repressors regulate gene expression by interacting with basal transcription machinery, remodeling chromatin structure and/or chemically modifying histones. Acetylation is the most studied epigenetic mechanism of histones modifications related to gene expression. This process is regulated by histone acetylases (HATs) and histone deacetylases (HDACs). More than 5 years ago, we began a line of research about the role of histone acetylation during memory consolidation. Here we review our work, presenting evidence about the critical role of this epigenetic mechanism during consolidation of context-signal memory in the crab Neohelice granulata, as well as during consolidation of novel object recognition memory in the mouse Mus musculus. Our evidence demonstrates that histone acetylation is a key mechanism in memory consolidation, functioning as a distinctive molecular feature of strong memories. Furthermore, we found that the strength of a memory can be characterized by its persistence or its resistance to extinction. Besides, we found that the role of this epigenetic mechanism regulating gene expression only in the formation of strongest memories is evolutionarily conserved. Copyright © 2014 Elsevier Ltd. All rights reserved.
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Involvement of DNA methylation in memory processing in the honey bee.
Lockett, Gabrielle A; Helliwell, Paul; Maleszka, Ryszard
2010-08-23
DNA methylation, an important and evolutionarily conserved epigenetic mechanism, is implicated in learning and memory processes in vertebrates, but its role in behaviour in invertebrates is unknown. We examined the role of DNA methylation in memory in the honey bee using an appetitive Pavlovian olfactory discrimination task, and by assessing the expression of DNA methyltransferase3, a key driver of epigenetic reprogramming. Here we report that DNA methyltransferase inhibition reduces acquisition retention and alters the extinction depending on treatment time, and DNA methyltransferase3 is upregulated after training. Our findings add to the understanding of epigenetic mechanisms in learning and memory, extending known roles of DNA methylation to appetitive and extinction memory, and for the first time implicate DNA methylation in memory in invertebrates.
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Chronic exposure to water pollutant trichloroethylene increased epigenetic drift in CD4+ T cells
Gilbert, Kathleen M; Blossom, Sarah J; Erickson, Stephen W; Reisfeld, Brad; Zurlinden, Todd J; Broadfoot, Brannon; West, Kirk; Bai, Shasha; Cooney, Craig A
2016-01-01
Aim: Autoimmune disease and CD4+ T-cell alterations are induced in mice exposed to the water pollutant trichloroethylene (TCE). We examined here whether TCE altered gene-specific DNA methylation in CD4+ T cells as a possible mechanism of immunotoxicity. Materials & methods: Naive and effector/memory CD4+ T cells from mice exposed to TCE (0.5 mg/ml in drinking water) for 40 weeks were examined by bisulfite next-generation DNA sequencing. Results: A probabilistic model calculated from multiple genes showed that TCE decreased methylation control in CD4+ T cells. Data from individual genes fitted to a quadratic regression model showed that TCE increased gene-specific methylation variance in both CD4 subsets. Conclusion: TCE increased epigenetic drift of specific CpG sites in CD4+ T cells. PMID:27092578
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Altered Cellular Metabolism Drives Trained Immunity.
Sohrabi, Yahya; Godfrey, Rinesh; Findeisen, Hannes M
2018-04-04
Exposing innate immune cells to an initial insult induces a long-term proinflammatory response due to metabolic and epigenetic alterations which encompass an emerging new concept called trained immunity. Recent studies provide novel insights into mechanisms centered on metabolic reprogramming which induce innate immune memory in hematopoietic stem cells and monocytes. Copyright © 2018 Elsevier Ltd. All rights reserved.
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IL-15 regulates memory CD8+ T cell O-glycan synthesis and affects trafficking
Nolz, Jeffrey C.; Harty, John T.
2014-01-01
Memory and naive CD8+ T cells exhibit distinct trafficking patterns. Specifically, memory but not naive CD8+ T cells are recruited to inflamed tissues in an antigen-independent manner. However, the molecular mechanisms that regulate memory CD8+ T cell trafficking are largely unknown. Here, using murine models of infection and T cell transfer, we found that memory but not naive CD8+ T cells dynamically regulate expression of core 2 O-glycans, which interact with P- and E-selectins to modulate trafficking to inflamed tissues. Following infection, antigen-specific effector CD8+ T cells strongly expressed core 2 O-glycans, but this glycosylation pattern was lost by most memory CD8+ T cells. After unrelated infection or inflammatory challenge, memory CD8+ T cells synthesized core 2 O-glycans independently of antigen restimulation. The presence of core 2 O-glycans subsequently directed these cells to inflamed tissue. Memory and naive CD8+ T cells exhibited the opposite pattern of epigenetic modifications at the Gcnt1 locus, which encodes the enzyme that initiates core 2 O-glycan synthesis. The open chromatin configuration in memory CD8+ T cells permitted de novo generation of core 2 O-glycans in a TCR-independent, but IL-15–dependent, manner. Thus, IL-15 stimulation promotes antigen-experienced memory CD8+ T cells to generate core 2 O-glycans, which subsequently localize them to inflamed tissues. These findings suggest that CD8+ memory T cell trafficking potentially can be manipulated to improve host defense and immunotherapy. PMID:24509081
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Environmental perception and epigenetic memory: mechanistic insight through FLC
Berry, Scott; Dean, Caroline
2015-01-01
Chromatin plays a central role in orchestrating gene regulation at the transcriptional level. However, our understanding of how chromatin states are altered in response to environmental and developmental cues, and then maintained epigenetically over many cell divisions, remains poor. The floral repressor gene FLOWERING LOCUS C (FLC) in Arabidopsis thaliana is a useful system to address these questions. FLC is transcriptionally repressed during exposure to cold temperatures, allowing studies of how environmental conditions alter expression states at the chromatin level. FLC repression is also epigenetically maintained during subsequent development in warm conditions, so that exposure to cold may be remembered. This memory depends on molecular complexes that are highly conserved among eukaryotes, making FLC not only interesting as a paradigm for understanding biological decision-making in plants, but also an important system for elucidating chromatin-based gene regulation more generally. In this review, we summarize our understanding of how cold temperature induces a switch in the FLC chromatin state, and how this state is epigenetically remembered. We also discuss how the epigenetic state of FLC is reprogrammed in the seed to ensure a requirement for cold exposure in the next generation. Significance Statement FLOWERING LOCUS C (FLC) regulation provides a paradigm for understanding how chromatin can be modulated to determine gene expression in a developmental context. This review describes our current mechanistic understanding of how FLC expression is genetically specified and epigenetically regulated throughout the plant life cycle, and how this determines plant life-history strategy. PMID:25929799
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Epigenetic influences of low-dose bisphenol A in primary human breast epithelial cells
DOE Office of Scientific and Technical Information (OSTI.GOV)
Weng, Yu-I; Hsu, Pei-Yin; Liyanarachchi, Sandya
Substantial evidence indicates that exposure to bisphenol A (BPA) during early development may increase breast cancer risk later in life. The changes may persist into puberty and adulthood, suggesting an epigenetic process being imposed in differentiated breast epithelial cells. The molecular mechanisms by which early memory of BPA exposure is imprinted in breast progenitor cells and then passed onto their epithelial progeny are not well understood. The aim of this study was to examine epigenetic changes in breast epithelial cells treated with low-dose BPA. We also investigated the effect of BPA on the ER{alpha} signaling pathway and global gene expressionmore » profiles. Compared to control cells, nuclear internalization of ER{alpha} was observed in epithelial cells preexposed to BPA. We identified 170 genes with similar expression changes in response to BPA. Functional analysis confirms that gene suppression was mediated in part through an ER{alpha}-dependent pathway. As a result of exposure to BPA or other estrogen-like chemicals, the expression of lysosomal-associated membrane protein 3 (LAMP3) became epigenetically silenced in breast epithelial cells. Furthermore, increased DNA methylation in the LAMP3 CpG island was this repressive mark preferentially occurred in ER{alpha}-positive breast tumors. These results suggest that the in vitro system developed in our laboratory is a valuable tool for exposure studies of BPA and other xenoestrogens in human cells. Individual and geographical differences may contribute to altered patterns of gene expression and DNA methylation in susceptible loci. Combination of our exposure model with epigenetic analysis and other biochemical assays can give insight into the heritable effect of low-dose BPA in human cells.« less
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Inheritable Silencing of Endogenous Genes by Hit-and-Run Targeted Epigenetic Editing.
Amabile, Angelo; Migliara, Alessandro; Capasso, Paola; Biffi, Mauro; Cittaro, Davide; Naldini, Luigi; Lombardo, Angelo
2016-09-22
Gene silencing is instrumental to interrogate gene function and holds promise for therapeutic applications. Here, we repurpose the endogenous retroviruses' silencing machinery of embryonic stem cells to stably silence three highly expressed genes in somatic cells by epigenetics. This was achieved by transiently expressing combinations of engineered transcriptional repressors that bind to and synergize at the target locus to instruct repressive histone marks and de novo DNA methylation, thus ensuring long-term memory of the repressive epigenetic state. Silencing was highly specific, as shown by genome-wide analyses, sharply confined to the targeted locus without spreading to nearby genes, resistant to activation induced by cytokine stimulation, and relieved only by targeted DNA demethylation. We demonstrate the portability of this technology by multiplex gene silencing, adopting different DNA binding platforms and interrogating thousands of genomic loci in different cell types, including primary T lymphocytes. Targeted epigenome editing might have broad application in research and medicine. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.
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Role of human oocyte-enriched factors in somatic cell reprograming.
El-Gammal, Zaynab; AlOkda, Abdelrahman; El-Badri, Nagwa
2018-06-08
Cellular reprograming paves the way for creating functional patient-specific tissues to eliminate immune rejection responses by applying the same genetic profile. However, the epigenetic memory of a cell remains a challenge facing the current reprograming methods and does not allow transcription factors to bind properly. Because somatic cells can be reprogramed by transferring their nuclear contents into oocytes, introducing specific oocyte factors into differentiated cells is considered a promising approach for mimicking the reprograming process that occurs during fertilization. Mammalian metaphase II oocyte possesses a superior capacity to epigenetically reprogram somatic cell nuclei towards an embryonic stem cell-like state than the current factor-based reprograming approaches. This may be due to the presence of specific factors that are lacking in the current factor-based reprograming approaches. In this review, we focus on studies identifying human oocyte-enriched factors aiming to understand the molecular mechanisms mediating cellular reprograming. We describe the role of oocyte-enriched factors in metabolic switch, chromatin remodelling, and global epigenetic transformation. This is critical for improving the quality of resulting reprogramed cells, which is crucial for therapeutic applications. Copyright © 2018 Elsevier B.V. All rights reserved.
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[Pain and emotional dysregulation: Cellular memory due to pain].
Narita, Minoru; Watanabe, Moe; Hamada, Yusuke; Tamura, Hideki; Ikegami, Daigo; Kuzumaki, Naoko; Igarashi, Katsuhide
2015-08-01
Genetic factors are involved in determinants for the risk of psychiatric disorders, and neurological and neurodegenerative diseases. Chronic pain stimuli and intense pain have effects at a cellular and/or gene expression level, and will eventually induce "cellular memory due to pain", which means that tissue damage, even if only transient, can elicit epigenetically abnormal transcription/translation and post-translational modification in related cells depending on the degree or kind of injury or associated conditions. Such cell memory/transformation due to pain can cause an abnormality in a fundamental intracellular response, such as a change in the three-dimensional structure of DNA, transcription, or translation. On the other hand, pain is a multidimensional experience with sensory-discriminative and motivational-affective components. Recent human brain imaging studies have examined differences in activity in the nucleus accumbens between controls and patients with chronic pain, and have revealed that the nucleus accumbens plays a role in predicting the value of a noxious stimulus and its offset, and in the consequent changes in the motivational state. In this review, we provide a very brief overview of a comprehensive understanding of chronic pain associated with emotional dysregulation due to transcriptional regulation, epigenetic modification and miRNA regulation.
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Marasca, Federica; Bodega, Beatrice; Orlando, Valerio
2018-04-01
Cells and tissues are continuously exposed to a changing microenvironment, hence the necessity of a flexible modulation of gene expression that in complex organism have been achieved through specialized chromatin mechanisms. Chromatin-based cell memory enables cells to maintain their identity by fixing lineage specific transcriptional programs, ensuring their faithful transmission through cell division; in particular PcG-based memory system evolved to maintain the silenced state of developmental and cell cycle genes. In evolution the complexity of this system have increased, particularly in vertebrates, indicating combinatorial and dynamic properties of Polycomb proteins, in some cases even overflowing outside the cell nucleus. Therefore, their function may not be limited to the imposition of rigid states of genetic programs, but on the ability to recognize signals and allow plastic transcriptional changes in response to different stimuli. Here, we discuss the most novel PcG mediated memory functions in facing and responding to the challenges posed by a fluctuating environment. © 2018 The Authors. BioEssays Published by WILEY Periodicals, Inc.
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Genomically Encoded Analog Memory with Precise In vivo DNA Writing in Living Cell Populations
Farzadfard, Fahim; Lu, Timothy K.
2014-01-01
Cellular memory is crucial to many natural biological processes and for sophisticated synthetic-biology applications. Existing cellular memories rely on epigenetic switches or recombinases, which are limited in scalability and recording capacity. Here, we use the DNA of living cell populations as genomic ‘tape recorders’ for the analog and distributed recording of long-term event histories. We describe a platform for generating single-stranded DNA (ssDNA) in vivo in response to arbitrary transcriptional signals. When co-expressed with a recombinase, these intracellularly expressed ssDNAs target specific genomic DNA addresses, resulting in precise mutations that accumulate in cell populations as a function of the magnitude and duration of the inputs. This platform could enable long-term cellular recorders for environmental and biomedical applications, biological state machines, and enhanced genome engineering strategies. PMID:25395541
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de la Paz Sanchez, Maria; Aceves-García, Pamela; Petrone, Emilio; Steckenborn, Stefan; Vega-León, Rosario; Álvarez-Buylla, Elena R; Garay-Arroyo, Adriana; García-Ponce, Berenice
2015-11-01
Current advances indicate that epigenetic mechanisms play important roles in the regulatory networks involved in plant developmental responses to environmental conditions. Hence, understanding the role of such components becomes crucial to understanding the mechanisms underlying the plasticity and variability of plant traits, and thus the ecology and evolution of plant development. We now know that important components of phenotypic variation may result from heritable and reversible epigenetic mechanisms without genetic alterations. The epigenetic factors Polycomb group (PcG) and Trithorax group (TrxG) are involved in developmental processes that respond to environmental signals, playing important roles in plant plasticity. In this review, we discuss current knowledge of TrxG and PcG functions in different developmental processes in response to internal and environmental cues and we also integrate the emerging evidence concerning their function in plant plasticity. Many such plastic responses rely on meristematic cell behavior, including stem cell niche maintenance, cellular reprogramming, flowering and dormancy as well as stress memory. This information will help to determine how to integrate the role of epigenetic regulation into models of gene regulatory networks, which have mostly included transcriptional interactions underlying various aspects of plant development and its plastic response to environmental conditions. © 2015 The Authors. New Phytologist © 2015 New Phytologist Trust.
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Epigenetic Changes in Diabetes and Cardiovascular Risk
Keating, Samuel T; Plutzky, Jorge; El-Osta, Assam
2016-01-01
Cardiovascular complications remain the leading causes of morbidity and premature mortality in patients with diabetes. Studies in humans and preclinical models demonstrate lasting gene expression changes in the vasculopathies initiated by previous exposure to high glucose concentrations and the associated overproduction of reactive oxygen species. The molecular signatures of chromatin architectures that sensitize the genome to these and other cardiometabolic risk factors of the diabetic milieu are increasingly implicated in the biologic memory underlying cardiovascular complications and now widely considered as promising therapeutic targets. Atherosclerosis is a complex heterocellular disease where the contributing cell types possess distinct epigenomes shaping diverse gene expression. While the extent that pathological chromatin changes can be manipulated in human cardiovascular disease remains to be established, the clinical applicability of epigenetic interventions will be greatly advanced by a deeper understanding of the cell type-specific roles played by writers, erasers, and readers of chromatin modifications in the diabetic vasculature. This review details a current perspective of epigenetic mechanisms of macrovascular disease in diabetes, and highlights recent key descriptions of chromatinized changes associated with persistent gene expression in endothelial, smooth muscle, and circulating immune cells relevant to atherosclerosis. Furthermore we discuss the challenges associated with pharmacological targeting of epigenetic networks to correct abnormal or deregulated gene expression as a strategy to alleviate the clinical burden of diabetic cardiovascular disease. PMID:27230637
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BETAINE PREVENTS MALLORY-DENK BODY FORMATION IN DRUG-PRIMED MICE BY EPIGENETIC MECHANISMS
Oliva, Joan; Bardag-Gorce, Fawzia; Li, Jun; French, Barbara A; Nguyen, Sheila K.; Lu, Shelly C.; French, Samuel W.
2012-01-01
Previous studies showed that S-Adenosylmethionine (SAMe) prevented MDB formation and the hypomethylation of histones induced by DDC feeding. These results suggest that formation of MDBs is an epigenetic phenomenon. To further test this theory, drug-primed mice were fed the methyl donor, betaine, together with DDC, which was refed for 7 days. Betaine significantly reduced MDB formation, decreased the liver/body weight ratio and decreased the number of FAT10 positive liver cells when they proliferate in response to DDC refeeding. Betaine also significantly prevented the decreased expression of BHMT, AHCY, MAT1a and GNMT and the increased expression of MTHFR, caused by DDC refeeding. S-Adenosylhomocysteine (SAH) levels were reduced by DDC refeeding and this was prevented by betaine. The results support the concept that betaine donates methyl groups, increasing methionine available in the cell. SAMe metabolism was reduced by the decrease in GNMT expression, which prevented the conversion of SAMe to SAH. As a consequence, betaine prevented MDB formation and FAT10 positive cell proliferation by blocking the epigenetic memory expressed by hepatocytes. The results further support the concept that MDB formation is the result of an epigenetic phenomenon, where a change in methionine metabolism causes global gene expression changes in hepatocytes. PMID:19073172
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Epigenetic Characteristics of the Mitotic Chromosome in 1D and 3D
Oomen, Marlies E.; Dekker, Job
2017-01-01
While chromatin characteristics in interphase are widely studied, characteristics of mitotic chromatin and their inheritance through mitosis are still poorly understood. During mitosis chromatin undergoes dramatic changes: Transcription stalls, chromatin binding factors leave the chromatin, histone modifications change and chromatin becomes highly condensed. Many key insights into mitotic chromosome state and conformation have come from extensive microscopy studies over the last century. Over the last decade the development of 3C-based techniques has enabled the study of higher order chromosome organization during mitosis in a genome-wide manner. During mitosis chromosomes lose their cell type specific and locus-dependent chromatin organization that characterizes interphase chromatin and fold into randomly positioned loop arrays. Upon exit of mitosis cells are capable of quickly rearranging the chromosome conformation to form the cell type specific interphase organization again. The information that enables this rearrangement after mitotic exit is thought to be encoded at least in part in mitotic bookmarks, e.g. histone modifications and variants, histone remodelers, chromatin factors and non-coding RNA. Here we give an overview of the chromosomal organization and epigenetic characteristics of the interphase and mitotic chromatin in vertebrates. Second, we describe different ways in which mitotic bookmarking enables epigenetic memory of the features of the interphase chromatin through mitosis. And third, we explore the role of epigenetic modifications and mitotic bookmarking in cell differentiation. PMID:28228067
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Epigenetic dysregulation of epstein-barr virus latency and development of autoimmune disease.
Niller, Hans Helmut; Wolf, Hans; Ay, Eva; Minarovits, Janos
2011-01-01
Epstein-Barr virus (EBV) is ahumanherpesvirus thatpersists in the memory B-cells of the majority of the world population in a latent form. Primary EBV infection is asymptomatic or causes a self-limiting disease, infectious mononucleosis. Virus latency is associated with a wide variety of neoplasms whereof some occur in immune suppressed individuals. Virus production does not occur in strict latency. The expression of latent viral oncoproteins and nontranslated RNAs is under epigenetic control via DNA methylation and histone modifications that results either in a complete silencing of the EBV genome in memory B cells, or in a cell-type dependent usage of a couple of latency promoters in tumor cells, germinal center B cells and lymphoblastoid cells (LCL, transformed by EBV in vitro). Both, latent and lytic EBV proteins elicit a strong immune response. In immune suppressed and infectious mononucleosis patients, an increased viral load can be detected in the blood. Enhanced lytic replication may result in new infection- and transformation-events and thus is a risk factor both for malignant transformation and the development of autoimmune diseases. An increased viral load or a changed presentation of a subset of lytic or latent EBV proteins that cross-react with cellular antigens may trigger pathogenic processes through molecular mimicry that result in multiple sclerosis (MS), systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA).
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Mosaic epigenetic dysregulation of ectodermal cells in autism spectrum disorder.
Berko, Esther R; Suzuki, Masako; Beren, Faygel; Lemetre, Christophe; Alaimo, Christine M; Calder, R Brent; Ballaban-Gil, Karen; Gounder, Batya; Kampf, Kaylee; Kirschen, Jill; Maqbool, Shahina B; Momin, Zeineen; Reynolds, David M; Russo, Natalie; Shulman, Lisa; Stasiek, Edyta; Tozour, Jessica; Valicenti-McDermott, Maria; Wang, Shenglong; Abrahams, Brett S; Hargitai, Joseph; Inbar, Dov; Zhang, Zhengdong; Buxbaum, Joseph D; Molholm, Sophie; Foxe, John J; Marion, Robert W; Auton, Adam; Greally, John M
2014-01-01
DNA mutational events are increasingly being identified in autism spectrum disorder (ASD), but the potential additional role of dysregulation of the epigenome in the pathogenesis of the condition remains unclear. The epigenome is of interest as a possible mediator of environmental effects during development, encoding a cellular memory reflected by altered function of progeny cells. Advanced maternal age (AMA) is associated with an increased risk of having a child with ASD for reasons that are not understood. To explore whether AMA involves covert aneuploidy or epigenetic dysregulation leading to ASD in the offspring, we tested a homogeneous ectodermal cell type from 47 individuals with ASD compared with 48 typically developing (TD) controls born to mothers of ≥35 years, using a quantitative genome-wide DNA methylation assay. We show that DNA methylation patterns are dysregulated in ectodermal cells in these individuals, having accounted for confounding effects due to subject age, sex and ancestral haplotype. We did not find mosaic aneuploidy or copy number variability to occur at differentially-methylated regions in these subjects. Of note, the loci with distinctive DNA methylation were found at genes expressed in the brain and encoding protein products significantly enriched for interactions with those produced by known ASD-causing genes, representing a perturbation by epigenomic dysregulation of the same networks compromised by DNA mutational mechanisms. The results indicate the presence of a mosaic subpopulation of epigenetically-dysregulated, ectodermally-derived cells in subjects with ASD. The epigenetic dysregulation observed in these ASD subjects born to older mothers may be associated with aging parental gametes, environmental influences during embryogenesis or could be the consequence of mutations of the chromatin regulatory genes increasingly implicated in ASD. The results indicate that epigenetic dysregulatory mechanisms may complement and interact with DNA mutations in the pathogenesis of the disorder.
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Shtrichman, R; Germanguz, I; Itskovitz-Eldor, J
2013-06-01
Human induced pluripotent stem cells (hiPSCs) have great potential as a robust source of progenitors for regenerative medicine. The novel technology also enables the derivation of patient-specific cells for applications to personalized medicine, such as for personal drug screening and toxicology. However, the biological characteristics of iPSCs are not yet fully understood and their similarity to human embryonic stem cells (hESCs) is still unresolved. Variations among iPSCs, resulting from their original tissue or cell source, and from the experimental protocols used for their derivation, significantly affect epigenetic properties and differentiation potential. Here we review the potential of iPSCs for regenerative and personalized medicine, and assess their expression pattern, epigenetic memory and differentiation capabilities in relation to their parental tissue source. We also summarize the patient-specific iPSCs that have been derived for applications in biological research and drug discovery; and review risks that must be overcome in order to use iPSC technology for clinical applications.
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Histone lysine methylation: critical regulator of memory and behavior.
Jarome, Timothy J; Lubin, Farah D
2013-01-01
Histone lysine methylation is a well-established transcriptional mechanism for the regulation of gene expression changes in eukaryotic cells and is now believed to function in neurons of the central nervous system to mediate the process of memory formation and behavior. In mature neurons, methylation of histone proteins can serve to both activate and repress gene transcription. This is in stark contrast to other epigenetic modifications, including histone acetylation and DNA methylation, which have largely been associated with one transcriptional state in the brain. In this review, we discuss the evidence for histone methylation mechanisms in the coordination of complex cognitive processes such as long-term memory formation and storage. In addition, we address the current literature highlighting the role of histone methylation in intellectual disability, addiction, schizophrenia, autism, depression, and neurodegeneration. Further, we discuss histone methylation within the context of other epigenetic modifications and the potential advantages of exploring this newly identified mechanism of cognition, emphasizing the possibility that this molecular process may provide an alternative locus for intervention in long-term psychopathologies that cannot be clearly linked to genes or environment alone.
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Mahan, Amy L.; Mou, Liping; Shah, Nirali; Hu, Jia Hua; Worley, Paul; Ressler, Kerry J.
2012-01-01
The consolidation of conditioned fear involves upregulation of genes necessary for long-term memory formation. An important question remains as to whether this results in part from epigenetic regulation and chromatin modulation. We examined whether homer1a, which is required for memory formation, is necessary for Pavlovian cued fear conditioning, whether it is downstream of BDNF - TrkB activation, and whether this pathway utilizes histone modifications for activity-dependent transcriptional regulation. We initially found that Homer1a ko mice exhibited deficits in cued fear conditioning (5 tone-shock presentations with 70 dB, 6kHz tones and 0.5s, 0.6mA footshocks). We then demonstrate that homer1a mRNA 1) increases after fear conditioning in vivo within both amygdala and hippocampus of wild type mice, 2) increases after BDNF application to primary hippocampal and amygdala cultures in vitro, and 3) these increases are dependent on transcription and MAPK signaling. Furthermore, using chromatin immunoprecipitation we found that both in vitro and in vivo manipulations result in decreases in homer1 promoter H3K9 methylation in amygdala cells but increases in homer1 promoter H3 acetylation in hippocampal cells. However no changes were observed in H4 acetylation or H3K27 dimethylation. Inhibition of H3 acetylation by sodium butyrate enhanced contextual but not cued fear conditioning and enhanced homer1 H3 acetylation in the hippocampus. These data provide evidence for dynamic epigenetic regulation of homer1a following BDNF-induced plasticity and during a BDNF-dependent learning process. Furthermore, upregulation of this gene may be regulated through distinct epigenetic modifications in the hippocampus and amygdala. PMID:22457511
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Farzadfard, Fahim; Lu, Timothy K
2014-11-14
Cellular memory is crucial to many natural biological processes and sophisticated synthetic biology applications. Existing cellular memories rely on epigenetic switches or recombinases, which are limited in scalability and recording capacity. In this work, we use the DNA of living cell populations as genomic "tape recorders" for the analog and distributed recording of long-term event histories. We describe a platform for generating single-stranded DNA (ssDNA) in vivo in response to arbitrary transcriptional signals. When coexpressed with a recombinase, these intracellularly expressed ssDNAs target specific genomic DNA addresses, resulting in precise mutations that accumulate in cell populations as a function of the magnitude and duration of the inputs. This platform could enable long-term cellular recorders for environmental and biomedical applications, biological state machines, and enhanced genome engineering strategies. Copyright © 2014, American Association for the Advancement of Science.
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Epigenetic Memory as a Basis for Intelligent Behavior in Clonal Plants.
Latzel, Vít; Rendina González, Alejandra P; Rosenthal, Jonathan
2016-01-01
Environmentally induced epigenetic change enables plants to remember past environmental interactions. If this memory capability is exploited to prepare plants for future challenges, it can provide a basis for highly sophisticated behavior, considered intelligent by some. Against the backdrop of an overview of plant intelligence, we hypothesize: (1) that the capability of plants to engage in such intelligent behavior increases with the additional level of complexity afforded by clonality, and; (2) that more faithful inheritance of epigenetic information in clonal plants, in conjunction with information exchange and coordination between connected ramets, is likely to enable especially advanced intelligent behavior in this group. We therefore further hypothesize that this behavior provides ecological and evolutionary advantages to clonal plants, possibly explaining, at least in part, their widespread success. Finally, we suggest avenues of inquiry to enable assessing intelligent behavior and the role of epigenetic memory in clonal species.
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Epigenetics in women's health care.
Pozharny, Yevgeniya; Lambertini, Luca; Clunie, Garfield; Ferrara, Lauren; Lee, Men-Jean
2010-01-01
Epigenetics refers to structural modifications to genes that do not change the nucleotide sequence itself but instead control and regulate gene expression. DNA methylation, histone modification, and RNA regulation are some of the mechanisms involved in epigenetic modification. Epigenetic changes are believed to be a result of changes in an organism's environment that result in fixed and permanent changes in most differentiated cells. Some environmental changes that have been linked to epigenetic changes include starvation, folic acid, and various chemical exposures. There are periods in an organism's life cycle in which the organism is particularly susceptible to epigenetic influences; these include fertilization, gametogenesis, and early embryo development. These are also windows of opportunity for interventions during the reproductive life cycle of women to improve maternal-child health. New data suggest that epigenetic influences might be involved in the regulation of fetal development and the pathophysiology of adult diseases such as cancer, diabetes, obesity, and neurodevelopmental disorders. Various epigenetic mechanisms may also be involved in the pathogenesis of preeclampsia and intrauterine growth restriction. Additionally, environmental exposures are being held responsible for causing epigenetic changes that lead to a disease process. Exposure to heavy metals, bioflavonoids, and endocrine disruptors, such as bisphenol A and phthalates, has been shown to affect the epigenetic memory of an organism. Their long-term effects are unclear at this point, but many ongoing studies are attempting to elucidate the pathophysiological effects of such gene-environment interactions. (c) 2010 Mount Sinai School of Medicine.
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Epigenetic gene regulation in the adult mammalian brain: multiple roles in memory formation.
Lubin, Farah D
2011-07-01
Brain-derived neurotrophic factor (bdnf) is one of numerous gene products necessary for long-term memory formation and dysregulation of bdnf has been implicated in the pathogenesis of cognitive and mental disorders. Recent work indicates that epigenetic-regulatory mechanisms including the markings of histone proteins and associated DNA remain labile throughout the life-span and represent an attractive molecular process contributing to gene regulation in the brain. In this review, important information will be discussed on epigenetics as a set of newly identified dynamic transcriptional mechanisms serving to regulate gene expression changes in the adult brain with particular emphasis on bdnf transcriptional readout in learning and memory formation. This review will also highlight evidence for the role of epigenetics in aberrant bdnf gene regulation in the pathogenesis of cognitive dysfunction associated with seizure disorders, Rett syndrome, Schizophrenia, and Alzheimer's disease. Such research offers novel concepts for understanding epigenetic transcriptional mechanisms subserving adult cognition and mental health, and furthermore promises novel avenues for therapeutic approach in the clinic. Copyright © 2011 Elsevier Inc. All rights reserved.
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Epigenetic changes in solid and hematopoietic tumors.
Toyota, Minoru; Issa, Jean-Pierre J
2005-10-01
There are three connected molecular mechanisms of epigenetic cellular memory in mammalian cells: DNA methylation, histone modifications, and RNA interference. The first two have now been firmly linked to neoplastic transformation. Hypermethylation of CpG-rich promoters triggers local histone code modifications resulting in a cellular camouflage mechanism that sequesters gene promoters away from transcription factors and results in stable silencing. This normally restricted mechanism is ubiquitously used in cancer to silence hundreds of genes, among which some critically contribute to the neoplastic phenotype. Virtually every pathway important to cancer formation is affected by this process. Methylation profiling of human cancers reveals tissue-specific epigenetic signatures, as well as tumor-specific signatures, reflecting in particular the presence of epigenetic instability in a subset of cancers affected by the CpG island methylator phenotype. Generally, methylation patterns can be traced to a tissue-specific, proliferation-dependent accumulation of aberrant promoter methylation in aging tissues, a process that can be accelerated by chronic inflammation and less well-defined mechanisms including, possibly, diet and genetic predisposition. The epigenetic machinery can also be altered in cancer by specific lesions in epigenetic effector genes, or by aberrant recruitment of these genes by mutant transcription factors and coactivators. Epigenetic patterns are proving clinically useful in human oncology via risk assessment, early detection, and prognostic classification. Pharmacologic manipulation of these patterns-epigenetic therapy-is also poised to change the way we treat cancer in the clinic.
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Kim, Jaekyoon; Tuscher, Jennifer J.; Fortress, Ashley M.
2015-01-01
Ample evidence has demonstrated that sex steroid hormones, such as the potent estrogen 17β-estradiol (E2), affect hippocampal morphology, plasticity, and memory in male and female rodents. Yet relatively few investigators who work with male subjects consider the effects of these hormones on learning and memory. This review describes the effects of E2 on hippocampal spinogenesis, neurogenesis, physiology, and memory, with particular attention paid to the effects of E2 in male rodents. The estrogen receptors, cell-signaling pathways, and epigenetic processes necessary for E2 to enhance memory in female rodents are also discussed in detail. Finally, practical considerations for working with female rodents are described for those investigators thinking of adding females to their experimental designs. PMID:26286657
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CD4+CD62L+ Central Memory T Cells Can Be Converted to Foxp3+ T Cells
Zhang, Xiaolong; Chang Li, Xian; Xiao, Xiang; Sun, Rui; Tian, Zhigang; Wei, Haiming
2013-01-01
The peripheral Foxp3+ Treg pool consists of naturally arising Treg (nTreg) and adaptive Treg cells (iTreg). It is well known that naive CD4+ T cells can be readily converted to Foxp3+ iTreg in vitro, and memory CD4+ T cells are resistant to conversion. In this study, we investigated the induction of Foxp3+ T cells from various CD4+ T-cell subsets in human peripheral blood. Though naive CD4+ T cells were readily converted to Foxp3+ T cells with TGF-β and IL-2 treatment in vitro, such Foxp3+ T cells did not express the memory marker CD45RO as do Foxp3+ T cells induced in the peripheral blood of Hepatitis B Virus (HBV) patients. Interestingly, a subset of human memory CD4+ T cells, defined as CD62L+ central memory T cells, could be induced by TGF-β to differentiate into Foxp3+ T cells. It is well known that Foxp3+ T cells derived from human CD4+CD25- T cells in vitro are lack suppressive functions. Our data about the suppressive functions of CD4+CD62L+ central memory T cell-derived Foxp3+ T cells support this conception, and an epigenetic analysis of these cells showed a similar methylation pattern in the FOXP3 Treg-specific demethylated region as the naive CD4+ T cell-derived Foxp3+ T cells. But further research showed that mouse CD4+ central memory T cells also could be induced to differentiate into Foxp3+ T cells, such Foxp3+ T cells could suppress the proliferation of effector T cells. Thus, our study identified CD4+CD62L+ central memory T cells as a novel potential source of iTreg. PMID:24155942
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Webb, William M; Sanchez, Richard G; Perez, Gabriella; Butler, Anderson A; Hauser, Rebecca M; Rich, Megan C; O'Bierne, Aidan L; Jarome, Timothy J; Lubin, Farah D
2017-07-01
Epigenetic mechanisms such as DNA methylation and histone methylation are critical regulators of gene transcription changes during memory consolidation. However, it is unknown how these epigenetic modifications coordinate control of gene expression following reactivation of a previously consolidated memory. Here, we found that retrieval of a recent contextual fear conditioned memory increased global levels of H3 lysine 4-trimethylation (H3K4me3) and DNA 5-hydroxymethylation (5hmC) in area CA1 of the dorsal hippocampus. Further experiments revealed increased levels of H3K4me3 and DNA 5hmC within a CpG-enriched coding region of the Npas4, but not c-fos, gene. Intriguingly, retrieval of a 30-day old memory increased H3K4me3 and DNA 5hmC levels at a CpG-enriched coding region of c-fos, but not Npas4, in the anterior cingulate cortex, suggesting that while these two epigenetic mechanisms co-occur following the retrieval of a recent or remote memory, their gene targets differ depending on the brain region. Additionally, we found that in vivo siRNA-mediated knockdown of the H3K4me3 methyltransferase Mll1 in CA1 abolished retrieval-induced increases in DNA 5hmC levels at the Npas4 gene, suggesting that H3K4me3 couples to DNA 5hmC mechanisms. Consistent with this, loss of Mll1 prevented retrieval-induced increases in Npas4 mRNA levels in CA1 and impaired fear memory. Collectively, these findings suggest an important link between histone methylation and DNA hydroxymethylation mechanisms in the epigenetic control of de novo gene transcription triggered by memory retrieval. Copyright © 2017 Elsevier Inc. All rights reserved.
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Regulation of germinal center responses and B-cell memory by the chromatin modifier MOZ.
Good-Jacobson, Kim L; Chen, Yunshun; Voss, Anne K; Smyth, Gordon K; Thomas, Tim; Tarlinton, David
2014-07-01
Memory B cells and long-lived bone marrow-resident plasma cells maintain humoral immunity. Little is known about the intrinsic mechanisms that are essential for forming memory B cells or endowing them with the ability to rapidly differentiate upon reexposure while maintaining the population over time. Histone modifications have been shown to regulate lymphocyte development, but their role in regulating differentiation and maintenance of B-cell subsets during an immune response is unclear. Using stage-specific deletion of monocytic leukemia zinc finger protein (MOZ), a histone acetyltransferase, we demonstrate that mutation of this chromatin modifier alters fate decisions in both primary and secondary responses. In the absence of MOZ, germinal center B cells were significantly impaired in their ability to generate dark zone centroblasts, with a concomitant decrease in both cell-cycle progression and BCL-6 expression. In contrast, there was increased differentiation to IgM and low-affinity IgG1(+) memory B cells. The lack of MOZ affected the functional outcome of humoral immune responses, with an increase in secondary germinal centers and a corresponding decrease in secondary high-affinity antibody-secreting cell formation. Therefore, these data provide strong evidence that manipulating epigenetic modifiers can regulate fate decisions during humoral responses, and thus could be targeted for therapeutic intervention.
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Footprints of the sun: memory of UV and light stress in plants
Müller-Xing, Ralf; Xing, Qian; Goodrich, Justin
2014-01-01
Sunlight provides the necessary energy for plant growth via photosynthesis but high light and particular its integral ultraviolet (UV) part causes stress potentially leading to serious damage to DNA, proteins, and other cellular components. Plants show adaptation to environmental stresses, sometimes referred to as “plant memory.” There is growing evidence that plants memorize exposure to biotic or abiotic stresses through epigenetic mechanisms at the cellular level. UV target genes such as CHALCONE SYNTHASE (CHS) respond immediately to UV treatment and studies of the recently identified UV-B receptor UV RESISTANCE LOCUS 8 (UVR8) confirm the expedite nature of UV signaling. Considering these findings, an UV memory seems redundant. However, several lines of evidence suggest that plants may develop an epigenetic memory of UV and light stress, but in comparison to other abiotic stresses there has been relatively little investigation. Here we summarize the state of knowledge about acclimation and adaptation of plants to UV light and discuss the possibility of chromatin based epigenetic memory. PMID:25278950
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Generalized nucleation and looping model for epigenetic memory of histone modifications
Erdel, Fabian; Greene, Eric C.
2016-01-01
Histone modifications can redistribute along the genome in a sequence-independent manner, giving rise to chromatin position effects and epigenetic memory. The underlying mechanisms shape the endogenous chromatin landscape and determine its response to ectopically targeted histone modifiers. Here, we simulate linear and looping-driven spreading of histone modifications and compare both models to recent experiments on histone methylation in fission yeast. We find that a generalized nucleation-and-looping mechanism describes key observations on engineered and endogenous methylation domains including intrinsic spatial confinement, independent regulation of domain size and memory, variegation in the absence of antagonists, and coexistence of short- and long-term memory at loci with weak and strong constitutive nucleation. These findings support a straightforward relationship between the biochemical properties of chromatin modifiers and the spatiotemporal modification pattern. The proposed mechanism gives rise to a phase diagram for cellular memory that may be generally applicable to explain epigenetic phenomena across different species. PMID:27382173
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Hiler, Daniel; Chen, Xiang; Hazen, Jennifer; Kupriyanov, Sergey; Carroll, Patrick A; Qu, Chunxu; Xu, Beisi; Johnson, Dianna; Griffiths, Lyra; Frase, Sharon; Rodriguez, Alberto R; Martin, Greg; Zhang, Jiakun; Jeon, Jongrye; Fan, Yiping; Finkelstein, David; Eisenman, Robert N; Baldwin, Kristin; Dyer, Michael A
2015-07-02
Cell-based therapies to treat retinal degeneration are now being tested in clinical trials. However, it is not known whether the source of stem cells is important for the production of differentiated cells suitable for transplantation. To test this, we generated induced pluripotent stem cells (iPSCs) from murine rod photoreceptors (r-iPSCs) and scored their ability to make retinae by using a standardized quantitative protocol called STEM-RET. We discovered that r-iPSCs more efficiently produced differentiated retinae than did embryonic stem cells (ESCs) or fibroblast-derived iPSCs (f-iPSCs). Retinae derived from f-iPSCs had fewer amacrine cells and other inner nuclear layer cells. Integrated epigenetic analysis showed that DNA methylation contributes to the defects in f-iPSC retinogenesis and that rod-specific CTCF insulator protein-binding sites may promote r-iPSC retinogenesis. Together, our data suggest that the source of stem cells is important for producing retinal neurons in three-dimensional (3D) organ cultures. Copyright © 2015 Elsevier Inc. All rights reserved.
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Vernalizing cold is registered digitally at FLC.
Angel, Andrew; Song, Jie; Yang, Hongchun; Questa, Julia I; Dean, Caroline; Howard, Martin
2015-03-31
A fundamental property of many organisms is an ability to sense, evaluate, and respond to environmental signals. In some situations, generation of an appropriate response requires long-term information storage. A classic example is vernalization, where plants quantitatively sense long-term cold and epigenetically store this cold-exposure information to regulate flowering time. In Arabidopsis thaliana, stable epigenetic memory of cold is digital: following long-term cold exposure, cells respond autonomously in an all-or-nothing fashion, with the fraction of cells that stably silence the floral repressor flowering locus C (FLC) increasing with the cold exposure duration. However, during cold exposure itself it is unknown whether vernalizing cold is registered at FLC in individual cells in an all-or-nothing (digital) manner or is continuously varying (analog). Using mathematical modeling, we found that analog registration of cold temperature is problematic due to impaired analog-to-digital conversion into stable memory. This disadvantage is particularly acute when responding to short cold periods, but is absent when cold temperatures are registered digitally at FLC. We tested this prediction experimentally, exposing plants to short periods of cold interrupted with even shorter warm breaks. For FLC expression, we found that the system responds similarly to both interrupted and uninterrupted cold, arguing for a digital mechanism integrating long-term temperature exposure.
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Vernalizing cold is registered digitally at FLC
Angel, Andrew; Song, Jie; Yang, Hongchun; Questa, Julia I.; Dean, Caroline; Howard, Martin
2015-01-01
A fundamental property of many organisms is an ability to sense, evaluate, and respond to environmental signals. In some situations, generation of an appropriate response requires long-term information storage. A classic example is vernalization, where plants quantitatively sense long-term cold and epigenetically store this cold-exposure information to regulate flowering time. In Arabidopsis thaliana, stable epigenetic memory of cold is digital: following long-term cold exposure, cells respond autonomously in an all-or-nothing fashion, with the fraction of cells that stably silence the floral repressor FLOWERING LOCUS C (FLC) increasing with the cold exposure duration. However, during cold exposure itself it is unknown whether vernalizing cold is registered at FLC in individual cells in an all-or-nothing (digital) manner or is continuously varying (analog). Using mathematical modeling, we found that analog registration of cold temperature is problematic due to impaired analog-to-digital conversion into stable memory. This disadvantage is particularly acute when responding to short cold periods, but is absent when cold temperatures are registered digitally at FLC. We tested this prediction experimentally, exposing plants to short periods of cold interrupted with even shorter warm breaks. For FLC expression, we found that the system responds similarly to both interrupted and uninterrupted cold, arguing for a digital mechanism integrating long-term temperature exposure. PMID:25775579
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Wang, Yonggang; Neumann, Melanie; Hansen, Katharina; Hong, Shuwhey M.; Kim, Sharon; Noble-Haeusslein, Linda J.
2011-01-01
Abstract The selective serotonin reuptake inhibitor fluoxetine induces hippocampal neurogenesis, stimulates maturation and synaptic plasticity of adult hippocampal neurons, and reduces motor/sensory and memory impairments in several CNS disorders. In the setting of traumatic brain injury (TBI), its effects on neuroplasticity and function have yet to be thoroughly investigated. Here we examined the efficacy of fluoxetine after a moderate to severe TBI, produced by a controlled cortical impact. Three days after TBI or sham surgery, mice were treated with fluoxetine (10 mg/kg/d) or vehicle for 4 weeks. To evaluate the effects of fluoxetine on neuroplasticity, hippocampal neurogenesis and epigenetic modification were studied. Stereologic analysis of the dentate gyrus revealed a significant increase in doublecortin-positive cells in brain-injured animals treated with fluoxetine relative to controls, a finding consistent with enhanced hippocampal neurogenesis. Epigenetic modifications, including an increase in histone 3 acetylation and induction of methyl-CpG-binding protein, a transcription factor involved in DNA methylation, were likewise seen by immunohistochemistry and quantitative Western immunoblots, respectively, in brain-injured animals treated with fluoxetine. To determine if fluoxetine improves neurological outcomes after TBI, gait function and spatial learning and memory were assessed by the CatWalk-assisted gait test and Barnes maze test, respectively. No differences in these parameters were seen between fluoxetine- and vehicle-treated animals. Thus while fluoxetine enhanced neuroplasticity in the hippocampus after TBI, its chronic administration did not restore locomotor function or ameliorate memory deficits. PMID:21175261
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Yakovlev, Igor A; Fossdal, Carl G
2017-01-01
Epigenetic memory in Norway spruce affects the timing of bud burst and bud set, vitally important adaptive traits for this long-lived forest species. Epigenetic memory is established in response to the temperature conditions during embryogenesis. Somatic embryogenesis at different epitype inducing (EpI) temperatures closely mimics the natural processes of epigenetic memory formation in seeds, giving rise to epigenetically different clonal plants in a reproducible and predictable manner, with respect to altered bud phenology. MicroRNAs (miRNAs) and other small non-coding RNAs (sRNAs) play an essential role in the regulation of plant gene expression and may affect this epigenetic mechanism. We used NGS sequencing and computational in silico methods to identify and profile conserved and novel miRNAs among small RNAs in embryogenic tissues of Norway spruce at three EpI temperatures (18, 23 and 28°C). We detected three predominant classes of sRNAs related to a length of 24 nt, followed by a 21-22 nt class and a third 31 nt class of sRNAs. More than 2100 different miRNAs within the prevailing length 21-22 nt were identified. Profiling these putative miRNAs allowed identification of 1053 highly expressed miRNAs, including 523 conserved and 530 novels. 654 of these miRNAs were found to be differentially expressed (DEM) depending on EpI temperature. For most DEMs, we defined their putative mRNA targets. The targets represented mostly by transcripts of multiple-repeats proteins, like TIR, NBS-LRR, PPR and TPR repeat, Clathrin/VPS proteins, Myb-like, AP2, etc. Notably, 124 DE miRNAs targeted 203 differentially expressed epigenetic regulators. Developing Norway spruce embryos possess a more complex sRNA structure than that reported for somatic tissues. A variety of the predicted miRNAs showed distinct EpI temperature dependent expression patterns. These putative EpI miRNAs target spruce genes with a wide range of functions, including genes known to be involved in epigenetic regulation, which in turn could provide a feedback process leading to the formation of epigenetic marks. We suggest that TIR, NBS and LRR domain containing proteins could fulfill more general functions for signal transduction from external environmental stimuli and conversion them into molecular response. Fine-tuning of the miRNA production likely participates in both developmental regulation and epigenetic memory formation in Norway spruce.
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Epigenetic Principles and Mechanisms Underlying Nervous System Functions in Health and Disease
Mehler, Mark F.
2009-01-01
Epigenetics and epigenomic medicine encompass a new science of brain and behavior that are already providing unique insights into the mechanisms underlying brain development, evolution, neuronal and network plasticity and homeostasis, senescence, the etiology of diverse neurological diseases and neural regenerative processes. Epigenetic mechanisms include DNA methylation, histone modifications, nucleosome repositioning, higher-order chromatin remodeling, non-coding RNAs, and RNA and DNA editing. RNA is centrally involved in directing these processes, implying that the transcriptional state of the cell is the primary determinant of epigenetic memory. This transcriptional state can be modified by internal and external cues affecting gene expression and post-transcriptional processing, but also by RNA and DNA editing through activity-dependent intracellular transport and modulation of RNAs and RNA regulatory supercomplexes, and through trans-neuronal and systemic trafficking of functional RNA subclasses. These integrated processes promote dynamic reorganization of nuclear architecture and the genomic landscape to modulate functional gene and neural networks with complex temporal and spatial trajectories. Epigenetics represents the long sought after molecular interface mediating gene-environmental interactions during critical periods throughout the lifecycle. The discipline of environmental epigenomics has begun to identify combinatorial profiles of environmental stressors modulating the latency, initiation and progression of specific neurological disorders, and more selective disease biomarkers and graded molecular responses to emerging therapeutic interventions. Pharmacoepigenomic therapies will promote accelerated recovery of impaired and seemingly irrevocably lost cognitive, behavioral, sensorimotor functions through epigenetic reprogramming of endogenous regional neural stem cell fate decisions, targeted tissue remodeling and restoration of neural network integrity, plasticity and connectivity. PMID:18940229
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Rapid and reversible epigenome editing by endogenous chromatin regulators.
Braun, Simon M G; Kirkland, Jacob G; Chory, Emma J; Husmann, Dylan; Calarco, Joseph P; Crabtree, Gerald R
2017-09-15
Understanding the causal link between epigenetic marks and gene regulation remains a central question in chromatin biology. To edit the epigenome we developed the FIRE-Cas9 system for rapid and reversible recruitment of endogenous chromatin regulators to specific genomic loci. We enhanced the dCas9-MS2 anchor for genome targeting with Fkbp/Frb dimerizing fusion proteins to allow chemical-induced proximity of a desired chromatin regulator. We find that mSWI/SNF (BAF) complex recruitment is sufficient to oppose Polycomb within minutes, leading to activation of bivalent gene transcription in mouse embryonic stem cells. Furthermore, Hp1/Suv39h1 heterochromatin complex recruitment to active promoters deposits H3K9me3 domains, resulting in gene silencing that can be reversed upon washout of the chemical dimerizer. This inducible recruitment strategy provides precise kinetic information to model epigenetic memory and plasticity. It is broadly applicable to mechanistic studies of chromatin in mammalian cells and is particularly suited to the analysis of endogenous multi-subunit chromatin regulator complexes.Understanding the link between epigenetic marks and gene regulation requires the development of new tools to directly manipulate chromatin. Here the authors demonstrate a Cas9-based system to recruit chromatin remodelers to loci of interest, allowing rapid, reversible manipulation of epigenetic states.
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Is an epigenetic switch the key to persistent extinction?
Stafford, James M.; Lattal, K. Matthew
2011-01-01
Many studies of learning have demonstrated that conditioned behavior can be eliminated when previously established relations between stimuli are severed. This extinction process has been extremely important for the development of learning theories and, more recently, for delineating the neurobiological mechanisms that underlie memory. A key finding from behavioral studies of extinction is that extinction eliminates behavior without eliminating the original memory; extinguished behavior often returns with time or with a return to the context in which the original learning occurred. This persistence of the original memory after extinction creates a challenge for clinical applications that use extinction as part of a treatment intervention. Consequently, a goal of recent neurobiological research on extinction is to identify potential pharmacological targets that may result in persistent extinction. Drugs that promote epigenetic changes are particularly promising because they can result in a long-term molecular signal that, combined with the appropriate behavioral treatment, can cause persistent changes in behavior induced by extinction. We will review evidence demonstrating extinction enhancements by drugs that target epigenetic mechanisms and will describe some of the challenges that epigenetic approaches face in promoting persistent suppression of memories. PMID:21536141
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Epigenetic mechanisms in experience-driven memory formation and behavior.
Puckett, Rosemary E; Lubin, Farah D
2011-10-01
Epigenetic mechanisms have long been associated with the regulation of gene-expression changes accompanying normal neuronal development and cellular differentiation; however, until recently these mechanisms were believed to be statically quiet in the adult brain. Behavioral neuroscientists have now begun to investigate these epigenetic mechanisms as potential regulators of gene-transcription changes in the CNS subserving synaptic plasticity and long-term memory (LTM) formation. Experimental evidence from learning and memory animal models has demonstrated that active chromatin remodeling occurs in terminally differentiated postmitotic neurons, suggesting that these molecular processes are indeed intimately involved in several stages of LTM formation, including consolidation, reconsolidation and extinction. Such chromatin modifications include the phosphorylation, acetylation and methylation of histone proteins and the methylation of associated DNA to subsequently affect transcriptional gene readout triggered by learning. The present article examines how such learning-induced epigenetic changes contribute to LTM formation and influence behavior. In particular, this article is a survey of the specific epigenetic mechanisms that have been demonstrated to regulate gene expression for both transcription factors and growth factors in the CNS, which are critical for LTM formation and storage, as well as how aberrant epigenetic processing can contribute to psychological states such as schizophrenia and drug addiction. Together, the findings highlighted in this article support a novel role for epigenetic mechanisms in the adult CNS serving as potential key molecular regulators of gene-transcription changes necessary for LTM formation and adult behavior.
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Trained immunity: a program of innate immune memory in health and disease
Netea, Mihai G.; Joosten, Leo A.B.; Latz, Eicke; Mills, Kingston H.G.; Natoli, Gioacchino; Stunnenberg, Hendrik G.; O’Neill, Luke A.J.; Xavier, Ramnik J.
2016-01-01
The general view that only adaptive immunity can build immunological memory has recently been challenged. In organisms lacking adaptive immunity as well as in mammals, the innate immune system can mount resistance to reinfection, a phenomenon termed trained immunity or innate immune memory. Trained immunity is orchestrated by epigenetic reprogramming, broadly defined as sustained changes in gene expression and cell physiology that do not involve permanent genetic changes such as mutations and recombination, which are essential for adaptive immunity. The discovery of trained immunity may open the door for novel vaccine approaches, for new therapeutic strategies for the treatment of immune deficiency states, and for modulation of exaggerated inflammation in autoinflammatory diseases. PMID:27102489
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Adult Neurogenesis and Neurodegenerative Diseases: A Systems Biology Perspective
Horgusluoglu, Emrin; Nudelman, Kelly; Nho, Kwangsik; Saykin, Andrew J.
2016-01-01
New neurons are generated throughout adulthood in two regions of the brain, the olfactory bulb and dentate gyrus of the hippocampus, and are incorporated into the hippocampal network circuitry; disruption of this process has been postulated to contribute to neurodegenerative diseases including Alzheimer’s disease and Parkinson’s disease. Known modulators of adult neurogenesis include signal transduction pathways, the vascular and immune systems, metabolic factors, and epigenetic regulation. Multiple intrinsic and extrinsic factors such as neurotrophic factors, transcription factors, and cell cycle regulators control neural stem cell proliferation, maintenance in the adult neurogenic niche, and differentiation into mature neurons; these factors act in networks of signaling molecules that influence each other during construction and maintenance of neural circuits, and in turn contribute to learning and memory. The immune system and vascular system are necessary for neuronal formation and neural stem cell fate determination. Inflammatory cytokines regulate adult neurogenesis in response to immune system activation, whereas the vasculature regulates the neural stem cell niche. Vasculature, immune/support cell populations (microglia/astrocytes), adhesion molecules, growth factors, and the extracellular matrix also provide a homing environment for neural stem cells. Epigenetic changes during hippocampal neurogenesis also impact memory and learning. Some genetic variations in neurogenesis related genes may play important roles in the alteration of neural stem cells differentiation into new born neurons during adult neurogenesis, with important therapeutic implications. In this review, we discuss mechanisms of and interactions between these modulators of adult neurogenesis, as well as implications for neurodegenerative disease and current therapeutic research. PMID:26879907
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DNA methylation regulates neurophysiological spatial representation in memory formation
Roth, Eric D.; Roth, Tania L.; Money, Kelli M.; SenGupta, Sonda; Eason, Dawn E.; Sweatt, J. David
2015-01-01
Epigenetic mechanisms including altered DNA methylation are critical for altered gene transcription subserving synaptic plasticity and the retention of learned behavior. Here we tested the idea that one role for activity-dependent altered DNA methylation is stabilization of cognition-associated hippocampal place cell firing in response to novel place learning. We observed that a behavioral protocol (spatial exploration of a novel environment) known to induce hippocampal place cell remapping resulted in alterations of hippocampal Bdnf DNA methylation. Further studies using neurophysiological in vivo single unit recordings revealed that pharmacological manipulations of DNA methylation decreased long-term but not short-term place field stability. Together our data highlight a role for DNA methylation in regulating neurophysiological spatial representation and memory formation. PMID:25960947
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Alivand, Mohammad Reza; Soheili, Zahra-Soheila; Pornour, Majid; Solali, Saeed; Sabouni, Farzaneh
2017-10-01
CpG methylation of DNA takes part in a specific epigenetic memory that plays crucial roles in the differentiation and abnormality of the cells. The methylation pattern aberration of genomes is affected in three ways, namely DNA methyltransferase (DNMT), ten-eleven translocation (TET), and methyl-binding domain (MBD) proteins. Of these, TET enzymes have recently been demonstrated to be master modifier enzymes in the DNA methylation process. Additionally, recent studies emphasize that not only epigenetic phenomena play a role in controlling hypoxia pathway, but the hypoxia condition also triggers hypomethylation of genomes that may help with the expression of hypoxia pathway genes. In this study, we suggested that TET1 and TET2 could play a role in the demethylation of genomes under chemical hypoxia conditions. Herein, the evaluating methylation status and mRNA expression of mentioned genes were utilized through real-time PCR and methylation-specific PCR (MSP), respectively. Our results showed that TET1 and TET2 genes were overexpressed (P < 0.05) under chemical hypoxia conditions in Retinal Pigment Epithelial (RPE) cells, whereas the promoter methylation status of them were hypomethylated in the same condition. Therefore, chemical hypoxia not only causes overexpression of TET1 and TET2 but also could gradually do promoter demethylation of same genes. This is the first study to show the relationship between epigenetics and the expression of mentioned genes related to hypoxia pathways. Furthermore, it seems that these associations in RPE cells are subjected to chemical hypoxia as a mechanism that could play a crucial role in methylation pattern changes of hypoxia-related diseases such as cancer and ischemia. J. Cell. Biochem. 118: 3193-3204, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.
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Epigenetic Priming of Memory Updating during Reconsolidation to Attenuate Remote Fear Memories
Gräff, Johannes; Joseph, Nadine F.; Horn, Meryl E.; Samiei, Alireza; Meng, Jia; Seo, Jinsoo; Rei, Damien; Bero, Adam W.; Phan, Trongha X.; Wagner, Florence; Holson, Edward; Xu, Jinbin; Sun, Jianjun; Neve, Rachael L.; Mach, Robert H.; Haggarty, Stephen J.; Tsai, Li-Huei
2014-01-01
Summary Traumatic events generate some of the most enduring forms of memories. Despite the elevated lifetime prevalence of anxiety disorders, effective strategies to attenuate long-term traumatic memories are scarce. The most efficacious treatments to diminish recent (i.e., day-old) traumata capitalize on memory updating mechanisms during reconsolidation that are initiated upon memory recall. Here, we show that, in mice, successful reconsolidation-updating paradigms for recent memories fail to attenuate remote (i.e., month-old) ones. We find that, whereas recent memory recall induces a limited period of hippocampal neuroplasticity mediated, in part, by S-nitrosylation of HDAC2 and histone acetylation, such plasticity is absent for remote memories. However, by using an HDAC2-targeting inhibitor (HDACi) during reconsolidation, even remote memories can be persistently attenuated. This intervention epigenetically primes the expression of neuroplasticity-related genes, which is accompanied by higher metabolic, synaptic, and structural plasticity. Thus, applying HDACis during memory reconsolidation might constitute a treatment option for remote traumata. PMID:24439381
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Epigenetic events in plant male germ cell heat stress responses.
Chen, Yuanyuan; Müller, Florian; Rieu, Ivo; Winter, Peter
2016-06-01
A review on pollen epigenetics. Plants grow in an ever-changing environment and are used to environmental fluctuations such as high and low temperatures during their life cycles. To cope with adverse conditions, plants have evolved intricate short-term and long-term mechanisms to respond and adapt to external stresses. The plant's ability to respond to stresses largely depends on its capacity to modulate the transcriptome rapidly and specifically. Epigenetic mechanisms, including DNA methylation, chromatin dynamics and small RNAs, play an essential role in the regulation of stress-responsive gene expression. Stress-related covalent modifications of DNA and histones can be passed on during mitosis and meiosis to the next generation and provide a memory that enables the plant and even its offspring to adopt better to a subsequent stress. Plant reproduction, in particular pollen development, is the most stress-sensitive process in the life cycle of the organism. In particular, developmental stages around the meiotic and mitotic divisions are the most vulnerable. In this review, we highlight the current understanding of epigenetic mechanisms involved in pollen development and speculate on their roles in pollen heat stress response.
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Samiec, M; Skrzyszowska, M
2018-03-01
The efficiency of somatic cell cloning in mammals remains disappointingly low. Incomplete and aberrant reprogramming of epigenetic memory of somatic cell nuclei in preimplantation nuclear- transferred (NT) embryos is one of the most important factors that limit the cloning effectiveness. The extent of epigenetic genome-wide alterations, involving histone or DNA methylation and histone deacetylation, that are mediated by histone-lysine methyltransferases (HMTs) or DNA methyltransferases (DNMTs) and histone deacetylases (HDACs) can be modulated/reversed via exogenous inhibitors of these enzymes throughout in vitro culture of nuclear donor cells, nuclear recipient oocytes and/or cloned embryos. The use of the artificial modifiers of epigenomically-conditioned gene expression leads to inhibition of both chromatin condensation and transcriptional silencing the genomic DNA of somatic cells that provide a source of nuclear donors for reconstruction of enucleated oocytes and generation of cloned embryos. The onset of chromatin decondensation and gene transcriptional activity is evoked both through specific/selective inactivating HMTs by BIX-01294 and through non-specific/non-selective blocking the activity of either DNMTs by 5-aza-2'-deoxycytidine, zebularine, S-adenosylhomocysteine or HDACs by trichostatin A, valproic acid, scriptaid, oxamflatin, sodium butyrate, m-carboxycinnamic acid bishydroxamide, panobinostat, abexinostat, quisinostat, dacinostat, belinostat and psammaplin A. Epigenomic modulation of nuclear donor cells, nuclear recipient cells and/or cloned embryos may facilitate and accelerate the reprogrammability for gene expression of donor cell nuclei that have been transplanted into a host ooplasm and subsequently underwent dedifferentiating and re-establishing the epigenetically dependent status of their transcriptional activity during pre- and postimplantation development of NT embryos. Nevertheless, a comprehensive additional work is necessary to determine whether failures in the early-stage reprogramming of somatic cell-inherited genome are magnified downstream in development of cloned conceptuses and neonates. Copyright© by the Polish Academy of Sciences.
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Shang, Andrea; Bylipudi, Sooraz; Bieszczad, Kasia M
2018-05-31
Epigenetic mechanisms are key for regulating long-term memory (LTM) and are known to exert control on memory formation in multiple systems of the adult brain, including the sensory cortex. One epigenetic mechanism is chromatin modification by histone acetylation. Blocking the action of histone de-acetylases (HDACs) that normally negatively regulate LTM by repressing transcription has been shown to enable memory formation. Indeed, HDAC inhibition appears to facilitate memory by altering the dynamics of gene expression events important for memory consolidation. However, less understood are the ways in which molecular-level consolidation processes alter subsequent memory to enhance storage or facilitate retrieval. Here we used a sensory perspective to investigate whether the characteristics of memory formed with HDAC inhibitors are different from naturally-formed memory. One possibility is that HDAC inhibition enables memory to form with greater sensory detail than normal. Because the auditory system undergoes learning-induced remodeling that provides substrates for sound-specific LTM, we aimed to identify behavioral effects of HDAC inhibition on memory for specific sound features using a standard model of auditory associative cue-reward learning, memory, and cortical plasticity. We found that three systemic post-training treatments of an HDAC3-inhibitor (RGPF966, Abcam Inc.) in rats in the early phase of training facilitated auditory discriminative learning, changed auditory cortical tuning, and increased the specificity for acoustic frequency formed in memory of both excitatory (S+) and inhibitory (S-) associations for at least 2 weeks. The findings support that epigenetic mechanisms act on neural and behavioral sensory acuity to increase the precision of associative cue memory, which can be revealed by studying the sensory characteristics of long-term associative memory formation with HDAC inhibitors. Published by Elsevier B.V.
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Wang, Wei-Sheng; Kang, Shuo; Liu, Wen-Tao; Li, Mu; Liu, Yao; Yu, Chuan; Chen, Jie; Chi, Zhi-Qiang; He, Ling; Liu, Jing-Gen
2012-10-03
Recent evidence suggests that histone deacetylase (HDAC) inhibitors facilitate extinction of rewarding memory of drug taking. However, little is known about the role of chromatin modification in the extinction of aversive memory of drug withdrawal. In this study, we used conditioned place aversion (CPA), a highly sensitive model for measuring aversive memory of drug withdrawal, to investigate the role of epigenetic regulation of brain-derived neurotrophic factor (BDNF) gene expression in extinction of aversive memory. We found that CPA extinction training induced an increase in recruiting cAMP response element-binding protein (CREB) to and acetylation of histone H3 at the promoters of BDNF exon I transcript and increased BDNF mRNA and protein expression in the ventromedial prefrontal cortex (vmPFC) of acute morphine-dependent rats and that such epigenetic regulation of BDNF gene transcription could be facilitated or diminished by intra-vmPFC infusion of HDAC inhibitor trichostatin A or extracellular signal-regulated kinase (ERK) inhibitor U0126 (1,4-diamino-2,3-dicyano-1,4-bis(methylthio)butadiene) before extinction training. Correspondingly, disruption of the epigenetic regulation of BDNF gene transcription with U0126 or suppression of BDNF signaling with Trk receptor antagonist K252a or BDNF scavenger tyrosine kinase receptor B (TrkB)-Fc blocked extinction of CPA behavior. We also found that extinction training-induced activation of ERK and CREB and extinction of CPA behavior could be potentiated or suppressed by intra-vmPFC infusion of d-cycloserine, a NMDA receptor partial agonist or aminophosphonopentanoic acid, a NMDA receptor antagonist. We conclude that extinction of aversive memory of morphine withdrawal requires epigenetic regulation of BDNF gene transcription in the vmPFC through activation of the ERK-CREB signaling pathway perhaps in a NMDA receptor-dependent manner.
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Dnmts and Tet target memory-associated genes after appetitive olfactory training in honey bees
Biergans, Stephanie D.; Giovanni Galizia, C.; Reinhard, Judith; Claudianos, Charles
2015-01-01
DNA methylation and demethylation are epigenetic mechanisms involved in memory formation. In honey bees DNA methyltransferase (Dnmt) function is necessary for long-term memory to be stimulus specific (i.e. to reduce generalization). So far, however, it remains elusive which genes are targeted and what the time-course of DNA methylation is during memory formation. Here, we analyse how DNA methylation affects memory retention, gene expression, and differential methylation in stimulus-specific olfactory long-term memory formation. Out of 30 memory-associated genes investigated here, 9 were upregulated following Dnmt inhibition in trained bees. These included Dnmt3 suggesting a negative feedback loop for DNA methylation. Within these genes also the DNA methylation pattern changed during the first 24 hours after training. Interestingly, this was accompanied by sequential activation of the DNA methylation machinery (i.e. Dnmts and Tet). In sum, memory formation involves a temporally complex epigenetic regulation of memory-associated genes that facilitates stimulus specific long-term memory in the honey bee. PMID:26531238
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A comparative approach to the principal mechanisms of different memory systems
NASA Astrophysics Data System (ADS)
Rensing, Ludger; Koch, Michael; Becker, Annette
2009-12-01
The term “memory” applies not only to the preservation of information in neuronal and immune systems but also to phenomena observed for example in plants, single cells, and RNA viruses. We here compare the different forms of information storage with respect to possible common features. The latter may be characterized by (1) selection of pre-existing information, (2) activation of memory systems often including transcriptional, and translational, as well as epigenetic and genetic mechanisms, (3) subsequent consolidation of the activated state in a latent form ( standby mode), and (4) reactivation of the latent state of memory systems when the organism is exposed to the same (or conditioned) signal or to previous selective constraints. These features apparently also exist in the “evolutionary memory,” i.e., in evolving populations which have highly variable mutant spectra.
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Leontovich, Alexey A; Intine, Robert V; Sarras, Michael P
2016-01-01
Metabolic memory (MM) is defined as the persistence of diabetic (DM) complications even after glycemic control is pharmacologically achieved. Using a zebrafish diabetic model that induces a MM state, we previously reported that, in this model, tissue dysfunction was of a heritable nature based on cell proliferation studies in limb tissue and this correlated with epigenetic DNA methylation changes that paralleled alterations in gene expression. In the current study, control, DM, and MM excised fin tissues were further analyzed by MeDIP sequencing and microarray techniques. Bioinformatics analysis of the data found that genes of the DNA replication/DNA metabolism process group (with upregulation of the apex1, mcm2, mcm4, orc3, lig1, and dnmt1 genes) were altered in the DM state and these molecular changes continued into MM. Interestingly, DNA methylation changes could be found as far as 6-13 kb upstream of the transcription start site for these genes suggesting potential higher levels of epigenetic control. In conclusion, DNA methylation changes in members of the DNA replication/repair process group best explain the heritable nature of cell proliferation impairment found in the zebrafish DM/MM model. These results are consistent with human diabetic epigenetic studies and provide one explanation for the persistence of long term tissue complications as seen in diabetes.
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Lämke, Jörn; Bäurle, Isabel
2017-06-27
Plants frequently have to weather both biotic and abiotic stressors, and have evolved sophisticated adaptation and defense mechanisms. In recent years, chromatin modifications, nucleosome positioning, and DNA methylation have been recognized as important components in these adaptations. Given their potential epigenetic nature, such modifications may provide a mechanistic basis for a stress memory, enabling plants to respond more efficiently to recurring stress or even to prepare their offspring for potential future assaults. In this review, we discuss both the involvement of chromatin in stress responses and the current evidence on somatic, intergenerational, and transgenerational stress memory.
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Srivas, Sweta; Thakur, Mahendra K
2017-09-01
Recently, we reported a correlation of scopolamine mediated decline in memory consolidation with increase in the expression of DNA methyltransferase 1 (DNMT1) and histone deacetylase 2 (HDAC2) in the mouse hippocampus. Memory consolidation is a protein synthesis-dependent process which involves the expression of synaptic plasticity genes, particularly neuronal immediate early genes (IEGs). However, the mechanism of regulation of these genes during decline in memory is poorly understood. Therefore, we have studied the epigenetic regulation of expression of neuronal IEGs in scopolamine-induced amnesic mice. Scopolamine significantly impaired memory consolidation as tested by radial arm maze, and the expression of neuronal IEGs was downregulated in the hippocampus as revealed by qRT-PCR and Western blotting. Further, methylated DNA immunoprecipitation (MeDIP) analysis showed increase in DNA methylation, while chromatin immunoprecipitation (ChIP) revealed decrease in H3K9/14 acetylation at the promoter of neuronal IEGs. Taken together, the present study shows that increased DNA methylation and decreased histone acetylation at the promoter of neuronal IEGs are associated with decline in their expression and memory consolidation during scopolamine-induced amnesia. These findings suggest that the epigenetic regulation through altered DNA methylation and histone acetylation might be explored further to develop potential therapeutic interventions for amnesia.
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Advancing neuroscience through epigenetics: molecular mechanisms of learning and memory.
Molfese, David L
2011-01-01
Humans share 96% of our 30,000 genes with Chimpanzees. The 1,200 genes that differ appear at first glance insufficient to describe what makes us human and them apes. However, we are now discovering that the mechanisms that regulate how genes are expressed tell a much richer story than our DNA alone. Sections of our DNA are constantly being turned on or off, marked for easy access, or secluded and hidden away, all in response to ongoing cellular activity. In the brain, neurons encode information-in effect memories-at the cellular level. Yet while memories may last a lifetime, neurons are dynamic structures. Every protein in the synapse undergoes some form of turnover, some with half-lives of only hours. How can a memory persist beyond the lifetimes of its constitutive molecular building blocks? Epigenetics-changes in gene expression that do not alter the underlying DNA sequence-may be the answer. In this article, epigenetic mechanisms including DNA methylation and acetylation or methylation of the histone proteins that package DNA are described in the context of animal learning. Through the interaction of these modifications a "histone code" is emerging wherein individual memories leave unique memory traces at the molecular level with distinct time courses. A better understanding of these mechanisms has implications for treatment of memory disorders caused by normal aging or diseases including schizophrenia, Alzheimer's, depression, and drug addiction.
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Bioelectric memory: modeling resting potential bistability in amphibian embryos and mammalian cells.
Law, Robert; Levin, Michael
2015-10-15
Bioelectric gradients among all cells, not just within excitable nerve and muscle, play instructive roles in developmental and regenerative pattern formation. Plasma membrane resting potential gradients regulate cell behaviors by regulating downstream transcriptional and epigenetic events. Unlike neurons, which fire rapidly and typically return to the same polarized state, developmental bioelectric signaling involves many cell types stably maintaining various levels of resting potential during morphogenetic events. It is important to begin to quantitatively model the stability of bioelectric states in cells, to understand computation and pattern maintenance during regeneration and remodeling. To facilitate the analysis of endogenous bioelectric signaling and the exploitation of voltage-based cellular controls in synthetic bioengineering applications, we sought to understand the conditions under which somatic cells can stably maintain distinct resting potential values (a type of state memory). Using the Channelpedia ion channel database, we generated an array of amphibian oocyte and mammalian membrane models for voltage evolution. These models were analyzed and searched, by simulation, for a simple dynamical property, multistability, which forms a type of voltage memory. We find that typical mammalian models and amphibian oocyte models exhibit bistability when expressing different ion channel subsets, with either persistent sodium or inward-rectifying potassium, respectively, playing a facilitative role in bistable memory formation. We illustrate this difference using fast sodium channel dynamics for which a comprehensive theory exists, where the same model exhibits bistability under mammalian conditions but not amphibian conditions. In amphibians, potassium channels from the Kv1.x and Kv2.x families tend to disrupt this bistable memory formation. We also identify some common principles under which physiological memory emerges, which suggest specific strategies for implementing memories in bioengineering contexts. Our results reveal conditions under which cells can stably maintain one of several resting voltage potential values. These models suggest testable predictions for experiments in developmental bioelectricity, and illustrate how cells can be used as versatile physiological memory elements in synthetic biology, and unconventional computation contexts.
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Specifying and protecting germ cell fate
Strome, Susan; Updike, Dustin
2015-01-01
Germ cells are the special cells in the body that undergo meiosis to generate gametes and subsequently entire new organisms after fertilization, a process that continues generation after generation. Recent studies have expanded our understanding of the factors and mechanisms that specify germ cell fate, including the partitioning of maternally supplied ‘germ plasm’, inheritance of epigenetic memory and expression of transcription factors crucial for primordial germ cell (PGC) development. Even after PGCs are specified, germline fate is labile and thus requires protective mechanisms, such as global transcriptional repression, chromatin state alteration and translation of only germline-appropriate transcripts. Findings from diverse species continue to provide insights into the shared and divergent needs of these special reproductive cells. PMID:26122616
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Learning and memory: Steroids and epigenetics.
Colciago, Alessandra; Casati, Lavinia; Negri-Cesi, Paola; Celotti, Fabio
2015-06-01
Memory formation and utilization is a complex process involving several brain structures in conjunction as the hippocampus, the amygdala and the adjacent cortical areas, usually defined as medial temporal lobe structures (MTL). The memory processes depend on the formation and modulation of synaptic connectivity affecting synaptic strength, synaptic plasticity and synaptic consolidation. The basic neurocognitive mechanisms of learning and memory are shortly recalled in the initial section of this paper. The effect of sex hormones (estrogens, androgens and progesterone) and of adrenocortical steroids on several aspects of memory processes are then analyzed on the basis of animal and human studies. A specific attention has been devoted to the different types of steroid receptors (membrane or nuclear) involved and on local metabolic transformations when required. The review is concluded by a short excursus on the steroid activated epigenetic mechanisms involved in memory formation. Copyright © 2015 Elsevier Ltd. All rights reserved.
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Molecular Mechanisms of Induced Pluripotency
Muchkaeva, I.A.; Dashinimaev, E.B.; Terskikh, V.V.; Sukhanov, Y.V.; Vasiliev, A.V.
2012-01-01
In this review the distinct aspects of somatic cell reprogramming are discussed. The molecular mechanisms of generation of induced pluripotent stem (iPS) cells from somatic cells via the introduction of transcription factors into adult somatic cells are considered. Particular attention is focused on the generation of iPS cells without genome modifications via the introduction of the mRNA of transcription factors or the use of small molecules. Furthermore, the strategy of direct reprogramming of somatic cells omitting the generation of iPS cells is considered. The data concerning the differences between ES and iPS cells and the problem of epigenetic memory are also discussed. In conclusion, the possibility of using iPS cells in regenerative medicine is considered. PMID:22708059
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Kisliouk, Tatiana; Cramer, Tomer; Meiri, Noam
2017-05-01
Depending on its stringency, exposure to heat in early life leads to either resilience or vulnerability to heat stress later in life. We hypothesized that epigenetic alterations in genes belonging to the cell proteostasis pathways are attributed to long-term responses to heat stress. Epigenetic regulation of the mRNA expression of the molecular chaperone heat-shock protein (HSP) 70 (HSPA2) was evaluated in the chick hypothalamus during the critical period of thermal-control establishment on day 3 post-hatch and during heat challenge on day 10. Both the level and duration of HSP70 expression during heat challenge a week after heat conditioning were more pronounced in chicks conditioned under harsh versus mild temperature. Analyzing different segments of the promoter in vitro indicated that methylation of a distal part altered its transcriptional activity. In parallel, DNA-methylation level of this segment in vivo was higher in harsh- compared to mild-heat-conditioned chicks. Hypermethylation of the HSP70 promoter in high-temperature-conditioned chicks was accompanied by a reduction in both POU Class 2 Homeobox 1 (POU2F1) binding and recruitment of the nucleosome remodeling deacetylase (NuRD) chromatin-remodeling complex. As a result, histone H3 acetylation levels at the HSP70 promoter were higher in harsh-temperature-conditioned chicks than in their mild-heat-conditioned counterparts. These results suggest that methylation level of a distal part of the HSP70 promoter and POU2F1 recruitment may reflect heat-stress-related epigenetic memory and may be useful in differentiating between individuals that are resilient or vulnerable to stress. © 2017 International Society for Neurochemistry.
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Epigenetic regulation of memory formation and maintenance
Zovkic, Iva B.; Guzman-Karlsson, Mikael C.; Sweatt, J. David
2013-01-01
Understanding the cellular and molecular mechanisms underlying the formation and maintenance of memories is a central goal of the neuroscience community. It is well regarded that an organism's ability to lastingly adapt its behavior in response to a transient environmental stimulus relies on the central nervous system's capability for structural and functional plasticity. This plasticity is dependent on a well-regulated program of neurotransmitter release, post-synaptic receptor activation, intracellular signaling cascades, gene transcription, and subsequent protein synthesis. In the last decade, epigenetic markers like DNA methylation and post-translational modifications of histone tails have emerged as important regulators of the memory process. Their ability to regulate gene transcription dynamically in response to neuronal activation supports the consolidation of long-term memory. Furthermore, the persistent and self-propagating nature of these mechanisms, particularly DNA methylation, suggests a molecular mechanism for memory maintenance. In this review, we will examine the evidence that supports a role of epigenetic mechanisms in learning and memory. In doing so, we hope to emphasize (1) the widespread involvement of these mechanisms across different behavioral paradigms and distinct brain regions, (2) the temporal and genetic specificity of these mechanisms in response to upstream signaling cascades, and (3) the functional outcome these mechanisms may have on structural and functional plasticity. Finally, we consider the future directions of neuroepigenetic research as it relates to neuronal storage of information. PMID:23322554
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p38 МАРK is Involved in Regulation of Epigenetic Mechanisms of Food Aversion Learning.
Grinkevich, L N
2017-08-01
Consolidation of the conditioned food aversion response in Helix lucorum was associated with induction of histone H3 acetylation and methylation. We hypothesized that not only activatory, but also inhibitory p38 MARK-mediated pathways are involved in these processes. To assess the contribution of p38 MAPK to epigenetic processes, we studied the effect p38 MAPK inhibitor SB203580 on acetylation of histone H3 during training of Helix lucorum. Administration of SB203580 decreased learning-induced enhancement of histone H3 acetylation in the CNS of Helix lucorum, which was accompanied by long-term memory impairment. Thus, p38 MAPK is involved in the regulation of epigenetic mechanisms of long-term memory.
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Sidoli, Simone; Cheng, Lei; Jensen, Ole N
2012-06-27
Histone proteins contribute to the maintenance and regulation of the dynamic chromatin structure, to gene activation, DNA repair and many other processes in the cell nucleus. Site-specific reversible and irreversible post-translational modifications of histone proteins mediate biological functions, including recruitment of transcription factors to specific DNA regions, assembly of epigenetic reader/writer/eraser complexes onto DNA, and modulation of DNA-protein interactions. Histones thereby regulate chromatin structure and function, propagate inheritance and provide memory functions in the cell. Dysfunctional chromatin structures and misregulation may lead to pathogenic states, including diabetes and cancer, and the mapping and quantification of multivalent post-translational modifications has therefore attracted significant interest. Mass spectrometry has quickly been accepted as a versatile tool to achieve insights into chromatin biology and epigenetics. High sensitivity and high mass accuracy and the ability to sequence post-translationally modified peptides and perform large-scale analyses make this technique very well suited for histone protein characterization. In this review we discuss a range of analytical methods and various mass spectrometry-based approaches for histone analysis, from sample preparation to data interpretation. Mass spectrometry-based proteomics is already an integrated and indispensable tool in modern chromatin biology, providing insights into the mechanisms and dynamics of nuclear and epigenetic processes. This article is part of a Special Section entitled: Understanding genome regulation and genetic diversity by mass spectrometry. Copyright © 2011 Elsevier B.V. All rights reserved.
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Epigenetic regulation of BDNF gene transcription in the consolidation of fear memory.
Lubin, Farah D; Roth, Tania L; Sweatt, J David
2008-10-15
Long-term memory formation requires selective changes in gene expression. Here, we determined the contribution of chromatin remodeling to learning-induced changes in brain-derived neurotrophic factor (bdnf) gene expression in the adult hippocampus. Contextual fear learning induced differential regulation of exon-specific bdnf mRNAs (I, IV, VI, IX) that was associated with changes in bdnf DNA methylation and altered local chromatin structure. Infusions of zebularine (a DNA methyltransferase inhibitor) significantly altered bdnf DNA methylation and triggered changes in exon-specific bdnf mRNA levels, indicating that altered DNA methylation is sufficient to drive differential bdnf transcript regulation in the hippocampus. In addition, NMDA receptor blockade prevented memory-associated alterations in bdnf DNA methylation, resulting in a block of altered bdnf gene expression in hippocampus and a deficit in memory formation. These results suggest epigenetic modification of the bdnf gene as a mechanism for isoform-specific gene readout during memory consolidation.
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Whitton, Laura; Cosgrove, Donna; Clarkson, Christopher; Harold, Denise; Kendall, Kimberley; Richards, Alex; Mantripragada, Kiran; Owen, Michael J; O'Donovan, Michael C; Walters, James; Hartmann, Annette; Konte, Betina; Rujescu, Dan; Gill, Michael; Corvin, Aiden; Rea, Stephen; Donohoe, Gary; Morris, Derek W
2016-12-01
Epigenetic mechanisms are an important heritable and dynamic means of regulating various genomic functions, including gene expression, to orchestrate brain development, adult neurogenesis, and synaptic plasticity. These processes when perturbed are thought to contribute to schizophrenia pathophysiology. A core feature of schizophrenia is cognitive dysfunction. For genetic disorders where cognitive impairment is more severe such as intellectual disability, there are a disproportionally high number of genes involved in the epigenetic regulation of gene transcription. Evidence now supports some shared genetic aetiology between schizophrenia and intellectual disability. GWAS have identified 108 chromosomal regions associated with schizophrenia risk that span 350 genes. This study identified genes mapping to those loci that have epigenetic functions, and tested the risk alleles defining those loci for association with cognitive deficits. We developed a list of 350 genes with epigenetic functions and cross-referenced this with the GWAS loci. This identified eight candidate genes: BCL11B, CHD7, EP300, EPC2, GATAD2A, KDM3B, RERE, SATB2. Using a dataset of Irish psychosis cases and controls (n = 1235), the schizophrenia risk SNPs at these loci were tested for effects on IQ, working memory, episodic memory, and attention. Strongest associations were for rs6984242 with both measures of IQ (P = 0.001) and episodic memory (P = 0.007). We link rs6984242 to CHD7 via a long range eQTL. These associations were not replicated in independent samples. Our study highlights that a number of genes mapping to risk loci for schizophrenia may function as epigenetic regulators of gene expression but further studies are required to establish a role for these genes in cognition. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.
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Epigenetics: A novel therapeutic approach for the treatment of Alzheimer’s disease
Adwan, Lina; Zawia, Nasser H.
2013-01-01
Alzheimer’s disease (AD) is the most common type of dementia in the elderly. It is characterized by the deposition of two forms of aggregates within the brain, the amyloid β plaques and tau neurofibrillary tangles. Currently, no disease-modifying agent is approved for the treatment of AD. Approved pharmacotherapies target the peripheral symptoms but they do not prevent or slow down the progression of the disease. Although several disease-modifying immunotherapeutic agents are in clinical development, many have failed due to lack of efficacy or serious adverse events. Epigenetic changes including DNA methylation and histone modifications are involved in learning and memory and have been recently highlighted for holding promise as potential targets for AD therapeutics. Dynamic and latent epigenetic alterations are incorporated in AD pathological pathways and present valuable reversible targets for AD and other neurological disorders. The approval of epigenetic drugs for cancer treatment has opened the door for the development of epigenetic drugs for other disorders including neurodegenerative diseases. In particular, methyl donors and histone deacetylase inhibitors are being investigated for possible therapeutic effects to rescue memory and cognitive decline found in such disorders. This review explores the area of epigenetics for potential AD interventions and presents the most recent findings in this field. PMID:23562602
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Zhang, Jenny; Jima, Dereje; Moffitt, Andrea B.; Liu, Qingquan; Czader, Magdalena; Hsi, Eric D.; Fedoriw, Yuri; Dunphy, Cherie H.; Richards, Kristy L.; Gill, Javed I.; Sun, Zhen; Love, Cassandra; Scotland, Paula; Lock, Eric; Levy, Shawn; Hsu, David S.; Dunson, David; Dave, Sandeep S.
2014-01-01
In this study, we define the genetic landscape of mantle cell lymphoma (MCL) through exome sequencing of 56 cases of MCL. We identified recurrent mutations in ATM, CCND1, MLL2, and TP53. We further identified a number of novel genes recurrently mutated in patients with MCL including RB1, WHSC1, POT1, and SMARCA4. We noted that MCLs have a distinct mutational profile compared with lymphomas from other B-cell stages. The ENCODE project has defined the chromatin structure of many cell types. However, a similar characterization of primary human mature B cells has been lacking. We defined, for the first time, the chromatin structure of primary human naïve, germinal center, and memory B cells through chromatin immunoprecipitation and sequencing for H3K4me1, H3K4me3, H3Ac, H3K36me3, H3K27me3, and PolII. We found that somatic mutations that occur more frequently in either MCLs or Burkitt lymphomas were associated with open chromatin in their respective B cells of origin, naïve B cells, and germinal center B cells. Our work thus elucidates the landscape of gene-coding mutations in MCL and the critical interplay between epigenetic alterations associated with B-cell differentiation and the acquisition of somatic mutations in cancer. PMID:24682267
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Shaping epigenetic memory via genomic bookmarking.
Michieletto, Davide; Chiang, Michael; Colì, Davide; Papantonis, Argyris; Orlandini, Enzo; Cook, Peter R; Marenduzzo, Davide
2018-01-09
Reconciling the stability of epigenetic patterns with the rapid turnover of histone modifications and their adaptability to external stimuli is an outstanding challenge. Here, we propose a new biophysical mechanism that can establish and maintain robust yet plastic epigenetic domains via genomic bookmarking (GBM). We model chromatin as a recolourable polymer whose segments bear non-permanent histone marks (or colours) which can be modified by 'writer' proteins. The three-dimensional chromatin organisation is mediated by protein bridges, or 'readers', such as Polycomb Repressive Complexes and Transcription Factors. The coupling between readers and writers drives spreading of biochemical marks and sustains the memory of local chromatin states across replication and mitosis. In contrast, GBM-targeted perturbations destabilise the epigenetic patterns. Strikingly, we demonstrate that GBM alone can explain the full distribution of Polycomb marks in a whole Drosophila chromosome. We finally suggest that our model provides a starting point for an understanding of the biophysics of cellular differentiation and reprogramming. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.
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Shaping epigenetic memory via genomic bookmarking
Chiang, Michael; Colì, Davide; Papantonis, Argyris; Orlandini, Enzo; Cook, Peter R
2018-01-01
Abstract Reconciling the stability of epigenetic patterns with the rapid turnover of histone modifications and their adaptability to external stimuli is an outstanding challenge. Here, we propose a new biophysical mechanism that can establish and maintain robust yet plastic epigenetic domains via genomic bookmarking (GBM). We model chromatin as a recolourable polymer whose segments bear non-permanent histone marks (or colours) which can be modified by ‘writer’ proteins. The three-dimensional chromatin organisation is mediated by protein bridges, or ‘readers’, such as Polycomb Repressive Complexes and Transcription Factors. The coupling between readers and writers drives spreading of biochemical marks and sustains the memory of local chromatin states across replication and mitosis. In contrast, GBM-targeted perturbations destabilise the epigenetic patterns. Strikingly, we demonstrate that GBM alone can explain the full distribution of Polycomb marks in a whole Drosophila chromosome. We finally suggest that our model provides a starting point for an understanding of the biophysics of cellular differentiation and reprogramming. PMID:29190361
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Epileptogenesis: can the science of epigenetics give us answers?
Lubin, Farah D
2012-05-01
Epigenetic mechanisms are regulatory processes that control gene expression changes involved in multiple aspects of neuronal function, including central nervous system development, synaptic plasticity, and memory. Recent evidence indicates that dysregulation of epigenetic mechanisms occurs in several human epilepsy syndromes. Despite this discovery of a potential role for epigenetic mechanisms in epilepsy, few studies have fully explored their contribution to the process of epilepsy development known as epileptogenesis. The purpose of this article is to discuss recent findings suggesting that the process of epileptogenesis may alter the epigenetic landscape, affecting the gene expression patterns observed in epilepsy. Future studies focused on a better characterization of these aberrant epigenetic mechanisms hold the promise of revealing novel treatment options for the prevention and even the reversal of epilepsy.
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Buggert, Marcus; Nguyen, Son; Salgado-Montes de Oca, Gonzalo; Bengsch, Bertram; Darko, Samuel; Ransier, Amy; Roberts, Emily R; Del Alcazar, Daniel; Brody, Irene Bukh; Vella, Laura A; Beura, Lalit; Wijeyesinghe, Sathi; Herati, Ramin S; Del Rio Estrada, Perla M; Ablanedo-Terrazas, Yuria; Kuri-Cervantes, Leticia; Sada Japp, Alberto; Manne, Sasikanth; Vartanian, Shant; Huffman, Austin; Sandberg, Johan K; Gostick, Emma; Nadolski, Gregory; Silvestri, Guido; Canaday, David H; Price, David A; Petrovas, Constantinos; Su, Laura F; Vahedi, Golnaz; Dori, Yoav; Frank, Ian; Itkin, Maxim G; Wherry, E John; Deeks, Steven G; Naji, Ali; Reyes-Terán, Gustavo; Masopust, David; Douek, Daniel C; Betts, Michael R
2018-06-01
Current paradigms of CD8 + T cell-mediated protection in HIV infection center almost exclusively on studies of peripheral blood, which is thought to provide a window into immune activity at the predominant sites of viral replication in lymphoid tissues (LTs). Through extensive comparison of blood, thoracic duct lymph (TDL), and LTs in different species, we show that many LT memory CD8 + T cells bear phenotypic, transcriptional, and epigenetic signatures of resident memory T cells (T RMs ). Unlike their circulating counterparts in blood or TDL, most of the total and follicular HIV-specific CD8 + T cells in LTs also resemble T RMs Moreover, high frequencies of HIV-specific CD8 + T RMs with skewed clonotypic profiles relative to matched blood samples are present in LTs of individuals who spontaneously control HIV replication in the absence of antiretroviral therapy (elite controllers). Single-cell RNA sequencing analysis confirmed that HIV-specific T RMs are enriched for effector-related immune genes and signatures compared with HIV-specific non-T RMs in elite controllers. Together, these data indicate that previous studies in blood have largely failed to capture the major component of HIV-specific CD8 + T cell responses resident within LTs. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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Histone chaperones: an escort network regulating histone traffic.
De Koning, Leanne; Corpet, Armelle; Haber, James E; Almouzni, Geneviève
2007-11-01
In eukaryotes, DNA is organized into chromatin in a dynamic manner that enables it to be accessed for processes such as transcription and repair. Histones, the chief protein component of chromatin, must be assembled, replaced or exchanged to preserve or change this organization according to cellular needs. Histone chaperones are key actors during histone metabolism. Here we classify known histone chaperones and discuss how they build a network to escort histone proteins. Molecular interactions with histones and their potential specificity or redundancy are also discussed in light of chaperone structural properties. The multiplicity of histone chaperone partners, including histone modifiers, nucleosome remodelers and cell-cycle regulators, is relevant to their coordination with key cellular processes. Given the current interest in chromatin as a source of epigenetic marks, we address the potential contributions of histone chaperones to epigenetic memory and genome stability.
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Zheng, Fei; Zuo, Jian
2017-01-01
Noise-induced hearing loss (NIHL) affects a large number of military personnel and civilians. Regenerating inner-ear cochlear hair cells (HCs) is a promising strategy to restore hearing after NIHL. In this review, we first summarize recent transcriptome profile analysis of zebrafish lateral lines and chick utricles where spontaneous HC regeneration occurs after HC damage. We then discuss recent studies in other mammalian regenerative systems such as pancreas, heart and central nervous system. Both spontaneous and forced HC regeneration occurs in mammalian cochleae in vivo involving proliferation and direct lineage conversion. However, both processes are inefficient and incomplete, and decline with age. For direct lineage conversion in vivo in cochleae and in other systems, further improvement requires multiple factors, including transcription, epigenetic and trophic factors, with appropriate stoichiometry in appropriate architectural niche. Increasing evidence from other systems indicates that the molecular paths of direct lineage conversion may be different from those of normal developmental lineages. We therefore hypothesize that HC regeneration does not have to follow HC development and that epigenetic memory of supporting cells influences the HC regeneration, which may be a key to successful cochlear HC regeneration. Finally, we discuss recent efforts in viral gene therapy and drug discovery for HC regeneration. We hope that combination therapy targeting multiple factors and epigenetic signaling pathways will provide promising avenues for HC regeneration in humans with NIHL and other types of hearing loss. PMID:28034617
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Phenotypic effects of somatic cell cloning in the mouse.
Ogura, A; Inoue, K; Ogonuki, N; Lee, J; Kohda, T; Ishino, F
2002-01-01
Although a variety of phenotypes and epigenetic alterations have been reported in animals cloned from somatic cells, the exact nature and consequences of cloning remain unclear. We cloned mice using fresh or short-term cultures of donor cells (cumulus cells, immature Sertoli cells, and fetal or adult fibroblast cells) with defined genetic backgrounds, and then compared the phenotypic and epigenetic characteristics of the cloned mice with those of fertilization-derived control mice. Irrespective of the nucleus-donor cell type, about 50% of the reconstructed embryos developed to the morula/blastocyst stage, but about 90% of these clones showed arrested development between days 5 and 8, shortly after implantation. Most of the clones were alive at term, readily recovered respiration, and did not show any malformations or overgrowths. However, their placentas were two- to threefold larger than those of the controls, due to hyperplasia of the basal (or spongiotrophoblast) layer. Although there was significant suppression of a subset of both imprinted and non-imprinted placental genes, fetal gene suppression was minimal. The seven imprinted genes that we examined were all expressed correctly from the parental alleles. These findings were consistent for every cell type from the midgestation through term stages. Therefore, cloning by nuclear transfer does not perturb the parent-specific imprinting memory that is established during gametogenesis, and the phenotypic and epigenetic effects of cloning are restricted to placental development at the midgestation and term stages. Twelve male mice that were born in a normal manner following nuclear transfer with immature Sertoli cells (B6D2F1 genetic background) were subjected to long-term observation. They died earlier than the genotype-matched controls (50% survival point: 550 days vs. 1028 days, respectively), most probably due to severe pneumonia, which indicates that unexpected phenotypes can appear as a result of the long-term effects of somatic cell cloning.
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Seth, Meetu; Shirayama, Masaki; Gu, Weifeng; Ishidate, Takao; Conte, Darryl; Mello, Craig C
2013-12-23
Organisms can develop adaptive sequence-specific immunity by reexpressing pathogen-specific small RNAs that guide gene silencing. For example, the C. elegans PIWI-Argonaute/piwi-interacting RNA (piRNA) pathway recruits RNA-dependent RNA polymerase (RdRP) to foreign sequences to amplify a transgenerational small-RNA-induced epigenetic silencing signal (termed RNAe). Here, we provide evidence that, in addition to an adaptive memory of silenced sequences, C. elegans can also develop an opposing adaptive memory of expressed/self-mRNAs. We refer to this mechanism, which can prevent or reverse RNAe, as RNA-induced epigenetic gene activation (RNAa). We show that CSR-1, which engages RdRP-amplified small RNAs complementary to germline-expressed mRNAs, is required for RNAa. We show that a transgene with RNAa activity also exhibits accumulation of cognate CSR-1 small RNAs. Our findings suggest that C. elegans adaptively acquires and maintains a transgenerational CSR-1 memory that recognizes and protects self-mRNAs, allowing piRNAs to recognize foreign sequences innately, without the need for prior exposure
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Seth, Meetu; Shirayama, Masaki; Gu, Weifeng; Ishidate, Takao; Conte, Darryl; Mello, Craig C.
2014-01-01
SUMMARY Organisms can develop adaptive sequence-specific immunity by re-expressing pathogen-specific small RNAs that guide gene silencing. For example, the C. elegans PIWI-Argonaute/piRNA pathway recruits RNA-dependent RNA polymerase RdRP to foreign sequences to amplify a trans-generational small RNA-induced epigenetic silencing signal (termed RNAe). Here we provide evidence that in addition to an adaptive memory of silenced sequences, C. elegans can also develop an opposing adaptive memory of expressed/self mRNAs. We refer to this mechanism, which can prevent or reverse RNAe as RNA-induced epigenetic gene activation (RNAa). We show that CSR-1, which engages RdRP-amplified small RNAs complementary to germline-expressed mRNAs, is required for RNAa. We show that a transgene with RNAa activity also exhibits accumulation of cognate CSR-1 small RNAs. Our findings suggest that C. elegans adaptively acquires and maintains a trans-generational CSR-1 memory that recognizes and protects self mRNAs, allowing piRNAs to recognize foreign sequences innately, without need for prior exposure. PMID:24360782
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Carneros, Elena; Yakovlev, Igor; Viejo, Marcos; Olsen, Jorunn E; Fossdal, Carl Gunnar
2017-09-01
Epigenetic memory affects the timing of bud burst phenology and the expression of bud burst-related genes in genetically identical Norway spruce epitypes in a manner usually associated with ecotypes. In Norway spruce, a temperature-dependent epigenetic memory established during embryogenesis affects the timing of bud burst and bud set in a reproducible and predictable manner. We hypothesize that the clinal variation in these phenological traits, which is associated with adaptation to growth under frost-free conditions, has an epigenetic component. In Norway spruce, dehydrins (DHNs) have been associated with extreme frost tolerance. DHN transcript levels decrease gradually prior to flushing, a time when trees are highly sensitive to frost. Furthermore, EARLY BUD BREAK 1 genes (EBB1) and the FT-TFL1-LIKE 2-gene (PaFTL2) were previously suggested to be implied in control of bud phenology. Here we report an analysis of transcript levels of 12 DHNs, 3 EBB1 genes and FTL2 in epitypes of the same genotype generated at different epitype-inducing temperatures, before and during spring bud burst. Earlier flushing of epitypes originating from embryos developed at 18 °C as compared to 28 °C, was associated with differential expression of these genes between epitypes and between buds and last year's needles. The majority of these genes showed significantly different expressions between epitypes in at least one time point. The general trend in DHN expression pattern in buds showed the expected reduction in transcript levels when approaching flushing, whereas, surprisingly, transcript levels peaked later in needles, mainly at the moment of bud burst. Collectively, our results demonstrate that the epigenetic memory of temperature during embryogenesis affects bud burst phenology and expression of the bud burst-related DHN, EBB1 and FTL2 genes in genetically identical Norway spruce epitypes.
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Lungu, Cristiana; Pinter, Sabine; Broche, Julian; Rathert, Philipp; Jeltsch, Albert
2017-09-21
Investigation of the fundamental role of epigenetic processes requires methods for the locus-specific detection of epigenetic modifications in living cells. Here, we address this urgent demand by developing four modular fluorescence complementation-based epigenetic biosensors for live-cell microscopy applications. These tools combine engineered DNA-binding proteins with domains recognizing defined epigenetic marks, both fused to non-fluorescent fragments of a fluorescent protein. The presence of the epigenetic mark at the target DNA sequence leads to the reconstitution of a functional fluorophore. With this approach, we could for the first time directly detect DNA methylation and histone 3 lysine 9 trimethylation at endogenous genomic sites in live cells and follow dynamic changes in these marks upon drug treatment, induction of epigenetic enzymes and during the cell cycle. We anticipate that this versatile technology will improve our understanding of how specific epigenetic signatures are set, erased and maintained during embryonic development or disease onset.Tools for imaging epigenetic modifications can shed light on the regulation of epigenetic processes. Here, the authors present a fluorescence complementation approach for detection of DNA and histone methylation at endogenous genomic sites allowing following of dynamic changes of these marks by live-cell microscopy.
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Epigenetic Control of Stem Cell Potential During Homeostasis, Aging, and Disease
Beerman, Isabel; Rossi, Derrick J.
2015-01-01
Stem cell decline is an important cellular driver of aging-associated pathophysiology in multiple tissues. Epigenetic regulation is central to establishing and maintaining stem cell function, and emerging evidence indicates that epigenetic dysregulation contributes to the altered potential of stem cells during aging. Unlike terminally differentiated cells, the impact of epigenetic dysregulation in stem cells is propagated beyond self; alterations can be heritably transmitted to differentiated progeny, in addition to being perpetuated and amplified within the stem cell pool through self-renewal divisions. This review focuses on recent studies examining epigenetic regulation of tissue-specific stem cells in homeostasis, aging, and aging-related disease. PMID:26046761
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Role of Epigenetics in Biology and Human Diseases.
Moosavi, Azam; Motevalizadeh Ardekani, Ali
2016-11-01
For a long time, scientists have tried to describe disorders just by genetic or environmental factors. However, the role of epigenetics in human diseases has been considered from a half of century ago. In the last decade, this subject has attracted many interests, especially in complicated disorders such as behavior plasticity, memory, cancer, autoimmune disease, and addiction as well as neurodegenerative and psychological disorders. This review first explains the history and classification of epigenetic modifications, and then the role of epigenetic in biology and connection between the epigenetics and environment are explained. Furthermore, the role of epigenetics in human diseases is considered by focusing on some diseases with some complicated features, and at the end, we have given the future perspective of this field. The present review article provides concepts with some examples to reveal a broad view of different aspects of epigenetics in biology and human diseases.
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Epigenetics reloaded: the single-cell revolution.
Bheda, Poonam; Schneider, Robert
2014-11-01
Mechanistically, how epigenetic states are inherited through cellular divisions remains an important open question in the chromatin field and beyond. Defining the heritability of epigenetic states and the underlying chromatin-based mechanisms within a population of cells is complicated due to cell heterogeneity combined with varying levels of stability of these states; thus, efforts must be focused toward single-cell analyses. The approaches presented here constitute the forefront of epigenetics research at the single-cell level using classic and innovative methods to dissect epigenetics mechanisms from the limited material available in a single cell. This review further outlines exciting future avenues of research to address the significance of epigenetic heterogeneity and the contributions of microfluidics technologies to single-cell isolation and analysis. Copyright © 2014 Elsevier Ltd. All rights reserved.
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Histone Acetylation is Recruited in Consolidation as a Molecular Feature of Stronger Memories
ERIC Educational Resources Information Center
Federman, Noel; Fustinana, Maria Sol; Romano, Arturo
2009-01-01
Gene expression is a key process for memory consolidation. Recently, the participation of epigenetic mechanisms like histone acetylation was evidenced in long-term memories. However, until now the training strength required and the persistence of the chromatin acetylation recruited are not well characterized. Here we studied whether histone…
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Cancer Development, Progression, and Therapy: An Epigenetic Overview
Sarkar, Sibaji; Horn, Garrick; Moulton, Kimberly; Oza, Anuja; Byler, Shannon; Kokolus, Shannon; Longacre, McKenna
2013-01-01
Carcinogenesis involves uncontrolled cell growth, which follows the activation of oncogenes and/or the deactivation of tumor suppression genes. Metastasis requires down-regulation of cell adhesion receptors necessary for tissue-specific, cell–cell attachment, as well as up-regulation of receptors that enhance cell motility. Epigenetic changes, including histone modifications, DNA methylation, and DNA hydroxymethylation, can modify these characteristics. Targets for these epigenetic changes include signaling pathways that regulate apoptosis and autophagy, as well as microRNA. We propose that predisposed normal cells convert to cancer progenitor cells that, after growing, undergo an epithelial-mesenchymal transition. This process, which is partially under epigenetic control, can create a metastatic form of both progenitor and full-fledged cancer cells, after which metastasis to a distant location may occur. Identification of epigenetic regulatory mechanisms has provided potential therapeutic avenues. In particular, epigenetic drugs appear to potentiate the action of traditional therapeutics, often by demethylating and re-expressing tumor suppressor genes to inhibit tumorigenesis. Epigenetic drugs may inhibit both the formation and growth of cancer progenitor cells, thus reducing the recurrence of cancer. Adopting epigenetic alteration as a new hallmark of cancer is a logical and necessary step that will further encourage the development of novel epigenetic biomarkers and therapeutics. PMID:24152442
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Sleep Deprivation and the Epigenome.
Gaine, Marie E; Chatterjee, Snehajyoti; Abel, Ted
2018-01-01
Sleep deprivation disrupts the lives of millions of people every day and has a profound impact on the molecular biology of the brain. These effects begin as changes within a neuron, at the DNA and RNA level, and result in alterations in neuronal plasticity and dysregulation of many cognitive functions including learning and memory. The epigenome plays a critical role in regulating gene expression in the context of memory storage. In this review article, we begin by describing the effects of epigenetic alterations on the regulation of gene expression, focusing on the most common epigenetic mechanisms: (i) DNA methylation; (ii) histone modifications; and (iii) non-coding RNAs. We then discuss evidence suggesting that sleep loss impacts the epigenome and that these epigenetic alterations might mediate the changes in cognition seen following disruption of sleep. The link between sleep and the epigenome is only beginning to be elucidated, but clear evidence exists that epigenetic alterations occur following sleep deprivation. In the future, these changes to the epigenome could be utilized as biomarkers of sleep loss or as therapeutic targets for sleep-related disorders.
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Epigenetic-induced alterations in sex-ratios in response to climate change: An epigenetic trap?
Consuegra, Sofia; Rodríguez López, Carlos M
2016-10-01
We hypothesize that under the predicted scenario of climate change epigenetically mediated environmental sex determination could become an epigenetic trap. Epigenetically regulated environmental sex determination is a mechanism by which species can modulate their breeding strategies to accommodate environmental change. Growing evidence suggests that epigenetic mechanisms may play a key role in phenotypic plasticity and in the rapid adaptation of species to environmental change, through the capacity of organisms to maintain a non-genetic plastic memory of the environmental and ecological conditions experienced by their parents. However, inherited epigenetic variation could also be maladaptive, becoming an epigenetic trap. This is because environmental sex determination can alter sex ratios by increasing the survival of one of the sexes at the expense of negative fitness consequences for the other, which could lead not only to the collapse of natural populations, but also have an impact in farmed animal and plant species. © 2016 WILEY Periodicals, Inc.
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The epigenetic switches for neural development and psychiatric disorders.
Lv, Jingwen; Xin, Yongjuan; Zhou, Wenhao; Qiu, Zilong
2013-07-20
The most remarkable feature of the nervous system is that the development and functions of the brain are largely reshaped by postnatal experiences, in joint with genetic landscapes. The nature vs. nurture argument reminds us that both genetic and epigenetic information is indispensable for the normal function of the brain. The epigenetic regulatory mechanisms in the central nervous system have been revealed over last a decade. Moreover, the mutations of epigenetic modulator genes have been shown to be implicated in neuropsychiatric disorders, such as autism spectrum disorders. The epigenetic study has initiated in the neuroscience field for a relative short period of time. In this review, we will summarize recent discoveries about epigenetic regulation on neural development, synaptic plasticity, learning and memory, as well as neuropsychiatric disorders. Although the comprehensive view of how epigenetic regulation contributes to the function of the brain is still not completed, the notion that brain, the most complicated organ of organisms, is profoundly shaped by epigenetic switches is widely accepted. Copyright © 2013. Published by Elsevier Ltd.
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Epigenetic regulation of normal human mammary cell type-specific miRNAs
DOE Office of Scientific and Technical Information (OSTI.GOV)
Vrba, Lukas; Garbe, James C.; Stampfer, Martha R.
2011-08-26
Epigenetic mechanisms are important regulators of cell type–specific genes, including miRNAs. In order to identify cell type-specific miRNAs regulated by epigenetic mechanisms, we undertook a global analysis of miRNA expression and epigenetic states in three isogenic pairs of human mammary epithelial cells (HMEC) and human mammary fibroblasts (HMF), which represent two differentiated cell types typically present within a given organ, each with a distinct phenotype and a distinct epigenotype. While miRNA expression and epigenetic states showed strong interindividual concordance within a given cell type, almost 10% of the expressed miRNA showed a cell type–specific pattern of expression that was linkedmore » to the epigenetic state of their promoter. The tissue-specific miRNA genes were epigenetically repressed in nonexpressing cells by DNA methylation (38%) and H3K27me3 (58%), with only a small set of miRNAs (21%) showing a dual epigenetic repression where both DNA methylation and H3K27me3 were present at their promoters, such as MIR10A and MIR10B. Individual miRNA clusters of closely related miRNA gene families can each display cell type–specific repression by the same or complementary epigenetic mechanisms, such as the MIR200 family, and MIR205, where fibroblasts repress MIR200C/141 by DNA methylation, MIR200A/200B/429 by H3K27me3, and MIR205 by both DNA methylation and H3K27me3. Since deregulation of many of the epigenetically regulated miRNAs that we identified have been linked to disease processes such as cancer, it is predicted that compromise of the epigenetic control mechanisms is important for this process. Overall, these results highlight the importance of epigenetic regulation in the control of normal cell type–specific miRNA expression.« less
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Yoo, Miran; Choi, Kwang-Yeon; Kim, Jieun; Kim, Mujun; Shim, Jaehoon; Choi, Jun-Hyeok; Cho, Hye-Yeon; Oh, Jung-Pyo; Kim, Hyung-Su; Kaang, Bong-Kiun; Han, Jin-Hee
2017-03-29
Although epigenetic mechanisms of gene expression regulation have recently been implicated in memory consolidation and persistence, the role of nucleosome-remodeling is largely unexplored. Recent studies show that the functional loss of BAF53b, a postmitotic neuron-specific subunit of the BAF nucleosome-remodeling complex, results in the deficit of consolidation of hippocampus-dependent memory and cocaine-associated memory in the rodent brain. However, it is unclear whether BAF53b expression is regulated during memory formation and how BAF53b regulates fear memory in the amygdala, a key brain site for fear memory encoding and storage. To address these questions, we used viral vector approaches to either decrease or increase BAF53b function specifically in the lateral amygdala of adult mice in auditory fear conditioning paradigm. Knockdown of Baf53b before training disrupted long-term memory formation with no effect on short-term memory, basal synaptic transmission, and spine structures. We observed in our qPCR analysis that BAF53b was induced in the lateral amygdala neurons at the late consolidation phase after fear conditioning. Moreover, transient BAF53b overexpression led to persistently enhanced memory formation, which was accompanied by increase in thin-type spine density. Together, our results provide the evidence that BAF53b is induced after learning, and show that such increase of BAF53b level facilitates memory consolidation likely by regulating learning-related spine structural plasticity. SIGNIFICANCE STATEMENT Recent works in the rodent brain begin to link nucleosome remodeling-dependent epigenetic mechanism to memory consolidation. Here we show that BAF53b, an epigenetic factor involved in nucleosome remodeling, is induced in the lateral amygdala neurons at the late phase of consolidation after fear conditioning. Using specific gene knockdown or overexpression approaches, we identify the critical role of BAF53b in the lateral amygdala neurons for memory consolidation during long-term memory formation. Our results thus provide an idea about how nucleosome remodeling can be regulated during long-term memory formation and contributes to the permanent storage of associative fear memory in the lateral amygdala, which is relevant to fear and anxiety-related mental disorders. Copyright © 2017 the authors 0270-6474/17/373686-12$15.00/0.
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Using somatic-cell nuclear transfer to study aging.
Kishigami, Satoshi; Lee, Ah Reum; Wakayama, Teruhiko
2013-01-01
In mammals, a diploid genome following fertilization of haploid cells, an egg, and a spermatozoon is unique and irreproducible. This implies that the generated unique diploid genome is doomed with the individual's inevitable demise. Since it was first reported in 1997 that Dolly the sheep had been cloned, many mammalian species have been cloned successfully using somatic-cell nuclear transfer (SCNT). The success of SCNT in mammals enables us not only to reproduce offspring without germ cells, that is, to "passage" a unique diploid genome, but also to address valuable biological questions on development, nuclear reprogramming, and epigenetic memory. Successful cloning can also support epigenetic reprogramming where the aging clock is reset or reversed. Recent work using iPS cell technology has explored the practicality and led to the recapitulation of premature aging with iPSCs from progeroid laminopathies. As a result, reprogramming tools are also expected to contribute to studying biological age. However, the efficiency of animal cloning is still low in most cases and the mechanism of reprogramming in cloned embryos is still largely unclear. Here, based on recent advances, we describe an improved, more efficient mouse cloning protocol using histone deacetylase inhibitors (HDACis) and latrunculin A, which increases the success rates of producing cloned mice or establishing ES cells fivefold. This improved method of cloning will provide a strong tool to address many issues including biological aging more easily and with lower cost.
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Epigenetic Regulation: A New Frontier for Biomedical Engineers.
Chen, Zhen; Li, Shuai; Subramaniam, Shankar; Shyy, John Y-J; Chien, Shu
2017-06-21
Gene expression in mammalian cells depends on the epigenetic status of the chromatin, including DNA methylation, histone modifications, promoter-enhancer interactions, and noncoding RNA-mediated regulation. The coordinated actions of these multifaceted regulations determine cell development, cell cycle regulation, cell state and fate, and the ultimate responses in health and disease. Therefore, studies of epigenetic modulations are critical for our understanding of gene regulation mechanisms at the molecular, cellular, tissue, and organ levels. The aim of this review is to provide biomedical engineers with an overview of the principles of epigenetics, methods of study, recent findings in epigenetic regulation in health and disease, and computational and sequencing tools for epigenetics analysis, with an emphasis on the cardiovascular system. This review concludes with the perspectives of the application of bioengineering to advance epigenetics and the utilization of epigenetics to translate bioengineering research into clinical medicine.
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ERIC Educational Resources Information Center
Shu, Guanhua; Kramár, Enikö A.; López, Alberto J.; Huynh, Grace; Wood, Marcelo A.; Kwapis, Janine L.
2018-01-01
Multiple epigenetic mechanisms, including histone acetylation and nucleosome remodeling, are known to be involved in long-term memory formation. Enhancing histone acetylation by deleting histone deacetylases, like HDAC3, typically enhances long-term memory formation. In contrast, disrupting nucleosome remodeling by blocking the neuron-specific…
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Perinatally acquired HIV infection accelerates epigenetic aging in South African adolescents.
Horvath, Steve; Phillips, Nicole; Heany, Sarah J; Kobor, Michael S; Lin, David Ts; Myer, Landon; Zar, Heather J; Stein, Dan J; Levine, Andrew J; Hoare, Jacqueline
2018-05-08
Recent studies demonstrate that infection with the Human Immunodeficiency Virus-1 (HIV) is associated with accelerated aging effects in adults according to a highly accurate epigenetic biomarker of aging known as epigenetic clock. However, it not yet known whether epigenetic age acceleration occurs as early as adolescence in perinatally HIV-infected (PHIV+) youth. Observational study of PHIV and HIV-uninfected adolescents enrolled in the Cape Town Adolescent Antiretroviral Cohort (CTAAC) Study. The Illumina EPIC array was used to generate blood DNA methylation data from 204 PHIV and 44 age-matched, uninfected (HIV-) adolescents aged 9 to 12 years old. The epigenetic clock software and method was used to estimate two measures of epigenetic age acceleration. Each participant completed a comprehensive neuropsychological test battery upon enrolment to CTAAC. HIV is associated with biologically older blood in PHIV+ adolescents according to both measures of epigenetic age acceleration. One of the measures, extrinsic epigenetic age acceleration, is negatively correlated with measures of cognitive functioning (executive functioning, working memory, processing speed). Overall, our results indicate that epigenetic age acceleration in blood can be observed in PHIV+ adolescents and that these epigenetic changes accompany poorer cognitive functioning.
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Back to the future: transgenerational transmission of xenobiotic-induced epigenetic remodeling
Jiménez-Chillarón, Josep C; Nijland, Mark J; Ascensão, António A; Sardão, Vilma A; Magalhães, José; Hitchler, Michael J; Domann, Frederick E; Oliveira, Paulo J
2015-01-01
Epigenetics, or regulation of gene expression independent of DNA sequence, is the missing link between genotype and phenotype. Epigenetic memory, mediated by histone and DNA modifications, is controlled by a set of specialized enzymes, metabolite availability, and signaling pathways. A mostly unstudied subject is how sub-toxic exposure to several xenobiotics during specific developmental stages can alter the epigenome and contribute to the development of disease phenotypes later in life. Furthermore, it has been shown that exposure to low-dose xenobiotics can also result in further epigenetic remodeling in the germ line and contribute to increase disease risk in the next generation (multigenerational and transgenerational effects). We here offer a perspective on current but still incomplete knowledge of xenobiotic-induced epigenetic alterations, and their possible transgenerational transmission. We also propose several molecular mechanisms by which the epigenetic landscape may be altered by environmental xenobiotics and hypothesize how diet and physical activity may counteract epigenetic alterations. PMID:25774863
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The elucidation of stress memory inheritance in Brassica rapa plants.
Bilichak, Andriy; Ilnytskyy, Yaroslav; Wóycicki, Rafal; Kepeshchuk, Nina; Fogen, Dawson; Kovalchuk, Igor
2015-01-01
Plants are able to maintain the memory of stress exposure throughout their ontogenesis and faithfully propagate it into the next generation. Recent evidence argues for the epigenetic nature of this phenomenon. Small RNAs (smRNAs) are one of the vital epigenetic factors because they can both affect gene expression at the place of their generation and maintain non-cell-autonomous gene regulation. Here, we have made an attempt to decipher the contribution of smRNAs to the heat-shock-induced transgenerational inheritance in Brassica rapa plants using sequencing technology. To do this, we have generated comprehensive profiles of a transcriptome and a small RNAome (smRNAome) from somatic and reproductive tissues of stressed plants and their untreated progeny. We have demonstrated that the highest tissue-specific alterations in the transcriptome and smRNAome profile are detected in tissues that were not directly exposed to stress, namely, in the endosperm and pollen. Importantly, we have revealed that the progeny of stressed plants exhibit the highest fluctuations at the smRNAome level but not at the transcriptome level. Additionally, we have uncovered the existence of heat-inducible and transgenerationally transmitted tRNA-derived small RNA fragments in plants. Finally, we suggest that miR168 and braAGO1 are involved in the stress-induced transgenerational inheritance in plants.
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Transgenerational response to stress in plants and its application for breeding.
Bilichak, Andriy; Kovalchuk, Igor
2016-03-01
A growing number of reports indicate that plants possess the ability to maintain a memory of stress exposure throughout their ontogenesis and even transmit it faithfully to the following generation. Some of the features of transgenerational memory include elevated genome instability, a higher tolerance to stress experienced by parents, and a cross-tolerance. Although the underlying molecular mechanisms of this phenomenon are not clear, a likely contributing factor is the absence of full-scale reprogramming of the epigenetic landscape during gametogenesis; therefore, epigenetic marks can occasionally escape the reprogramming process and can be passed on to the progeny. To date, it is not entirely clear which part of the epigenetic landscape is more likely to escape the reprogramming events, and whether such a process is random or directed and sequence specific. The identification of specific epigenetic marks associated with specific stressors would allow generation of stress-tolerant plants through the recently discovered techniques for precision epigenome engineering. The engineered DNA-binding domains (e.g. ZF, TALE, and dCas9) fused to particular chromatin modifiers would make it possible to target epigenetic modifications to the selected loci, probably allowing stress tolerance to be achieved in the progeny. This approach, termed epigenetic breeding, along with other methods has great potential to be used for both the assessment of the propagation of epigenetic marks across generations and trait improvement in plants. In this communication, we provide a short overview of recent reports demonstrating a transgenerational response to stress in plants, and discuss the underlying potential molecular mechanisms of this phenomenon and its use for plant biotechnology applications. © The Author 2016. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.
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Li, Jun; Bardag-Gorce, Fawzia; Dedes, Jennifer; French, Barbara Alan; Amidi, Fataneh; Oliva, Joan; French, Samuel William
2010-01-01
In previous studies, microarray analysis of livers from mice fed diethyl-1,4-dihydro-2,4,6-trimethyl-3,5-pyridine decarboxylate (DDC) for 10 weeks followed by 1 month of drug withdrawal (drug-primed mice) and then 7 days of drug refeeding showed an increase in the expression of numerous genes referred to here as the molecular cellular memory. This memory predisposes the liver to Mallory Denk body formation in response to drug refeeding. In the current study, drug-primed mice were refed DDC with or without a daily dose of S-adenosylmethionine (SAMe; 4 g/kg of body weight). The livers were studied for evidence of oxidative stress and changes in gene expression with microarray analysis. SAMe prevented Mallory Denk body formation in vivo. The molecular cellular memory induced by DDC refeeding lasted for 4 months after drug withdrawal and was not manifest when SAMe was added to the diet in the in vivo experiment. Liver cells from drug-primed mice spontaneously formed Mallory Denk bodies in primary tissue cultures. SAMe prevented Mallory Denk bodies when it was added to the culture medium. Conclusion SAMe treatment prevented Mallory Denk body formation in vivo and in vitro by preventing the expression of a molecular cellular memory induced by prior DDC feeding. No evidence for the involvement of oxidative stress in induction of the memory was found. The molecular memory included the up-regulation of the expression of genes associated with the development of liver cell preneoplasia. PMID:18098314
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Wibowo, Anjar; Becker, Claude; Marconi, Gianpiero; Durr, Julius; Price, Jonathan; Hagmann, Jorg; Papareddy, Ranjith; Putra, Hadi; Kageyama, Jorge; Becker, Jorg; Weigel, Detlef; Gutierrez-Marcos, Jose
2016-01-01
Inducible epigenetic changes in eukaryotes are believed to enable rapid adaptation to environmental fluctuations. We have found distinct regions of the Arabidopsis genome that are susceptible to DNA (de)methylation in response to hyperosmotic stress. The stress-induced epigenetic changes are associated with conditionally heritable adaptive phenotypic stress responses. However, these stress responses are primarily transmitted to the next generation through the female lineage due to widespread DNA glycosylase activity in the male germline, and extensively reset in the absence of stress. Using the CNI1/ATL31 locus as an example, we demonstrate that epigenetically targeted sequences function as distantly-acting control elements of antisense long non-coding RNAs, which in turn regulate targeted gene expression in response to stress. Collectively, our findings reveal that plants use a highly dynamic maternal ‘short-term stress memory’ with which to respond to adverse external conditions. This transient memory relies on the DNA methylation machinery and associated transcriptional changes to extend the phenotypic plasticity accessible to the immediate offspring. DOI: http://dx.doi.org/10.7554/eLife.13546.001 PMID:27242129
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Epigenetic editing of the Dlg4/PSD95 gene improves cognition in aged and Alzheimer's disease mice.
Bustos, Fernando J; Ampuero, Estibaliz; Jury, Nur; Aguilar, Rodrigo; Falahi, Fahimeh; Toledo, Jorge; Ahumada, Juan; Lata, Jaclyn; Cubillos, Paula; Henríquez, Berta; Guerra, Miguel V; Stehberg, Jimmy; Neve, Rachael L; Inestrosa, Nibaldo C; Wyneken, Ursula; Fuenzalida, Marco; Härtel, Steffen; Sena-Esteves, Miguel; Varela-Nallar, Lorena; Rots, Marianne G; Montecino, Martin; van Zundert, Brigitte
2017-12-01
The Dlg4 gene encodes for post-synaptic density protein 95 (PSD95), a major synaptic protein that clusters glutamate receptors and is critical for plasticity. PSD95 levels are diminished in ageing and neurodegenerative disorders, including Alzheimer's disease and Huntington's disease. The epigenetic mechanisms that (dys)regulate transcription of Dlg4/PSD95, or other plasticity genes, are largely unknown, limiting the development of targeted epigenome therapy. We analysed the Dlg4/PSD95 epigenetic landscape in hippocampal tissue and designed a Dlg4/PSD95 gene-targeting strategy: a Dlg4/PSD95 zinc finger DNA-binding domain was engineered and fused to effector domains to either repress (G9a, Suvdel76, SKD) or activate (VP64) transcription, generating artificial transcription factors or epigenetic editors (methylating H3K9). These epi-editors altered critical histone marks and subsequently Dlg4/PSD95 expression, which, importantly, impacted several hippocampal neuron plasticity processes. Intriguingly, transduction of the artificial transcription factor PSD95-VP64 rescued memory deficits in aged and Alzheimer's disease mice. Conclusively, this work validates PSD95 as a key player in memory and establishes epigenetic editing as a potential therapy to treat human neurological disorders. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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2014-01-01
Background Molecular latency allows HIV-1 to persist in resting memory CD4+ T-cells as transcriptionally silent provirus integrated into host chromosomal DNA. Multiple transcriptional regulatory mechanisms for HIV-1 latency have been described in the context of progressive epigenetic silencing and maintenance. However, our understanding of the determinants critical for the establishment of latency in newly infected cells is limited. Results In this study, we used a recently described, doubly fluorescent HIV-1 latency model to dissect the role of proviral integration sites and cellular activation state on direct non-productive infections at the single cell level. Proviral integration site mapping of infected Jurkat T-cells revealed that productively and non-productively infected cells are indistinguishable in terms of genomic landmarks, surrounding epigenetic landscapes, and proviral orientation relative to host genes. However, direct non-productive infections were inversely correlated with both cellular activation state and NFκB activity. Furthermore, modulating NFκB with either small molecules or by conditional overexpression of NFκB subunits was sufficient to alter the propensity of HIV-1 to directly enter a non-productive latent state in newly infected cells. Importantly, this modulatory effect was limited to a short time window post-infection. Conclusions Taken together, our data suggest that cellular activation state and NFκB activity during the time of infection, but not the site of proviral integration, are important regulators of direct HIV-1 non-productive infections. PMID:24502247
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Bieszczad, Kasia M; Bechay, Kiro; Rusche, James R; Jacques, Vincent; Kudugunti, Shashi; Miao, Wenyan; Weinberger, Norman M; McGaugh, James L; Wood, Marcelo A
2015-09-23
Research over the past decade indicates a novel role for epigenetic mechanisms in memory formation. Of particular interest is chromatin modification by histone deacetylases (HDACs), which, in general, negatively regulate transcription. HDAC deletion or inhibition facilitates transcription during memory consolidation and enhances long-lasting forms of synaptic plasticity and long-term memory. A key open question remains: How does blocking HDAC activity lead to memory enhancements? To address this question, we tested whether a normal function of HDACs is to gate information processing during memory formation. We used a class I HDAC inhibitor, RGFP966 (C21H19FN4O), to test the role of HDAC inhibition for information processing in an auditory memory model of learning-induced cortical plasticity. HDAC inhibition may act beyond memory enhancement per se to instead regulate information in ways that lead to encoding more vivid sensory details into memory. Indeed, we found that RGFP966 controls memory induction for acoustic details of sound-to-reward learning. Rats treated with RGFP966 while learning to associate sound with reward had stronger memory and additional information encoded into memory for highly specific features of sounds associated with reward. Moreover, behavioral effects occurred with unusually specific plasticity in primary auditory cortex (A1). Class I HDAC inhibition appears to engage A1 plasticity that enables additional acoustic features to become encoded in memory. Thus, epigenetic mechanisms act to regulate sensory cortical plasticity, which offers an information processing mechanism for gating what and how much is encoded to produce exceptionally persistent and vivid memories. Significance statement: Here we provide evidence of an epigenetic mechanism for information processing. The study reveals that a class I HDAC inhibitor (Malvaez et al., 2013; Rumbaugh et al., 2015; RGFP966, chemical formula C21H19FN4O) alters the formation of auditory memory by enabling more acoustic information to become encoded into memory. Moreover, RGFP966 appears to affect cortical plasticity: the primary auditory cortex reorganized in a manner that was unusually "tuned-in" to the specific sound cues and acoustic features that were related to reward and subsequently remembered. We propose that HDACs control "informational capture" at a systems level for what and how much information is encoded by gating sensory cortical plasticity that underlies the sensory richness of newly formed memories. Copyright © 2015 the authors 0270-6474/15/3513125-09$15.00/0.
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Bechay, Kiro; Rusche, James R.; Jacques, Vincent; Kudugunti, Shashi; Miao, Wenyan; Weinberger, Norman M.; McGaugh, James L.
2015-01-01
Research over the past decade indicates a novel role for epigenetic mechanisms in memory formation. Of particular interest is chromatin modification by histone deacetylases (HDACs), which, in general, negatively regulate transcription. HDAC deletion or inhibition facilitates transcription during memory consolidation and enhances long-lasting forms of synaptic plasticity and long-term memory. A key open question remains: How does blocking HDAC activity lead to memory enhancements? To address this question, we tested whether a normal function of HDACs is to gate information processing during memory formation. We used a class I HDAC inhibitor, RGFP966 (C21H19FN4O), to test the role of HDAC inhibition for information processing in an auditory memory model of learning-induced cortical plasticity. HDAC inhibition may act beyond memory enhancement per se to instead regulate information in ways that lead to encoding more vivid sensory details into memory. Indeed, we found that RGFP966 controls memory induction for acoustic details of sound-to-reward learning. Rats treated with RGFP966 while learning to associate sound with reward had stronger memory and additional information encoded into memory for highly specific features of sounds associated with reward. Moreover, behavioral effects occurred with unusually specific plasticity in primary auditory cortex (A1). Class I HDAC inhibition appears to engage A1 plasticity that enables additional acoustic features to become encoded in memory. Thus, epigenetic mechanisms act to regulate sensory cortical plasticity, which offers an information processing mechanism for gating what and how much is encoded to produce exceptionally persistent and vivid memories. SIGNIFICANCE STATEMENT Here we provide evidence of an epigenetic mechanism for information processing. The study reveals that a class I HDAC inhibitor (Malvaez et al., 2013; Rumbaugh et al., 2015; RGFP966, chemical formula C21H19FN4O) alters the formation of auditory memory by enabling more acoustic information to become encoded into memory. Moreover, RGFP966 appears to affect cortical plasticity: the primary auditory cortex reorganized in a manner that was unusually “tuned-in” to the specific sound cues and acoustic features that were related to reward and subsequently remembered. We propose that HDACs control “informational capture” at a systems level for what and how much information is encoded by gating sensory cortical plasticity that underlies the sensory richness of newly formed memories. PMID:26400942
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Lam, Larry; Chin, Lydia; Halder, Ramesh C; Sagong, Bien; Famenini, Sam; Sayre, James; Montoya, Dennis; Rubbi, Liudmilla; Pellegrini, Matteo; Fiala, Milan
2016-10-01
We have investigated transcriptional and epigenetic differences in peripheral blood mononuclear cells (PBMCs) of monozygotic female twins discordant in the diagnosis of amyotrophic lateral sclerosis (ALS). Exploring DNA methylation differences by reduced representation bisulfite sequencing (RRBS), we determined that, over time, the ALS twin developed higher abundances of the CD14 macrophages and lower abundances of T cells compared to the non-ALS twin. Higher macrophage signature in the ALS twin was also shown by RNA sequencing (RNA-seq). Moreover, the twins differed in the methylome at loci near several genes, including EGFR and TNFRSF11A, and in the pathways related to the tretinoin and H3K27me3 markers. We also tested cytokine production by PBMCs. The ALS twin's PBMCs spontaneously produced IL-6 and TNF-α, whereas PBMCs of the healthy twin produced these cytokines only when stimulated by superoxide dismutase (SOD)-1. These results and flow cytometric detection of CD45 and CD127 suggest the presence of memory T cells in both twins, but effector T cells only in the ALS twin. The ALS twin's PBMC supernatants, but not the healthy twin's, were toxic to rat cortical neurons, and this toxicity was strongly inhibited by an IL-6 receptor antibody (tocilizumab) and less well by TNF-α and IL-1β antibodies. The putative neurotoxicity of IL-6 and TNF-α is in agreement with a high expression of these cytokines on infiltrating macrophages in the ALS spinal cord. We hypothesize that higher macrophage abundance and increased neurotoxic cytokines have a fundamental role in the phenotype and treatment of certain individuals with ALS.-Lam, L., Chin, L., Halder, R. C., Sagong, B., Famenini, S., Sayre, J., Montoya, D., Rubbi L., Pellegrini, M., Fiala, M. Epigenetic changes in T-cell and monocyte signatures and production of neurotoxic cytokines in ALS patients. © FASEB.
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Lam, Larry; Chin, Lydia; Halder, Ramesh C.; Sagong, Bien; Famenini, Sam; Sayre, James; Montoya, Dennis; Rubbi, Liudmilla; Pellegrini, Matteo; Fiala, Milan
2016-01-01
We have investigated transcriptional and epigenetic differences in peripheral blood mononuclear cells (PBMCs) of monozygotic female twins discordant in the diagnosis of amyotrophic lateral sclerosis (ALS). Exploring DNA methylation differences by reduced representation bisulfite sequencing (RRBS), we determined that, over time, the ALS twin developed higher abundances of the CD14 macrophages and lower abundances of T cells compared to the non-ALS twin. Higher macrophage signature in the ALS twin was also shown by RNA sequencing (RNA-seq). Moreover, the twins differed in the methylome at loci near several genes, including EGFR and TNFRSF11A, and in the pathways related to the tretinoin and H3K27me3 markers. We also tested cytokine production by PBMCs. The ALS twin’s PBMCs spontaneously produced IL-6 and TNF-α, whereas PBMCs of the healthy twin produced these cytokines only when stimulated by superoxide dismutase (SOD)-1. These results and flow cytometric detection of CD45 and CD127 suggest the presence of memory T cells in both twins, but effector T cells only in the ALS twin. The ALS twin’s PBMC supernatants, but not the healthy twin’s, were toxic to rat cortical neurons, and this toxicity was strongly inhibited by an IL-6 receptor antibody (tocilizumab) and less well by TNF-α and IL-1β antibodies. The putative neurotoxicity of IL-6 and TNF-α is in agreement with a high expression of these cytokines on infiltrating macrophages in the ALS spinal cord. We hypothesize that higher macrophage abundance and increased neurotoxic cytokines have a fundamental role in the phenotype and treatment of certain individuals with ALS.—Lam, L., Chin, L., Halder, R. C., Sagong, B., Famenini, S., Sayre, J., Montoya, D., Rubbi L., Pellegrini, M., Fiala, M. Epigenetic changes in T-cell and monocyte signatures and production of neurotoxic cytokines in ALS patients. PMID:27368295
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Cockerill, Peter N
2016-12-01
Gene expression programs are largely regulated by the tissue-specific expression of lineage-defining transcription factors or by the inducible expression of transcription factors in response to specific stimuli. Here I will review our own work over the last 20 years to show how specific activation signals also lead to the wide-spread re-distribution of pre-existing constitutive transcription factors to sites undergoing chromatin reorganization. I will summarize studies showing that activation of kinase signaling pathways creates open chromatin regions that recruit pre-existing factors which were previously unable to bind to closed chromatin. As models I will draw upon genes activated or primed by receptor signaling in memory T cells, and genes activated by cytokine receptor mutations in acute myeloid leukemia. I also summarize a hit-and-run model of stable epigenetic reprograming in memory T cells, mediated by transient Activator Protein 1 (AP-1) binding, which enables the accelerated activation of inducible enhancers.
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Post, Robert M
2016-06-01
The process of sensitization (increased responsivity) to the recurrence of stressors, affective episodes, and bouts of substance abuse that can drive illness progression in the recurrent affective disorders requires a memory of and increased reactivity to the prior exposures. A wealth of studies now supports the postulate that epigenetic mechanisms underlie both normal and pathological memory processes. We selectively reviewed the literature pertinent to the role of epigenetics in behavioral sensitization phenomena and discuss its clinical implications. Epigenetics means above genetics and refers to environmental effects on the chemistry of DNA, histones (around which DNA is wound), and microRNA that change how easily genes are turned on and off. The evidence supports that sensitization to repeated stressor, affective episodes, and substance is likely based on epigenetic mechanisms and that these environmentally based processes can then become targets for prevention, early intervention, and ongoing treatment. Sensitization processes are remediable or preventable risk factors for a poor illness outcome and deserve increased clinical, public health, and research attention in the hopes of making the recurrent unipolar and bipolar affective disorders less impairing, disabling, and lethal by suicide and increased medical mortality. The findings that epigenetic chemical marks, which change in the most fundamental way how genes are regulated, mediate the long-term increased responsivity to recurrent stressors, mood episodes, and bouts of substance abuse should help change how the affective disorders are conceptualized and move treatment toward earlier, more comprehensive, and sustained pharmacoprophylaxis. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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Liu, Cao; Sun, Xue; Wang, Zhilin; Le, Qiumin; Liu, Peipei; Jiang, Changyou; Wang, Feifei; Ma, Lan
2018-01-01
Abstract Background Memory retrieval refers to reexposure to information previously encoded and stored in the brain. Following retrieval, a once-consolidated memory destabilizes and undergoes reconsolidation, during which gene expression changes to restabilize memory. Investigating epigenetic regulation during reconsolidation could provide insights into normal memory formation and pathological memory associated with psychiatric disorders. Methods We used cocaine-induced conditioned place preference to assess the cocaine-associated memory of mice and used chemogenetic methods to manipulate the activity of the pyramidal neurons in the dorsal hippocampus. We isolated the ribosome-associated transcripts from the excitatory neurons in the dorsal hippocampus by RiboTag purification to identify the potential epigenetic regulators, and we specifically knocked down gene expression in pyramidal neurons with a Cre-dependent lentivirus. Results Chemogenetically silencing the activity of the pyramidal neurons in the dorsal hippocampus immediately after memory retrieval markedly impaired memory reconsolidation, and the ribosome-associated mRNA level of the ten-eleven translocation (Tet) family methylcytosine dioxygenase Tet3, but not Tet1 or Tet2, was dramatically upregulated 10 minutes after memory retrieval. The protein level of Tet3 in the dorsal hippocampus but not in the anterior cingulate cortex was dramatically increased 1 hour after memory retrieval. Specifically, knockdown of Tet3 in pyramidal neurons in the dorsal hippocampus decreased the activation of pyramidal neurons and impaired the reconsolidation of cocaine-associated memory. Conclusions Our findings highlight the new function of the DNA demethylation regulator Tet3 in pyramidal neurons of the dorsal hippocampus in regulating the reconsolidation of cocaine-associated memory. PMID:29106571
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Butler, Anderson A; Webb, William M; Lubin, Farah D
2016-01-01
The diverse functions of noncoding RNAs (ncRNAs) can influence virtually every aspect of the transcriptional process including epigenetic regulation of genes. In the CNS, regulatory RNA networks and epigenetic mechanisms have broad relevance to gene transcription changes involved in long-term memory formation and cognition. Thus, it is becoming increasingly clear that multiple classes of ncRNAs impact neuronal development, neuroplasticity, and cognition. Currently, a large gap exists in our knowledge of how ncRNAs facilitate epigenetic processes, and how this phenomenon affects cognitive function. In this review, we discuss recent findings highlighting a provocative role for ncRNAs including lncRNAs and piRNAs in the control of epigenetic mechanisms involved in cognitive function. Furthermore, we discuss the putative roles for these ncRNAs in cognitive disorders such as schizophrenia and Alzheimer's disease.
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The Emerging Role of Epigenetics in Inflammation and Immunometabolism.
Raghuraman, Sukanya; Donkin, Ida; Versteyhe, Soetkin; Barrès, Romain; Simar, David
2016-11-01
Recent research developments have shed light on the risk factors contributing to metabolic complications, implicating both genetic and environmental factors, potentially integrated by epigenetic mechanisms. Distinct epigenetic changes in immune cells are frequently observed in obesity and type 2 diabetes mellitus, and these are associated with alterations in the phenotype, function, and trafficking patterns of these cells. The first step in the development of effective therapeutic strategies is the identification of distinct epigenetic signatures associated with metabolic disorders. In this review we provide an overview of the epigenetic mechanisms influencing immune cell phenotype and function, summarize current knowledge about epigenetic changes affecting immune functions in the context of metabolic diseases, and discuss the therapeutic options currently available to counteract epigenetically driven metabolic complications. Copyright © 2016 Elsevier Ltd. All rights reserved.
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Clinical relevance of epigenetics in the onset and management of type 2 diabetes mellitus
Sommese, Linda; Zullo, Alberto; Mancini, Francesco Paolo; Fabbricini, Rossella; Soricelli, Andrea; Napoli, Claudio
2017-01-01
ABSTRACT Epigenetics is involved in the altered expression of gene networks that underlie insulin resistance and insufficiency. Major genes controlling β-cell differentiation and function, such as PAX4, PDX1, and GLP1 receptor, are epigenetically controlled. Epigenetics can cause insulin resistance through immunomediated pro-inflammatory actions related to several factors, such as NF-kB, osteopontin, and Toll-like receptors. Hereafter, we provide a critical and comprehensive summary on this topic with a particular emphasis on translational and clinical aspects. We discuss the effect of epigenetics on β-cell regeneration for cell replacement therapy, the emerging bioinformatics approaches for analyzing the epigenetic contribution to type 2 diabetes mellitus (T2DM), the epigenetic core of the transgenerational inheritance hypothesis in T2DM, and the epigenetic clinical trials on T2DM. Therefore, prevention or reversion of the epigenetic changes occurring during T2DM development may reduce the individual and societal burden of the disease. PMID:28059593
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Bédécarrats, Alexis; Chen, Shanping; Pearce, Kaycey; Cai, Diancai; Glanzman, David L
2018-01-01
The precise nature of the engram, the physical substrate of memory, remains uncertain. Here, it is reported that RNA extracted from the central nervous system of Aplysia given long-term sensitization (LTS) training induced sensitization when injected into untrained animals; furthermore, the RNA-induced sensitization, like training-induced sensitization, required DNA methylation. In cellular experiments, treatment with RNA extracted from trained animals was found to increase excitability in sensory neurons, but not in motor neurons, dissociated from naïve animals. Thus, the behavioral, and a subset of the cellular, modifications characteristic of a form of nonassociative long-term memory (LTM) in Aplysia can be transferred by RNA. These results indicate that RNA is sufficient to generate an engram for LTS in Aplysia and are consistent with the hypothesis that RNA-induced epigenetic changes underlie memory storage in Aplysia .
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Chen, Shanping; Pearce, Kaycey; Cai, Diancai
2018-01-01
The precise nature of the engram, the physical substrate of memory, remains uncertain. Here, it is reported that RNA extracted from the central nervous system of Aplysia given long-term sensitization (LTS) training induced sensitization when injected into untrained animals; furthermore, the RNA-induced sensitization, like training-induced sensitization, required DNA methylation. In cellular experiments, treatment with RNA extracted from trained animals was found to increase excitability in sensory neurons, but not in motor neurons, dissociated from naïve animals. Thus, the behavioral, and a subset of the cellular, modifications characteristic of a form of nonassociative long-term memory (LTM) in Aplysia can be transferred by RNA. These results indicate that RNA is sufficient to generate an engram for LTS in Aplysia and are consistent with the hypothesis that RNA-induced epigenetic changes underlie memory storage in Aplysia. PMID:29789810
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Epigenetic Regulation of Memory Formation and Maintenance
ERIC Educational Resources Information Center
Zovkic, Iva B.; Guzman-Karlsson, Mikael C.; Sweatt, J. David
2013-01-01
Understanding the cellular and molecular mechanisms underlying the formation and maintenance of memories is a central goal of the neuroscience community. It is well regarded that an organism's ability to lastingly adapt its behavior in response to a transient environmental stimulus relies on the central nervous system's capability for structural…
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Methionine increases BDNF DNA methylation and improves memory in epilepsy.
Parrish, R Ryley; Buckingham, Susan C; Mascia, Katherine L; Johnson, Jarvis J; Matyjasik, Michal M; Lockhart, Roxanne M; Lubin, Farah D
2015-04-01
Temporal lobe epilepsy (TLE) patients exhibit signs of memory impairments even when seizures are pharmacologically controlled. Surprisingly, the underlying molecular mechanisms involved in TLE-associated memory impairments remain elusive. Memory consolidation requires epigenetic transcriptional regulation of genes in the hippocampus; therefore, we aimed to determine how epigenetic DNA methylation mechanisms affect learning-induced transcription of memory-permissive genes in the epileptic hippocampus. Using the kainate rodent model of TLE and focusing on the brain-derived neurotrophic factor (Bdnf) gene as a candidate of DNA methylation-mediated transcription, we analyzed DNA methylation levels in epileptic rats following learning. After detection of aberrant DNA methylation at the Bdnf gene, we investigated functional effects of altered DNA methylation on hippocampus-dependent memory formation in our TLE rodent model. We found that behaviorally driven BdnfDNA methylation was associated with hippocampus-dependent memory deficits. Bisulfite sequencing revealed that decreased BdnfDNA methylation levels strongly correlated with abnormally high levels of BdnfmRNA in the epileptic hippocampus during memory consolidation. Methyl supplementation via methionine (Met) increased BdnfDNA methylation and reduced BdnfmRNA levels in the epileptic hippocampus during memory consolidation. Met administration reduced interictal spike activity, increased theta rhythm power, and reversed memory deficits in epileptic animals. The rescue effect of Met treatment on learning-induced BdnfDNA methylation, Bdnf gene expression, and hippocampus-dependent memory, were attenuated by DNA methyltransferase blockade. Our findings suggest that manipulation of DNA methylation in the epileptic hippocampus should be considered as a viable treatment option to ameliorate memory impairments associated with TLE.
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Induced pluripotent stem (iPS) cells: a new source for cell-based therapeutics?
de Lázaro, Irene; Yilmazer, Açelya; Kostarelos, Kostas
2014-07-10
The generation of induced pluripotent stem (iPS) cells from somatic cells by the ectopic expression of defined transcription factors has provided the regenerative medicine field with a new tool for cell replacement strategies. The advantages that these pluripotent cells can offer in comparison to other sources of stem cells include the generation of patient-derived cells and the lack of embryonic tissue while maintaining a versatile differentiation potential. The promise of iPS cell derivatives for therapeutic applications is encouraging albeit very early in development, with the first clinical study currently ongoing in Japan. Many challenges are yet to be circumvented before this technology can be clinically translated widely though. The delivery and expression of the reprogramming factors, the genomic instability, epigenetic memory and impact of cell propagation in culture are only some of the concerns. This article aims to critically discuss the potential of iPS cells as a new source of cell therapeutics. Copyright © 2014 Elsevier B.V. All rights reserved.
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Epigenetic regulation leading to induced pluripotency drives cancer development in vivo
DOE Office of Scientific and Technical Information (OSTI.GOV)
Ohnishi, Kotaro; Department of Medicine, Gifu University Graduate School of Medicine, Gifu 501-1194; Semi, Katsunori
Highlights: • Epigenetic regulation of failed reprogramming-associated cancer cells is discussed. • Similarity between pediatric cancer and reprogramming-associated cancer is discussed. • Concept for epigenetic cancer is discussed. - Abstract: Somatic cells can be reprogrammed into induced pluripotent stem cells (iPSCs) by the transient expression of reprogramming factors. During the reprogramming process, somatic cells acquire the ability to undergo unlimited proliferation, which is also an important characteristic of cancer cells, while their underlying DNA sequence remains unchanged. Based on the characteristics shared between pluripotent stem cells and cancer cells, the potential involvement of the factors leading to reprogramming toward pluripotencymore » in cancer development has been discussed. Recent in vivo reprogramming studies provided some clues to understanding the role of reprogramming-related epigenetic regulation in cancer development. It was shown that premature termination of the in vivo reprogramming result in the development of tumors that resemble pediatric cancers. Given that epigenetic modifications play a central role during reprogramming, failed reprogramming-associated cancer development may have provided a proof of concept for epigenetics-driven cancer development in vivo.« less
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Epigenetic Research of Neurodegenerative Disorders Using Patient iPSC-Based Models
2016-01-01
Epigenetic mechanisms play a role in human disease but their involvement in pathologies from the central nervous system has been hampered by the complexity of the brain together with its unique cellular architecture and diversity. Until recently, disease targeted neural types were only available as postmortem materials after many years of disease evolution. Current in vitro systems of induced pluripotent stem cells (iPSCs) generated by cell reprogramming of somatic cells from patients have provided valuable disease models recapitulating key pathological molecular events. Yet whether cell reprogramming on itself implies a truly epigenetic reprogramming, the epigenetic mechanisms governing this process are only partially understood. Moreover, elucidating epigenetic regulation using patient-specific iPSC-derived neural models is expected to have a great impact to unravel the pathophysiology of neurodegenerative diseases and to hopefully expand future therapeutic possibilities. Here we will critically review current knowledge of epigenetic involvement in neurodegenerative disorders focusing on the potential of iPSCs as a promising tool for epigenetic research of these diseases. PMID:26697081
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Identification of Epigenetic Changes in Prostate Cancer using Induced Pluripotent Stem Cells
2013-04-01
0240 TITLE: Identification of Epigenetic Changes in Prostate Cancer using Induced Pluripotent Stem Cells PRINCIPAL INVESTIGATOR: Donna M...TITLE AND SUBTITLE I Identification of Epigenetic Changes in Prostate Cancer using 5a. CONTRACT NUMBER Induced Pluripotent Stem Cells ... stem cells (iPSCs). Comparison of gene and protein expression of these prostatic iPSCs and embryonic stem cells (ESCs) revealed similarities but
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SFRP1 is a possible candidate for epigenetic therapy in non-small cell lung cancer.
Taguchi, Y-H; Iwadate, Mitsuo; Umeyama, Hideaki
2016-08-12
Non-small cell lung cancer (NSCLC) remains a lethal disease despite many proposed treatments. Recent studies have indicated that epigenetic therapy, which targets epigenetic effects, might be a new therapeutic methodology for NSCLC. However, it is not clear which objects (e.g., genes) this treatment specifically targets. Secreted frizzled-related proteins (SFRPs) are promising candidates for epigenetic therapy in many cancers, but there have been no reports of SFRPs targeted by epigenetic therapy for NSCLC. This study performed a meta-analysis of reprogrammed NSCLC cell lines instead of the direct examination of epigenetic therapy treatment to identify epigenetic therapy targets. In addition, mRNA expression/promoter methylation profiles were processed by recently proposed principal component analysis based unsupervised feature extraction and categorical regression analysis based feature extraction. The Wnt/β-catenin signalling pathway was extensively enriched among 32 genes identified by feature extraction. Among the genes identified, SFRP1 was specifically indicated to target β-catenin, and thus might be targeted by epigenetic therapy in NSCLC cell lines. A histone deacetylase inhibitor might reactivate SFRP1 based upon the re-analysis of a public domain data set. Numerical computation validated the binding of SFRP1 to WNT1 to suppress Wnt signalling pathway activation in NSCLC. The meta-analysis of reprogrammed NSCLC cell lines identified SFRP1 as a promising target of epigenetic therapy for NSCLC.
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Kim, Changsung
2014-03-01
Induced pluripotent stem cell (iPSC) technology has shown us great hope to treat various human diseases which have been known as untreatable and further endows personalized medicine for future therapy without ethical issues and immunological rejection which embryonic stem cell (hES) treatment has faced. It has been agreed that iPSCs knowledge can be harnessed from disease modeling which mimics human pathological development rather than trials utilizing conventional rodent and cell lines. Now, we can routinely generate iPSC from patient specific cell sources, such as skin fibroblast, hair follicle cells, patient blood samples and even urine containing small amount of epithelial cells. iPSC has both similarity and dissimilarity to hES. iPSC is similar enough to regenerate tissue and even full organism as ES does, however what we want for therapeutic advantage is limited to regenerated tissue and lineage specific differentiation. Depending on the lineage and type of cells, both tissue memory containing (DNA rearrangement/epigenetics) and non-containing iPSC can be generated. This makes iPSC even better choice to perform disease modeling as well as cell based therapy. Tissue memory containing iPSC from mature leukocytes would be beneficial for curing cancer and infectious disease. In this review, the benefit of iPSC for translational approaches will be presented.
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Imm, Jennifer; Kerrigan, Talitha L; Jeffries, Aaron; Lunnon, Katie
2017-11-01
It is thought that both genetic and epigenetic variation play a role in Alzheimer's disease initiation and progression. With the advent of somatic cell reprogramming into induced pluripotent stem cells it is now possible to generate patient-derived cells that are able to more accurately model and recapitulate disease. Furthermore, by combining this with recent advances in (epi)genome editing technologies, it is possible to begin to examine the functional consequence of previously nominated genetic variants and infer epigenetic causality from recently identified epigenetic variants. In this review, we explore the role of genetic and epigenetic variation in Alzheimer's disease and how the functional relevance of nominated loci can be investigated using induced pluripotent stem cells and (epi)genome editing techniques.
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MS-HRM assay identifies high levels of epigenetic heterogeneity in human immortalized cell lines.
Putnik, Milica; Wojdacz, Tomasz K; Pournara, Angeliki; Vahter, Marie; Wallberg, Annika E
2015-04-15
Immortalized cell lines are widely used in genetic and epigenetic studies, from exploration of basic molecular pathways to evaluation of disease-specific cellular properties. They are also used in biotechnology, e.g., in drug toxicity tests and vaccine production. Cellular and genetic uniformity is the main feature of immortalized cell lines and it has been particularly advantageous in functional genomic research, which has in recent years been expanded to include epigenetic mechanisms of gene expression regulation. Using the MS-HRM technique, we demonstrated heterogeneity in locus-specific methylation patterns in different cell cultures of four human cell lines: HEK293, HEK293T, LCL and DU145. Our results show that some human immortalized cell lines consist of cells that differ in the methylation status of specific loci, i.e., that they are epigenetically heterogeneous. We show that even two cultures of the same cell line obtained from different laboratories can differ in the methylation status of the specific loci. The results indicated that epigenetic uniformity of the cell lines cannot be assumed in experiments which utilize cell cultures and that the methylation status of the specific loci in the immortalized cell lines should be re-characterized and carefully profiled before epigenetic studies are performed. Copyright © 2015 Elsevier B.V. All rights reserved.
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Kinetic memory based on the enzyme-limited competition.
Hatakeyama, Tetsuhiro S; Kaneko, Kunihiko
2014-08-01
Cellular memory, which allows cells to retain information from their environment, is important for a variety of cellular functions, such as adaptation to external stimuli, cell differentiation, and synaptic plasticity. Although posttranslational modifications have received much attention as a source of cellular memory, the mechanisms directing such alterations have not been fully uncovered. It may be possible to embed memory in multiple stable states in dynamical systems governing modifications. However, several experiments on modifications of proteins suggest long-term relaxation depending on experienced external conditions, without explicit switches over multi-stable states. As an alternative to a multistability memory scheme, we propose "kinetic memory" for epigenetic cellular memory, in which memory is stored as a slow-relaxation process far from a stable fixed state. Information from previous environmental exposure is retained as the long-term maintenance of a cellular state, rather than switches over fixed states. To demonstrate this kinetic memory, we study several models in which multimeric proteins undergo catalytic modifications (e.g., phosphorylation and methylation), and find that a slow relaxation process of the modification state, logarithmic in time, appears when the concentration of a catalyst (enzyme) involved in the modification reactions is lower than that of the substrates. Sharp transitions from a normal fast-relaxation phase into this slow-relaxation phase are revealed, and explained by enzyme-limited competition among modification reactions. The slow-relaxation process is confirmed by simulations of several models of catalytic reactions of protein modifications, and it enables the memorization of external stimuli, as its time course depends crucially on the history of the stimuli. This kinetic memory provides novel insight into a broad class of cellular memory and functions. In particular, applications for long-term potentiation are discussed, including dynamic modifications of calcium-calmodulin kinase II and cAMP-response element-binding protein essential for synaptic plasticity.
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[Epigenetics of childhood obesity and diabetes].
Valladares-Salgado, Adán; Suárez-Sánchez, Fernando; Burguete-García, Ana I; Cruz, Miguel
2014-01-01
Obesity and type 2 diabetes mellitus (T2DM) result from sedentary lifestyle, high-carbohydrate diets and genetic predisposition. Epigenetics is a form of genetic regulation in specialized cells that does not involve changes in the deoxyribonucleic acid (DNA) sequence, but it can be inherited to one or more generations through mitosis or meiosis. Children whose mothers develop gestational diabetes are more likely to become obese and diabetic in adult life. DNA methylation is a major mechanism in the regulation of transcription and gene expression of several genes. High levels of glucose and insulin during pregnancy modify the risk of developing T2DM, suggesting that the expression pattern is modified due to cell memory in a specific tissue. If T2DM is linked to adaptation in utero, the obvious primary prevention is to protect the fetal development. Future epidemiological studies need to employ more accurate indicators or markers of development to show the relationship between a specific disease and the exposure to environmental factors. The mechanisms by which malnutrition, and intrauterine growth retardation produce changes in the metabolism of glucose and insuline are worth to explore in order to control obesity and T2DM.
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Skinner, Michael K.; Haque, Carlos Guerrero-Bosagna M.; Nilsson, Eric; Bhandari, Ramji; McCarrey, John R.
2013-01-01
A number of environmental factors (e.g. toxicants) have been shown to promote the epigenetic transgenerational inheritance of disease and phenotypic variation. Transgenerational inheritance requires the germline transmission of altered epigenetic information between generations in the absence of direct environmental exposures. The primary periods for epigenetic programming of the germ line are those associated with primordial germ cell development and subsequent fetal germline development. The current study examined the actions of an agricultural fungicide vinclozolin on gestating female (F0 generation) progeny in regards to the primordial germ cell (PGC) epigenetic reprogramming of the F3 generation (i.e. great-grandchildren). The F3 generation germline transcriptome and epigenome (DNA methylation) were altered transgenerationally. Interestingly, disruptions in DNA methylation patterns and altered transcriptomes were distinct between germ cells at the onset of gonadal sex determination at embryonic day 13 (E13) and after cord formation in the testis at embryonic day 16 (E16). A larger number of DNA methylation abnormalities (epimutations) and transcriptional alterations were observed in the E13 germ cells than in the E16 germ cells. These observations indicate that altered transgenerational epigenetic reprogramming and function of the male germline is a component of vinclozolin induced epigenetic transgenerational inheritance of disease. Insights into the molecular control of germline transmitted epigenetic inheritance are provided. PMID:23869203
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Epigenetic transmission of Holocaust trauma: can nightmares be inherited?
Kellermann, Natan Pf
2013-01-01
The Holocaust left its visible and invisible marks not only on the survivors, but also on their children. Instead of numbers tattooed on their forearms, however, they may have been marked epigenetically with a chemical coating upon their chromosomes, which would represent a kind of biological memory of what the parents experienced. as a result, some suffer from a general vulnerability to stress while others are more resilient. Previous research assumed that such transmission was caused by environmental factors, such as the parents' childrearing behavior. New research, however, indicates that these transgenerational effects may have been also (epi) genetically transmitted to their children. Integrating both hereditary and environmental factors, epigenetics adds a new and more comprehensive psychobiological dimension to the explanation of transgenerational transmission of trauma. Specifically, epigenetics may explain why latent transmission becomes manifest under stress. a general theoretical overview of epigenetics and its relevance to research on trauma transmission is presented.
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[Epigenetics, interface between environment and genes: role in complex diseases].
Scheen, A J; Junien, C
2012-01-01
Epigenetics is the study of heritable changes in gene expression or cellular phenotype caused by mechanisms other than changes in the underlying DNA sequence. Epigenetics is one of the major mechanisms explaining the "Developmental Origin of Health and Diseases" (DOHaD). Besides genetic background inherited from parents, which confers susceptibility to certain pathologies, epigenetic changes constitute the memory of previous events, either positive or negative, along the life cycle, including at the in utero stage. The later exposition to hostile environment may reveal such susceptibility, with the development of various pathologies, among them numerous chronic complex diseases. The demonstration of such a sequence of events has been shown for metabolic diseases as obesity, metabolic syndrome and type 2 diabetes, cardiovascular disease and cancer. In contrast to genetic predisposition, which is irreversible, epigenetic changes are potentially reversible, thus giving targets not only for prevention, but possibly also for the treatment of certain complex diseases.
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The potential of epigenetic therapies in neurodegenerative diseases
Coppedè, Fabio
2014-01-01
Available treatments for neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease, do not arrest disease progression but mainly help keeping patients from getting worse for a limited period of time. Increasing evidence suggests that epigenetic mechanisms such as DNA methylation and histone tail modifications are dynamically regulated in neurons and play a fundamental role in learning and memory processes. In addition, both global and gene-specific epigenetic changes and deregulated expression of the writer and eraser proteins of epigenetic marks are believed to contribute to the onset and progression of neurodegeneration. Studies in animal models of neurodegenerative diseases have highlighted the potential role of epigenetic drugs, including inhibitors of histone deacetylases and methyl donor compounds, in ameliorating the cognitive symptoms and preventing or delaying the motor symptoms of the disease, thereby opening the way for a potential application in human pathology. PMID:25071843
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Carroll, Judith E; Irwin, Michael R; Levine, Morgan; Seeman, Teresa E; Absher, Devin; Assimes, Themistocles; Horvath, Steve
2017-01-15
Insomnia symptoms are associated with vulnerability to age-related morbidity and mortality. Cross-sectional data suggest that accelerated biological aging may be a mechanism through which sleep influences risk. A novel method for determining age acceleration using epigenetic methylation to DNA has demonstrated predictive utility as an epigenetic clock and prognostic of age-related morbidity and mortality. We examined the association of epigenetic age and immune cell aging with sleep in the Women's Health Initiative study (N = 2078; mean 64.5 ± 7.1 years of age) with assessment of insomnia symptoms (restlessness, difficulty falling asleep, waking at night, trouble getting back to sleep, and early awakenings), sleep duration (short sleep 5 hours or less; long sleep greater than 8 hours), epigenetic age, naive T cell (CD8+CD45RA+CCR7+), and late differentiated T cells (CD8+CD28-CD45RA-). Insomnia symptoms were related to advanced epigenetic age (β ± SE = 1.02 ± 0.37, p = .005) after adjustments for covariates. Insomnia symptoms were also associated with more late differentiated T cells (β ± SE = 0.59 ± 0.21, p = .006), but not with naive T cells. Self-reported short and long sleep duration were unrelated to epigenetic age. Short sleep, but not long sleep, was associated with fewer naive T cells (p < .005) and neither was related to late differentiated T cells. Symptoms of insomnia were associated with increased epigenetic age of blood tissue and were associated with higher counts of late differentiated CD8+ T cells. Short sleep was unrelated to epigenetic age and late differentiated cell counts, but was related to a decline in naive T cells. In this large population-based study of women in the United States, insomnia symptoms are implicated in accelerated aging. Copyright © 2016. Published by Elsevier Inc.
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Mechanisms for the epigenetic inheritance of stress response in single cells.
Xue, Yuan; Acar, Murat
2018-05-30
Cells have evolved to dynamically respond to different types of environmental and physiological stress conditions. The information about a previous stress stimulus experience by a mother cell can be passed to its descendants, allowing them to better adapt to and survive in new environments. In recent years, live-cell imaging combined with cell-lineage tracking approaches has elucidated many important principles that guide stress inheritance at the single-cell and population level. In this review, we summarize different strategies that cells can employ to pass the 'memory' of previous stress responses to their descendants. Among these strategies, we focus on a recent discovery of how specific features of Msn2 nucleo-cytoplasmic shuttling dynamics could be inherited across cell lineages. We also discuss how stress response can be transmitted to progenies through changes in chromatin and through partitioning of anti-stress factors and/or damaged macromolecules between mother and daughter cells during cell division. Finally, we highlight how emergent technologies will help address open questions in the field.
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Epigenetics of cell fate reprogramming and its implications for neurological disorders modelling.
Grzybek, Maciej; Golonko, Aleksandra; Walczak, Marta; Lisowski, Pawel
2017-03-01
The reprogramming of human induced pluripotent stem cells (hiPSCs) proceeds in a stepwise manner with reprogramming factors binding and epigenetic composition changes during transition to maintain the epigenetic landscape, important for pluripotency. There arises a question as to whether the aberrant epigenetic state after reprogramming leads to epigenetic defects in induced stem cells causing unpredictable long term effects in differentiated cells. In this review, we present a comprehensive view of epigenetic alterations accompanying reprogramming, cell maintenance and differentiation as factors that influence applications of hiPSCs in stem cell based technologies. We conclude that sample heterogeneity masks DNA methylation signatures in subpopulations of cells and thus believe that beside a genetic evaluation, extensive epigenomic screening should become a standard procedure to ensure hiPSCs state before they are used for genome editing and differentiation into neurons of interest. In particular, we suggest that exploitation of the single-cell composition of the epigenome will provide important insights into heterogeneity within hiPSCs subpopulations to fast forward development of reliable hiPSC-based analytical platforms in neurological disorders modelling and before completed hiPSC technology will be implemented in clinical approaches. Copyright © 2016 Elsevier Inc. All rights reserved.
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Pizzimenti, C. L.; Lattal, K. M.
2015-01-01
Understanding the interaction between fear and reward at the circuit and molecular levels has implications for basic scientific approaches to memory and for understanding the etiology of psychiatric disorders. Both stress and exposure to drugs of abuse induce epigenetic changes that result in persistent behavioral changes, some of which may contribute to the formation of a drug addiction or a stress-related psychiatric disorder. Converging evidence suggests that similar behavioral, neurobiological and molecular mechanisms control the extinction of learned fear and drug-seeking responses. This may, in part, account for the fact that individuals with post-traumatic stress disorder have a significantly elevated risk of developing a substance use disorder and have high rates of relapse to drugs of abuse, even after long periods of abstinence. At the behavioral level, a major challenge in treatments is that extinguished behavior is often not persistent, returning with changes in context, the passage of time or exposure to mild stressors. A common goal of treatments is therefore to weaken the ability of stressors to induce relapse. With the discovery of epigenetic mechanisms that create persistent molecular signals, recent work on extinction has focused on how modulating these epigenetic targets can create lasting extinction of fear or drug-seeking behavior. Here, we review recent evidence pointing to common behavioral, systems and epigenetic mechanisms in the regulation of fear and drug seeking. We suggest that targeting these mechanisms in combination with behavioral therapy may promote treatment and weaken stress-induced relapse. PMID:25560936
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Abnormal Epigenetic Regulation of Immune System during Aging.
Jasiulionis, Miriam G
2018-01-01
Epigenetics refers to the study of mechanisms controlling the chromatin structure, which has fundamental role in the regulation of gene expression and genome stability. Epigenetic marks, such as DNA methylation and histone modifications, are established during embryonic development and epigenetic profiles are stably inherited during mitosis, ensuring cell differentiation and fate. Under the effect of intrinsic and extrinsic factors, such as metabolic profile, hormones, nutrition, drugs, smoke, and stress, epigenetic marks are actively modulated. In this sense, the lifestyle may affect significantly the epigenome, and as a result, the gene expression profile and cell function. Epigenetic alterations are a hallmark of aging and diseases, such as cancer. Among biological systems compromised with aging is the decline of immune response. Different regulators of immune response have their promoters and enhancers susceptible to the modulation by epigenetic marks, which is fundamental to the differentiation and function of immune cells. Consistent evidence has showed the regulation of innate immune cells, and T and B lymphocytes by epigenetic mechanisms. Therefore, age-dependent alterations in epigenetic marks may result in the decline of immune function and this might contribute to the increased incidence of diseases in old people. In order to maintain health, we need to better understand how to avoid epigenetic alterations related to immune aging. In this review, the contribution of epigenetic mechanisms to the loss of immune function during aging will be discussed, and the promise of new means of disease prevention and management will be pointed.
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Liu, Cao; Sun, Xue; Wang, Zhilin; Le, Qiumin; Liu, Peipei; Jiang, Changyou; Wang, Feifei; Ma, Lan
2018-03-01
Memory retrieval refers to reexposure to information previously encoded and stored in the brain. Following retrieval, a once-consolidated memory destabilizes and undergoes reconsolidation, during which gene expression changes to restabilize memory. Investigating epigenetic regulation during reconsolidation could provide insights into normal memory formation and pathological memory associated with psychiatric disorders. We used cocaine-induced conditioned place preference to assess the cocaine-associated memory of mice and used chemogenetic methods to manipulate the activity of the pyramidal neurons in the dorsal hippocampus. We isolated the ribosome-associated transcripts from the excitatory neurons in the dorsal hippocampus by RiboTag purification to identify the potential epigenetic regulators, and we specifically knocked down gene expression in pyramidal neurons with a Cre-dependent lentivirus. Chemogenetically silencing the activity of the pyramidal neurons in the dorsal hippocampus immediately after memory retrieval markedly impaired memory reconsolidation, and the ribosome-associated mRNA level of the ten-eleven translocation (Tet) family methylcytosine dioxygenase Tet3, but not Tet1 or Tet2, was dramatically upregulated 10 minutes after memory retrieval. The protein level of Tet3 in the dorsal hippocampus but not in the anterior cingulate cortex was dramatically increased 1 hour after memory retrieval. Specifically, knockdown of Tet3 in pyramidal neurons in the dorsal hippocampus decreased the activation of pyramidal neurons and impaired the reconsolidation of cocaine-associated memory. Our findings highlight the new function of the DNA demethylation regulator Tet3 in pyramidal neurons of the dorsal hippocampus in regulating the reconsolidation of cocaine-associated memory. © The Author 2017. Published by Oxford University Press on behalf of CINP.
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Cancer Progenitor Cells: The Result of an Epigenetic Event?
Lapinska, Karolina; Faria, Gabriela; McGonagle, Sandra; Macumber, Kate Morgan; Heerboth, Sarah; Sarkar, Sibaji
2018-01-01
The concept of cancer stem cells was proposed in the late 1990s. Although initially the idea seemed controversial, the existence of cancer stem cells is now well established. However, the process leading to the formation of cancer stem cells is still not clear and thus requires further research. This article discusses epigenetic events that possibly produce cancer progenitor cells from predisposed cells by the influence of their environment. Every somatic cell possesses an epigenetic signature in terms of histone modifications and DNA methylation, which are obtained during lineage-specific differentiation of pluripotent stem cells, which is specific to that particular tissue. We call this signature an epigenetic switch. The epigenetic switch is not fixed. Our epigenome alters with aging. However, depending on the predisposition of the cells of a particular tissue and their microenvironment, the balance of the switch (histone modifications and the DNA methylation) may be tilted to immortality in a few cells, which generates cancer progenitor cells. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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ERIC Educational Resources Information Center
Barrett, Ruth M.; Wood, Marcelo A.
2008-01-01
One of the alluring aspects of examining chromatin modifications in the role of modulating transcription required for long-term memory processes is that these modifications may provide transient and potentially stable epigenetic marks in the service of activating and/or maintaining transcriptional processes. These, in turn, may ultimately…
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FAT10 IS AN EPIGENETIC MARKER FOR LIVER PRENEOPLASIA IN A DRUG-PRIMED MOUSE MODEL OF TUMORIGENESIS
Oliva, Joan; Bardag-Gorce, Fawzia; French, Barbara A; Li, Jun; McPhaul, Laron; Amidi, Fataneh; Dedes, Jeniffer; Habibi, Amir; Nguyen, Sheila; French, Samuel W
2010-01-01
There is clinical evidence that chronic liver diseases in which MDBs (Mallory Denk Bodies) form progress to hepatocellular carcinoma. The present study provides evidence that links MDB formation induced by chronic drug injury, with preneoplasia and later to the formation of tumors, which develop long after drug withdrawal. Evidence indicated that this link was due to an epigenetic cellular memory induced by chronic drug ingestion. Microarray analysis showed that the expressions of many markers of preneoplasia (UBD, Alpha Fetoprotein, KLF6 and Glutathione-S-Transferase mu2) were increased together when the drug DDC was refed. These changes were suppressed by S-adenosylmethionine feeding, indicating that the drug was affecting DNA and histones methylation in an epigenetic manner. The link between MDB formation and neoplasia formation was likely due to the over expression of UBD (also called FAT10), which is up regulated in 90% of human hepatocellular carcinomas. Immunohistochemical staining of drug primed mouse livers showed that FAT10 positive liver cells persisted up to 4 months after drug withdrawal and they were still found in the livers of mice, 14 months after drug withdrawal. The refeeding of DDC increased the percent of FAT10 hepatocytes. PMID:18280469
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Emodin modulates epigenetic modifications and suppresses bladder carcinoma cell growth.
Cha, Tai-Lung; Chuang, Mei-Jen; Tang, Shou-Hung; Wu, Sheng-Tang; Sun, Kuang-Hui; Chen, Tzu-Ting; Sun, Guang-Huan; Chang, Sun-Yran; Yu, Cheng-Ping; Ho, Jar-Yi; Liu, Shu-Yu; Huang, Shih-Ming; Yu, Dah-Shyong
2015-03-01
The deregulation of epigenetics was involved in early and subsequent carcinogenic events. Reversing cancer epigenetics to restore a normal epigenetic condition could be a rational approach for cancer treatment and specialized prevention. In the present study, we found that the expression levels of two epigenetic markers, histone H3K27 trimethylation (H3K27me3), was low but histone H3S10 phosphorylation (pH3Ser10) was high in human bladder cancer tissues, which showed opposite expression patterns in their normal counterparts. Thus, we investigated whether a natural product, emodin, has the ability to reverse these two epigenetic modifications and inhibit bladder cancer cell growth. Emodin significantly inhibited the cell growth of four bladder cancer cell lines in a dose- and time-dependent manner. Emodin treatment did not induce specific cell cycle arrest, but it altered epigenetic modifications. Emodin treatment resulted in the suppression of pH3Ser10 and increased H3K27me3, contributing to gene silencing in bladder cancer cells. Microarray analysis demonstrated that oncogenic genes including fatty acid binding protein 4 (FABP4) and fibroblast growth factor binding protein 1 (HBP17), RGS4, tissue inhibitor of metalloproteinase 3 (TIMP3), WNT5b, URB, and collagen, type VIII, alpha 1 (COL8A1) responsible for proliferation, survival, inflammation, and carcinogenesis were significantly repressed by emodin. The ChIP assays also showed that emodin increased H3K27me3 but decreased pH3Ser10 modifications on the promoters of repressed genes, which indicate that emodin reverses the cancer epigenetics towards normal epigenetic situations. In conclusion, our work demonstrates the significant anti-neoplastic activity of emodin on bladder cancer cells and elucidates the novel mechanisms of emodin-mediated epigenetic modulation of target genes. Our study warrants further investigation of emodin as an effective therapeutic or preventive agent for bladder cancer. © 2013 Wiley Periodicals, Inc.
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Rossetti, Stefano; Ren, MingQiang; Visconti, Nicolo; Corlazzoli, Francesca; Gagliostro, Vincenzo; Somenzi, Giulia; Yao, Jin; Sun, Yijun; Sacchi, Nicoletta
2016-12-27
A hallmark of cancer cells is the ability to evade the growth inhibitory/pro-apoptotic action of physiological all-trans retinoic acid (RA) signal, the bioactive derivative of Vitamin A. However, as we and others reported, RA can also promote cancer cell growth and invasion. Here we show that anticancer and cancer-promoting RA actions in breast cancer have roots in a mechanism of mammary epithelial cell morphogenesis that involves both transcriptional (epigenetic) and non-transcriptional RARα (RARA) functions. We found that the mammary epithelial cell-context specific degree of functionality of the RARA transcriptional (epigenetic) component of this mechanism, by tuning the effects of the non-transcriptional RARA component, determines different cell fate decisions during mammary morphogenesis. Indeed, factors that hamper the RARA epigenetic function make physiological RA drive aberrant morphogenesis via non-transcriptional RARA, thus leading to cell transformation. Remarkably, also the cell context-specific degree of functionality of the RARA epigenetic component retained by breast cancer cells is critical to determine cell fate decisions in response to physiological as well as supraphysiological RA variation. Overall this study supports the proof of principle that the epigenetic functional plasticity of the mammary epithelial cell RARA mechanism, which is essential for normal morphogenetic processes, is necessary to deter breast cancer onset/progression consequent to the insidious action of physiological RA.
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Reconsidering plant memory: Intersections between stress recovery, RNA turnover, and epigenetics
Crisp, Peter A.; Ganguly, Diep; Eichten, Steven R.; Borevitz, Justin O.; Pogson, Barry J.
2016-01-01
Plants grow in dynamic environments where they can be exposed to a multitude of stressful factors, all of which affect their development, yield, and, ultimately, reproductive success. Plants are adept at rapidly acclimating to stressful conditions and are able to further fortify their defenses by retaining memories of stress to enable stronger or more rapid responses should an environmental perturbation recur. Indeed, one mechanism that is often evoked regarding environmental memories is epigenetics. Yet, there are relatively few examples of such memories; neither is there a clear understanding of their duration, considering the plethora of stresses in nature. We propose that this field would benefit from investigations into the processes and mechanisms enabling recovery from stress. An understanding of stress recovery could provide fresh insights into when, how, and why environmental memories are created and regulated. Stress memories may be maladaptive, hindering recovery and affecting development and potential yield. In some circumstances, it may be advantageous for plants to learn to forget. Accordingly, the recovery process entails a balancing act between resetting and memory formation. During recovery, RNA metabolism, posttranscriptional gene silencing, and RNA-directed DNA methylation have the potential to play key roles in resetting the epigenome and transcriptome and in altering memory. Exploration of this emerging area of research is becoming ever more tractable with advances in genomics, phenomics, and high-throughput sequencing methodology that will enable unprecedented profiling of high-resolution stress recovery time series experiments and sampling of large natural populations. PMID:26989783
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Epigenetics in cancer stem cells.
Toh, Tan Boon; Lim, Jhin Jieh; Chow, Edward Kai-Hua
2017-02-01
Compelling evidence have demonstrated that bulk tumors can arise from a unique subset of cells commonly termed "cancer stem cells" that has been proposed to be a strong driving force of tumorigenesis and a key mechanism of therapeutic resistance. Recent advances in epigenomics have illuminated key mechanisms by which epigenetic regulation contribute to cancer progression. In this review, we present a discussion of how deregulation of various epigenetic pathways can contribute to cancer initiation and tumorigenesis, particularly with respect to maintenance and survival of cancer stem cells. This information, together with several promising clinical and preclinical trials of epigenetic modulating drugs, offer new possibilities for targeting cancer stem cells as well as improving cancer therapy overall.
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Developmental origins of epigenetic transgenerational inheritance
Hanson, Mark A.; Skinner, Michael K.
2016-01-01
Abstract Environmental factors can induce epigenetic alterations in the germ cells that can potentially be transmitted transgenerationally. This non-genetic form of inheritance is termed epigenetic transgenerational inheritance and has been shown in a variety of species including plants, flies, worms, fish, rodents, pigs, and humans. This phenomenon operates during specific critical windows of exposure, linked to the developmental biology of the germ cells (sperm and eggs). Therefore, concepts of the developmental origins of transgenerational inheritance of phenotypic variation and subsequent disease risk need to include epigenetic processes affecting the developmental biology of the germ cell. These developmental impacts on epigenetic transgenerational inheritance, in contrast to multigenerational exposures, are the focus of this Perspective. PMID:27390622
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Obesity Weighs down Memory through a Mechanism Involving the Neuroepigenetic Dysregulation of Sirt1
Heyward, Frankie D.; Gilliam, Daniel; Coleman, Mark A.; Gavin, Cristin F.; Wang, Jing; Kaas, Garrett; Trieu, Richard; Lewis, John; Moulden, Jerome
2016-01-01
Aberrant gene expression within the hippocampus has recently been implicated in the pathogenesis of obesity-induced memory impairment. Whether a dysregulation of epigenetic modifications mediates this disruption in gene transcription has yet to be established. Here we report evidence of obesity-induced alterations in DNA methylation of memory-associated genes, including Sirtuin 1 (Sirt1), within the hippocampus, and thus offer a novel mechanism by which SIRT1 expression within the hippocampus is suppressed during obesity. Forebrain neuron-specific Sirt1 knock-out closely recapitulated the memory deficits exhibited by obese mice, consistent with the hypothesis that the high-fat diet-mediated reduction of hippocampal SIRT1 could be responsible for obesity-linked memory impairment. Obese mice fed a diet supplemented with the SIRT1-activating molecule resveratrol exhibited increased hippocampal SIRT1 activity and preserved hippocampus-dependent memory, further strengthening this conclusion. Thus, our findings suggest that the memory-impairing effects of diet-induced obesity may potentially be mediated by neuroepigenetic dysregulation of SIRT1 within the hippocampus. SIGNIFICANCE STATEMENT Previous studies have implicated transcriptional dysregulation within the hippocampus as being a relevant pathological concomitant of obesity-induced memory impairment, yet a deeper understanding of the basis for, and etiological significance of, transcriptional dysregulation in this context is lacking. Here we present the first evidence of epigenetic dysregulation (i.e., altered DNA methylation and hydroxymethylation) of memory-related genes, including Sirt1, within the hippocampus of obese mice. Furthermore, experiments using transgenic and pharmacological approaches strongly implicate reduced hippocampal SIRT1 as being a principal pathogenic mediator of obesity-induced memory impairment. This paper offers a novel working model that may serve as a conceptual basis for the development of therapeutic interventions for obesity-induced memory impairment. PMID:26818519
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Implication of epigenetics in pancreas development and disease.
Quilichini, Evans; Haumaitre, Cécile
2015-12-01
Pancreas development is controlled by a complex interaction of signaling pathways and transcription factor networks that determine pancreatic specification and differentiation of exocrine and endocrine cells. Epigenetics adds a new layer of gene regulation. DNA methylation, histone modifications and non-coding RNAs recently appeared as important epigenetic factors regulating pancreas development. In this review, we report recent findings obtained by analyses in model organisms as well as genome-wide approaches that demonstrate the role of these epigenetic regulators in the control of exocrine and endocrine cell differentiation, identity, function, proliferation and regeneration. We also highlight how altered epigenetic processes contribute to pancreatic disorders: diabetes and pancreatic cancer. Uncovering these epigenetic events can help to better understand these diseases, provide novel therapeutical targets for their treatment, and improve cell-based therapies for diabetes. Copyright © 2015 Elsevier Ltd. All rights reserved.
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Folguera-Blasco, Núria; Cuyàs, Elisabet; Menéndez, Javier A; Alarcón, Tomás
2018-03-01
Understanding the control of epigenetic regulation is key to explain and modify the aging process. Because histone-modifying enzymes are sensitive to shifts in availability of cofactors (e.g. metabolites), cellular epigenetic states may be tied to changing conditions associated with cofactor variability. The aim of this study is to analyse the relationships between cofactor fluctuations, epigenetic landscapes, and cell state transitions. Using Approximate Bayesian Computation, we generate an ensemble of epigenetic regulation (ER) systems whose heterogeneity reflects variability in cofactor pools used by histone modifiers. The heterogeneity of epigenetic metabolites, which operates as regulator of the kinetic parameters promoting/preventing histone modifications, stochastically drives phenotypic variability. The ensemble of ER configurations reveals the occurrence of distinct epi-states within the ensemble. Whereas resilient states maintain large epigenetic barriers refractory to reprogramming cellular identity, plastic states lower these barriers, and increase the sensitivity to reprogramming. Moreover, fine-tuning of cofactor levels redirects plastic epigenetic states to re-enter epigenetic resilience, and vice versa. Our ensemble model agrees with a model of metabolism-responsive loss of epigenetic resilience as a cellular aging mechanism. Our findings support the notion that cellular aging, and its reversal, might result from stochastic translation of metabolic inputs into resilient/plastic cell states via ER systems.
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ERIC Educational Resources Information Center
Bredy, Timothy W.; Barad, Mark
2008-01-01
Histone modifications contribute to the epigenetic regulation of gene expression, a process now recognized to be important for the consolidation of long-term memory. Valproic acid (VPA), used for many years as an anticonvulsant and a mood stabilizer, has effects on learning and memory and enhances the extinction of conditioned fear through its…
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Bifurcation in epigenetics: Implications in development, proliferation, and diseases
NASA Astrophysics Data System (ADS)
Jost, Daniel
2014-01-01
Cells often exhibit different and stable phenotypes from the same DNA sequence. Robustness and plasticity of such cellular states are controlled by diverse transcriptional and epigenetic mechanisms, among them the modification of biochemical marks on chromatin. Here, we develop a stochastic model that describes the dynamics of epigenetic marks along a given DNA region. Through mathematical analysis, we show the emergence of bistable and persistent epigenetic states from the cooperative recruitment of modifying enzymes. We also find that the dynamical system exhibits a critical point and displays, in the presence of asymmetries in recruitment, a bifurcation diagram with hysteresis. These results have deep implications for our understanding of epigenetic regulation. In particular, our study allows one to reconcile within the same formalism the robust maintenance of epigenetic identity observed in differentiated cells, the epigenetic plasticity of pluripotent cells during differentiation, and the effects of epigenetic misregulation in diseases. Moreover, it suggests a possible mechanism for developmental transitions where the system is shifted close to the critical point to benefit from high susceptibility to developmental cues.
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Zhao, Wen-Ning; Ghosh, Balaram; Tyler, Marshall; Lalonde, Jasmin; Joseph, Nadine F; Kosaric, Nina; Fass, Daniel M; Tsai, Li-Huei; Mazitschek, Ralph; Haggarty, Stephen J
2018-06-22
Through epigenetic and other regulatory functions, the histone deacetylase (HDAC) family of enzymes has emerged as a promising therapeutic target for central nervous system and other disorders. Here we report on the synthesis and functional characterization of new HDAC inhibitors based structurally on tianeptine, a drug used primarily to treat major depressive disorder (MDD) that has a poorly understood mechanism of action. Since the chemical structure of tianeptine resembles certain HDAC inhibitors, we profiled the in vitro HDAC inhibitory activity of tianeptine and demonstrated its ability to inhibit the lysine deacetylase activity of a subset of class I HDACs. Consistent with a model of active site Zn 2+ chelation by the carboxylic acid present in tianeptine, newly synthesized analogues containing either a hydroxamic acid or ortho-aminoanilide exhibited increased potency and selectivity among the HDAC family. This in vitro potency translated to improved efficacy in a panel of high-content imaging assays designed to assess HDAC target engagement and functional effects on critical pathways involved in neuroplasticity in both primary mouse neurons and, for the first time, human neurons differentiated from pluripotent stem cells. Most notably, tianeptinaline, a class I HDAC-selective analogue of tianeptine, but not tianeptine itself, increased histone acetylation, and enhanced CREB-mediated transcription and the expression of Arc (activity-regulated cytoskeleton-associated protein). Systemic in vivo administration of tianeptinaline to mice confirmed its brain penetration and was found to enhance contextual fear conditioning, a behavioral test of hippocampal-dependent memory. Tianeptinaline and its derivatives provide new pharmacological tools to dissect chromatin-mediated neuroplasticity underlying memory and other epigenetically related processes implicated in health and disease.
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A ketogenic diet rescues hippocampal memory defects in a mouse model of Kabuki syndrome.
Benjamin, Joel S; Pilarowski, Genay O; Carosso, Giovanni A; Zhang, Li; Huso, David L; Goff, Loyal A; Vernon, Hilary J; Hansen, Kasper D; Bjornsson, Hans T
2017-01-03
Kabuki syndrome is a Mendelian intellectual disability syndrome caused by mutations in either of two genes (KMT2D and KDM6A) involved in chromatin accessibility. We previously showed that an agent that promotes chromatin opening, the histone deacetylase inhibitor (HDACi) AR-42, ameliorates the deficiency of adult neurogenesis in the granule cell layer of the dentate gyrus and rescues hippocampal memory defects in a mouse model of Kabuki syndrome (Kmt2d +/βGeo ). Unlike a drug, a dietary intervention could be quickly transitioned to the clinic. Therefore, we have explored whether treatment with a ketogenic diet could lead to a similar rescue through increased amounts of beta-hydroxybutyrate, an endogenous HDACi. Here, we report that a ketogenic diet in Kmt2d +/βGeo mice modulates H3ac and H3K4me3 in the granule cell layer, with concomitant rescue of both the neurogenesis defect and hippocampal memory abnormalities seen in Kmt2d +/βGeo mice; similar effects on neurogenesis were observed on exogenous administration of beta-hydroxybutyrate. These data suggest that dietary modulation of epigenetic modifications through elevation of beta-hydroxybutyrate may provide a feasible strategy to treat the intellectual disability seen in Kabuki syndrome and related disorders.
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LRP8-Reelin-regulated Neuronal (LRN) Enhancer Signature Underlying Learning and Memory Formation
Telese, Francesca; Ma, Qi; Perez, Patricia Montilla; Notani, Dimple; Oh, Soohwan; Li, Wenbo; Comoletti, Davide; Ohgi, Kenneth A.; Taylor, Havilah; Rosenfeld, Michael G.
2015-01-01
Summary One of the exceptional properties of the brain is its ability to acquire new knowledge through learning and to store that information through memory. The epigenetic mechanisms linking changes in neuronal transcriptional programs to behavioral plasticity remain largely unknown. Here, we identify the epigenetic signature of the neuronal enhancers required for transcriptional regulation of synaptic plasticity genes during memory formation, linking this to Reelin signaling. The binding of Reelin to its receptor, LRP8, triggers activation of this cohort of LRP8-Reelin-regulated-Neuronal (LRN) enhancers that serve as the ultimate convergence point of a novel synapse-to-nucleus pathway. Reelin simultaneously regulates NMDA-receptor transmission, which reciprocally permits the required, γ-secretase-dependent cleavage of LRP8, revealing an unprecedented role for its intracellular domain in the regulation of synaptically generated signals. These results uncover an in vivo enhancer code serving as a critical molecular component of cognition and relevant to psychiatric disorders linked to defects in Reelin signaling. PMID:25892301
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Epigenetic regulation of hematopoietic stem cell aging
DOE Office of Scientific and Technical Information (OSTI.GOV)
Beerman, Isabel, E-mail: isabel.beerman@childrens.harvard.edu; Department of Pediatrics, Harvard Medical School, Boston, MA 02115; Program in Cellular and Molecular Medicine, Division of Hematology/Oncology, Boston Children's Hospital, MA 02116
2014-12-10
Aging is invariably associated with alterations of the hematopoietic stem cell (HSC) compartment, including loss of functional capacity, altered clonal composition, and changes in lineage contribution. Although accumulation of DNA damage occurs during HSC aging, it is unlikely such consistent aging phenotypes could be solely attributed to changes in DNA integrity. Another mechanism by which heritable traits could contribute to the changes in the functional potential of aged HSCs is through alterations in the epigenetic landscape of adult stem cells. Indeed, recent studies on hematopoietic stem cells have suggested that altered epigenetic profiles are associated with HSC aging and playmore » a key role in modulating the functional potential of HSCs at different stages during ontogeny. Even small changes of the epigenetic landscape can lead to robustly altered expression patterns, either directly by loss of regulatory control or through indirect, additive effects, ultimately leading to transcriptional changes of the stem cells. Potential drivers of such changes in the epigenetic landscape of aged HSCs include proliferative history, DNA damage, and deregulation of key epigenetic enzymes and complexes. This review will focus largely on the two most characterized epigenetic marks – DNA methylation and histone modifications – but will also discuss the potential role of non-coding RNAs in regulating HSC function during aging.« less
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Pizzimenti, C L; Lattal, K M
2015-01-01
Understanding the interaction between fear and reward at the circuit and molecular levels has implications for basic scientific approaches to memory and for understanding the etiology of psychiatric disorders. Both stress and exposure to drugs of abuse induce epigenetic changes that result in persistent behavioral changes, some of which may contribute to the formation of a drug addiction or a stress-related psychiatric disorder. Converging evidence suggests that similar behavioral, neurobiological and molecular mechanisms control the extinction of learned fear and drug-seeking responses. This may, in part, account for the fact that individuals with post-traumatic stress disorder have a significantly elevated risk of developing a substance use disorder and have high rates of relapse to drugs of abuse, even after long periods of abstinence. At the behavioral level, a major challenge in treatments is that extinguished behavior is often not persistent, returning with changes in context, the passage of time or exposure to mild stressors. A common goal of treatments is therefore to weaken the ability of stressors to induce relapse. With the discovery of epigenetic mechanisms that create persistent molecular signals, recent work on extinction has focused on how modulating these epigenetic targets can create lasting extinction of fear or drug-seeking behavior. Here, we review recent evidence pointing to common behavioral, systems and epigenetic mechanisms in the regulation of fear and drug seeking. We suggest that targeting these mechanisms in combination with behavioral therapy may promote treatment and weaken stress-induced relapse. © 2015 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.
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Prostate cancer epigenetics and its clinical implications
Yegnasubramanian, Srinivasan
2016-01-01
Normal cells have a level of epigenetic programming that is superimposed on the genetic code to establish and maintain their cell identity and phenotypes. This epigenetic programming can be thought as the architecture, a sort of cityscape, that is built upon the underlying genetic landscape. The epigenetic programming is encoded by a complex set of chemical marks on DNA, on histone proteins in nucleosomes, and by numerous context-specific DNA, RNA, protein interactions that all regulate the structure, organization, and function of the genome in a given cell. It is becoming increasingly evident that abnormalities in both the genetic landscape and epigenetic cityscape can cooperate to drive carcinogenesis and disease progression. Large-scale cancer genome sequencing studies have revealed that mutations in genes encoding the enzymatic machinery for shaping the epigenetic cityscape are among the most common mutations observed in human cancers, including prostate cancer. Interestingly, although the constellation of genetic mutations in a given cancer can be quite heterogeneous from person to person, there are numerous epigenetic alterations that appear to be highly recurrent, and nearly universal in a given cancer type, including in prostate cancer. The highly recurrent nature of these alterations can be exploited for development of biomarkers for cancer detection and risk stratification and as targets for therapeutic intervention. Here, we explore the basic principles of epigenetic processes in normal cells and prostate cancer cells and discuss the potential clinical implications with regards to prostate cancer biomarker development and therapy. PMID:27212125
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Prostate cancer epigenetics and its clinical implications.
Yegnasubramanian, Srinivasan
2016-01-01
Normal cells have a level of epigenetic programming that is superimposed on the genetic code to establish and maintain their cell identity and phenotypes. This epigenetic programming can be thought as the architecture, a sort of cityscape, that is built upon the underlying genetic landscape. The epigenetic programming is encoded by a complex set of chemical marks on DNA, on histone proteins in nucleosomes, and by numerous context-specific DNA, RNA, protein interactions that all regulate the structure, organization, and function of the genome in a given cell. It is becoming increasingly evident that abnormalities in both the genetic landscape and epigenetic cityscape can cooperate to drive carcinogenesis and disease progression. Large-scale cancer genome sequencing studies have revealed that mutations in genes encoding the enzymatic machinery for shaping the epigenetic cityscape are among the most common mutations observed in human cancers, including prostate cancer. Interestingly, although the constellation of genetic mutations in a given cancer can be quite heterogeneous from person to person, there are numerous epigenetic alterations that appear to be highly recurrent, and nearly universal in a given cancer type, including in prostate cancer. The highly recurrent nature of these alterations can be exploited for development of biomarkers for cancer detection and risk stratification and as targets for therapeutic intervention. Here, we explore the basic principles of epigenetic processes in normal cells and prostate cancer cells and discuss the potential clinical implications with regards to prostate cancer biomarker development and therapy.
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Epigenetic regulation of vascular smooth muscle cell function in atherosclerosis.
Findeisen, Hannes M; Kahles, Florian K; Bruemmer, Dennis
2013-04-01
Epigenetics involve heritable and acquired changes in gene transcription that occur independently of the DNA sequence. Epigenetic mechanisms constitute a hierarchic upper-level of transcriptional control through complex modifications of chromosomal components and nuclear structures. These modifications include, for example, DNA methylation or post-translational modifications of core histones; they are mediated by various chromatin-modifying enzymes; and ultimately they define the accessibility of a transcriptional complex to its target DNA. Integrating epigenetic mechanisms into the pathophysiologic concept of complex and multifactorial diseases such as atherosclerosis may significantly enhance our understanding of related mechanisms and provide promising therapeutic approaches. Although still in its infancy, intriguing scientific progress has begun to elucidate the role of epigenetic mechanisms in vascular biology, particularly in the control of smooth muscle cell phenotypes. In this review, we will summarize epigenetic pathways in smooth muscle cells, focusing on mechanisms involved in the regulation of vascular remodeling.
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Epigenetic regulation of vascular smooth muscle cell function in atherosclerosis.
Findeisen, Hannes M; Kahles, Florian K; Bruemmer, Dennis
2013-05-01
Epigenetics involve heritable and acquired changes in gene transcription that occur independently of the DNA sequence. Epigenetic mechanisms constitute a hierarchic upper-level of transcriptional control through complex modifications of chromosomal components and nuclear structures. These modifications include, for example, DNA methylation or post-translational modifications of core histones; they are mediated by various chromatin-modifying enzymes; and ultimately they define the accessibility of a transcriptional complex to its target DNA. Integrating epigenetic mechanisms into the pathophysiologic concept of complex and multifactorial diseases such as atherosclerosis may significantly enhance our understanding of related mechanisms and provide promising therapeutic approaches. Although still in its infancy, intriguing scientific progress has begun to elucidate the role of epigenetic mechanisms in vascular biology, particularly in the control of smooth muscle cell phenotypes. In this review, we will summarize epigenetic pathways in smooth muscle cells, focusing on mechanisms involved in the regulation of vascular remodeling.
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The changing concept of epigenetics.
Jablonka, Eva; Lamb, Marion J
2002-12-01
We discuss the changing use of epigenetics, a term coined by Conrad Waddington in the 1940s, and how the epigenetic approach to development differs from the genetic approach. Originally, epigenetics referred to the study of the way genes and their products bring the phenotype into being. Today, it is primarily concerned with the mechanisms through which cells become committed to a particular form or function and through which that functional or structural state is then transmitted in cell lineages. We argue that modern epigenetics is important not only because it has practical significance for medicine, agriculture, and species conservation, but also because it has implications for the way in which we should view heredity and evolution. In particular, recognizing that there are epigenetic inheritance systems through which non-DNA variations can be transmitted in cell and organismal lineages broadens the concept of heredity and challenges the widely accepted gene-centered neo-Darwinian version of Darwinism.
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Delgado-Morales, Raúl; Agís-Balboa, Roberto Carlos; Esteller, Manel; Berdasco, María
2017-01-01
Ageing is the main risk factor for human neurological disorders. Among the diverse molecular pathways that govern ageing, epigenetics can guide age-associated decline in part by regulating gene expression and also through the modulation of genomic instability and high-order chromatin architecture. Epigenetic mechanisms are involved in the regulation of neural differentiation as well as in functional processes related to memory consolidation, learning or cognition during healthy lifespan. On the other side of the coin, many neurodegenerative diseases are associated with epigenetic dysregulation. The reversible nature of epigenetic factors and, especially, their role as mediators between the genome and the environment make them exciting candidates as therapeutic targets. Rather than providing a broad description of the pathways epigenetically deregulated in human neurological disorders, in this review, we have focused on the potential use of epigenetic enzymes as druggable targets to ameliorate neural decline during normal ageing and especially in neurological disorders. We will firstly discuss recent progress that supports a key role of epigenetic regulation during healthy ageing with an emphasis on the role of epigenetic regulation in adult neurogenesis. Then, we will focus on epigenetic alterations associated with ageing-related human disorders of the central nervous system. We will discuss examples in the context of psychiatric disorders, including schizophrenia and posttraumatic stress disorders, and also dementia or Alzheimer's disease as the most frequent neurodegenerative disease. Finally, methodological limitations and future perspectives are discussed.
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Epigenetic mechanisms underlying cognitive impairment and Alzheimer disease hallmarks in 5XFAD mice.
Griñán-Ferré, Christian; Sarroca, Sara; Ivanova, Aleksandra; Puigoriol-Illamola, Dolors; Aguado, Fernando; Camins, Antoni; Sanfeliu, Coral; Pallàs, Mercè
2016-04-01
5XFAD is an early-onset mouse transgenic model of Alzheimer disease (AD). Up to now there are no studies that focus on the epigenetic changes produced as a result of Aβ-42 accumulation and the possible involvement in the different expression of related AD-genes. Under several behavioral and cognition test, we found impairment in memory and psychoemotional changes in female 5XFAD mice in reference to wild type that worsens with age. Cognitive changes correlated with alterations on protein level analysis and gene expression of markers related with tau aberrant phosphorylation, amyloidogenic pathway (APP, BACE1), Oxidative Stress (iNOS, Aldh2) and inflammation (astrogliosis, TNF-α and IL-6); no changes were found in non-amyloidogenic pathway indicators such as ADAM10. Epigenetics changes as higher CpG methylation and transcriptional changes in DNA methyltransferases (DNMTs) family were found. Dnmt1 increases in younger 5XFAD and Dnmt3a and b high levels in the oldest transgenic mice. Similar pattern was found with histone methyltransferases such as Jarid1a andG9a. Histone deacetylase 2 (Hdac2) or Sirt6, both related with cognition and memory, presented a similar pattern. Taken together, these hallmarks presented by the 5XFAD model prompted its use in assessing different potential therapeutic interventions based on epigenetic targets after earlier amyloid deposition.
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Nephrotoxicity of Epigenetic Inhibitors Used for the Treatment of Cancer
Scholpa, N.E.; Kolli, R.T.; Moore, M.; Arnold, R.D.; Glenn, T.C.; Cummings, B.S.
2016-01-01
This study determined the anti-neoplastic activity and nephrotoxicity of epigenetic inhibitors in vitro. The therapeutic efficacy of epigenetic inhibitors was determined in human prostate cancer cells (PC-3 and LNCaP) using the DNA methyltransferase inhibitor 5-azacytidine (5-Aza) and the histone deacetylase inhibitor trichostatin A (TSA). Cells were also treated with carbamazepine (CBZ), an anti-convulsant with histone deacetylase inhibitor-like properties. 5-Aza, TSA or CBZ alone did not decrease MTT staining in PC-3 or LNCaP cells after 48 hr. In contrast, docetaxel, a frontline chemotherapeutic induced concentration-dependent decreases in MTT staining. Pretreatment with 5-Aza or TSA increased docetaxel-induced cytotoxicity in LNCaP cells, but not PC-3 cells. TSA pretreatment also increased cisplatin-induced toxicity in LNCaP cells. Carfilzomib (CFZ), a protease inhibitor approved for the treatment of multiple myeloma had minimal effect on LNCaP cell viability, but reduced MTT staining 50% in PC-3 cells compared to control, and pretreatment with 5-Aza further enhanced toxicity. Treatment of normal rat kidney (NRK) and human embryonic kidney 293 (HEK293) cells with the same concentrations of epigenetic inhibitors used in prostate cancer cells significantly decreased MTT staining in all cell lines after 48 hr. Interestingly, we found that the toxicity of epigenetic inhibitors to kidney cells was dependent on both the compound and the stage of cell growth. The effect of 5-Aza and TSA on DNA methyltransferase and histone deacetylase activity, respectively, was confirmed by assessing the methylation and acetylation of the CDK inhibitor p21. Collectively, these data show that combinatorial treatment with epigenetic inhibitors alters the efficacy of chemotherapeutics in cancer cells in a compound- and cell-specific manner; however, this treatment also has the potential to induce nephrotoxic cell injury. PMID:27543423
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Epigenetics Research on the International Space Station
NASA Technical Reports Server (NTRS)
Love, John; Cooley, Vic
2016-01-01
The International Space Station (ISS) is a state-of-the orbiting laboratory focused on advancing science and technology research. Experiments being conducted on the ISS include investigations in the emerging field of Epigenetics. Epigenetics refers to stably heritable changes in gene expression or cellular phenotype (the transcriptional potential of a cell) resulting from changes in a chromosome without alterations to the underlying DNA nucleotide sequence (the genetic code), which are caused by external or environmental factors, such as spaceflight microgravity. Molecular mechanisms associated with epigenetic alterations regulating gene expression patterns include covalent chemical modifications of DNA (e.g., methylation) or histone proteins (e.g., acetylation, phorphorylation, or ubiquitination). For example, Epigenetics ("Epigenetics in Spaceflown C. elegans") is a recent JAXA investigation examining whether adaptations to microgravity transmit from one cell generation to another without changing the basic DNA of the organism. Mouse Epigenetics ("Transcriptome Analysis and Germ-Cell Development Analysis of Mice in Space") investigates molecular alterations in organ-specific gene expression patterns and epigenetic modifications, and analyzes murine germ cell development during long term spaceflight, as well as assessing changes in offspring DNA. NASA's first foray into human Omics research, the Twins Study ("Differential effects of homozygous twin astronauts associated with differences in exposure to spaceflight factors"), includes investigations evaluating differential epigenetic effects via comprehensive whole genome analysis, the landscape of DNA and RNA methylation, and biomolecular changes by means of longitudinal integrated multi-omics research. And the inaugural Genes in Space student challenge experiment (Genes in Space-1) is aimed at understanding how epigenetics plays a role in immune system dysregulation by assaying DNA methylation in immune cells directly in space using miniPCR technology. In addition, NASA's geneLAB campaign covers the epigenome as part of the "expressome", by employing an innovative open source science platform for multi-investigator high throughput utilization of the ISS. Earth benefits of Epigenetics research onboard the ISS range from contributions to the fundamental understanding of epigenetic phenomena with applications in countermeasure development for biomedical conditions, to the generation of integrated strategies for personalized medicine based on unique physiological responses.
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ERIC Educational Resources Information Center
Gupta-Agarwal, Swati; Jarome, Timothy J.; Fernandez, Jordan; Lubin, Farah D.
2014-01-01
It is well established that fear memory formation requires de novo gene transcription in the amygdala. We provide evidence that epigenetic mechanisms in the form of histone lysine methylation in the lateral amygdala (LA) are regulated by NMDA receptor (NMDAR) signaling and involved in gene transcription changes necessary for fear memory…
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Accelerated epigenetic aging in Werner syndrome.
Maierhofer, Anna; Flunkert, Julia; Oshima, Junko; Martin, George M; Haaf, Thomas; Horvath, Steve
2017-04-01
Individuals suffering from Werner syndrome (WS) exhibit many clinical signs of accelerated aging. While the underlying constitutional mutation leads to accelerated rates of DNA damage, it is not yet known whether WS is also associated with an increased epigenetic age according to a DNA methylation based biomarker of aging (the "Epigenetic Clock"). Using whole blood methylation data from 18 WS cases and 18 age matched controls, we find that WS is associated with increased extrinsic epigenetic age acceleration (p=0.0072) and intrinsic epigenetic age acceleration (p=0.04), the latter of which is independent of age-related changes in the composition of peripheral blood cells. A multivariate model analysis reveals that WS is associated with an increase in DNA methylation age (on average 6.4 years, p=0.011) even after adjusting for chronological age, gender, and blood cell counts. Further, WS might be associated with a reduction in naïve CD8+ T cells (p=0.025) according to imputed measures of blood cell counts. Overall, this study shows that WS is associated with an increased epigenetic age of blood cells which is independent of changes in blood cell composition. The extent to which this alteration is a cause or effect of WS disease phenotypes remains unknown.
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The mysteries of remote memory.
Albo, Zimbul; Gräff, Johannes
2018-03-19
Long-lasting memories form the basis of our identity as individuals and lie central in shaping future behaviours that guide survival. Surprisingly, however, our current knowledge of how such memories are stored in the brain and retrieved, as well as the dynamics of the circuits involved, remains scarce despite seminal technical and experimental breakthroughs in recent years. Traditionally, it has been proposed that, over time, information initially learnt in the hippocampus is stored in distributed cortical networks. This process-the standard theory of memory consolidation-would stabilize the newly encoded information into a lasting memory, become independent of the hippocampus, and remain essentially unmodifiable throughout the lifetime of the individual. In recent years, several pieces of evidence have started to challenge this view and indicate that long-lasting memories might already ab ovo be encoded, and subsequently stored in distributed cortical networks, akin to the multiple trace theory of memory consolidation. In this review, we summarize these recent findings and attempt to identify the biologically plausible mechanisms based on which a contextual memory becomes remote by integrating different levels of analysis: from neural circuits to cell ensembles across synaptic remodelling and epigenetic modifications. From these studies, remote memory formation and maintenance appear to occur through a multi-trace, dynamic and integrative cellular process ranging from the synapse to the nucleus, and represent an exciting field of research primed to change quickly as new experimental evidence emerges.This article is part of a discussion meeting issue 'Of mice and mental health: facilitating dialogue between basic and clinical neuroscientists'. © 2018 The Authors.
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The mysteries of remote memory
2018-01-01
Long-lasting memories form the basis of our identity as individuals and lie central in shaping future behaviours that guide survival. Surprisingly, however, our current knowledge of how such memories are stored in the brain and retrieved, as well as the dynamics of the circuits involved, remains scarce despite seminal technical and experimental breakthroughs in recent years. Traditionally, it has been proposed that, over time, information initially learnt in the hippocampus is stored in distributed cortical networks. This process—the standard theory of memory consolidation—would stabilize the newly encoded information into a lasting memory, become independent of the hippocampus, and remain essentially unmodifiable throughout the lifetime of the individual. In recent years, several pieces of evidence have started to challenge this view and indicate that long-lasting memories might already ab ovo be encoded, and subsequently stored in distributed cortical networks, akin to the multiple trace theory of memory consolidation. In this review, we summarize these recent findings and attempt to identify the biologically plausible mechanisms based on which a contextual memory becomes remote by integrating different levels of analysis: from neural circuits to cell ensembles across synaptic remodelling and epigenetic modifications. From these studies, remote memory formation and maintenance appear to occur through a multi-trace, dynamic and integrative cellular process ranging from the synapse to the nucleus, and represent an exciting field of research primed to change quickly as new experimental evidence emerges. This article is part of a discussion meeting issue ‘Of mice and mental health: facilitating dialogue between basic and clinical neuroscientists’. PMID:29352028
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Regulation of Stem Cell Aging by Metabolism and Epigenetics.
Ren, Ruotong; Ocampo, Alejandro; Liu, Guang-Hui; Izpisua Belmonte, Juan Carlos
2017-09-05
Stem cell aging and exhaustion are considered important drivers of organismal aging. Age-associated declines in stem cell function are characterized by metabolic and epigenetic changes. Understanding the mechanisms underlying these changes will likely reveal novel therapeutic targets for ameliorating age-associated phenotypes and for prolonging human healthspan. Recent studies have shown that metabolism plays an important role in regulating epigenetic modifications and that this regulation dramatically affects the aging process. This review focuses on current knowledge regarding the mechanisms of stem cell aging, and the links between cellular metabolism and epigenetic regulation. In addition, we discuss how these interactions sense and respond to environmental stress in order to maintain stem cell homeostasis, and how environmental stimuli regulate stem cell function. Additionally, we highlight recent advances in the development of therapeutic strategies to rejuvenate dysfunctional aged stem cells. Copyright © 2017 Elsevier Inc. All rights reserved.
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Does Simulated Spaceflight Modify Epigenetic Status During Bone Remodeling?
NASA Technical Reports Server (NTRS)
Thomas, Nicholas J.; Stevick, Rebecca J.; Tran, Luan H.; Nalavadi, Mohit O.; Almeida, Eduardo A.C.; Globus, Ruth K.; Alwood, Joshua S.
2015-01-01
Little is known about the effects of spaceflight conditions on epigenetics. The term epigenetics describes changes to the genome that can affect expression of a gene without changes to the sequence of DNA. Epigenetic processes are thought to underlie cellular differentiation, where transcription of specific genes occurs in response to key stimuli, and may be heritable - passing from one cell to its daughter cell. We hypothesize that the mechanical environment during spaceflight, namely microgravity-induced weightlessness or exercise regulate gene expression in the osteoblast-lineage cells both to control bone formation by osteoblasts and bone resorption by osteoclasts, which continually shapes bone structure throughout life. Similarly we intend to evaluate how radiation regulates these same bone cell activity and differentiation related genes. We further hypothesize that the regulation in bone cell gene expression is at least partially controlled through epigenetic mechanisms of methylation or small non-coding RNA (microRNAs). We have acquired preliminary data suggesting that global genome methylation is modified in response to axial compression of the tibia - a model of exercise. We intend to pursue these hypotheses wherein we will evaluate changes in gene expression and, congruently, changes in epigenetic state in bones from mice subjected to the aforementioned conditions: hindlimb unloading to simulate weightlessness, axial compression of the tibia, or radiation exposure in order to gain insight into the role of epigenetics in spaceflight-induced bone loss.
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Radiation-Induced Epigenetic Alterations after Low and High LET Irradiations
DOE Office of Scientific and Technical Information (OSTI.GOV)
Aypar, Umut; Morgan, William F.; Baulch, Janet E.
Epigenetics, including DNA methylation and microRNA (miRNA) expression, could be the missing link in understanding the delayed, non-targeted effects of radiation including radiationinduced genomic instability (RIGI). This study tests the hypothesis that irradiation induces epigenetic aberrations, which could eventually lead to RIGI, and that the epigenetic aberrations induced by low linear energy transfer (LET) irradiation are different than those induced by high LET irradiations. GM10115 cells were irradiated with low LET x-rays and high LET iron (Fe) ions and evaluated for DNA damage, cell survival and chromosomal instability. The cells were also evaluated for specific locus methylation of nuclear factor-kappamore » B (NFκB), tumor suppressor in lung cancer 1 (TSLC1) and cadherin 1 (CDH1) gene promoter regions, long interspersed nuclear element 1 (LINE-1) and Alu repeat element methylation, CpG and non-CpG global methylation and miRNA expression levels. Irradiated cells showed increased micronucleus induction and cell killing immediately following exposure, but were chromosomally stable at delayed times post-irradiation. At this same delayed time, alterations in repeat element and global DNA methylation and miRNA expression were observed. Analyses of DNA methylation predominantly showed hypomethylation, however hypermethylation was also observed. MiRNA shown to be altered in expression level after x-ray irradiation are involved in chromatin remodeling and DNA methylation. Different and higher incidence of epigenetic changes were observed after exposure to low LET x-rays than high LET Fe ions even though Fe ions elicited more chromosomal damage and cell killing. This study also shows that the irradiated cells acquire epigenetic changes even though they are chromosomally stable suggesting that epigenetic aberrations may arise in the cell without initiating RIGI.« less
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Chatterjee, Aniruddha; Stockwell, Peter A; Ahn, Antonio; Rodger, Euan J; Leichter, Anna L; Eccles, Michael R
2017-01-01
Epigenetic alterations are increasingly implicated in metastasis, whereas very few genetic mutations have been identified as authentic drivers of cancer metastasis. Yet, to date, few studies have identified metastasis-related epigenetic drivers, in part because a framework for identifying driver epigenetic changes in metastasis has not been established. Using reduced representation bisulfite sequencing (RRBS), we mapped genome-wide DNA methylation patterns in three cutaneous primary and metastatic melanoma cell line pairs to identify metastasis-related epigenetic drivers. Globally, metastatic melanoma cell lines were hypomethylated compared to the matched primary melanoma cell lines. Using whole genome RRBS we identified 75 shared (10 hyper- and 65 hypomethylated) differentially methylated fragments (DMFs), which were associated with 68 genes showing significant methylation differences. One gene, Early B Cell Factor 3 (EBF3), exhibited promoter hypermethylation in metastatic cell lines, and was validated with bisulfite sequencing and in two publicly available independent melanoma cohorts (n = 40 and 458 melanomas, respectively). We found that hypermethylation of the EBF3 promoter was associated with increased EBF3 mRNA levels in metastatic melanomas and subsequent inhibition of DNA methylation reduced EBF3 expression. RNAi-mediated knockdown of EBF3 mRNA levels decreased proliferation, migration and invasion in primary and metastatic melanoma cell lines. Overall, we have identified numerous epigenetic changes characterising metastatic melanoma cell lines, including EBF3-induced aggressive phenotypic behaviour with elevated EBF3 expression in metastatic melanoma, suggesting that EBF3 promoter hypermethylation may be a candidate epigenetic driver of metastasis. PMID:28030832
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Session 2: Personalised nutrition. Epigenomics: a basis for understanding individual differences?
Mathers, John C
2008-11-01
Epigenetics encompasses changes to marks on the genome that are copied from one cell generation to the next, which may alter gene expression but which do not involve changes in the primary DNA sequence. These marks include DNA methylation (methylation of cytosines within CpG dinucleotides) and post-translational modifications (acetylation, methylation, phosphorylation and ubiquitination) of the histone tails protruding from nucleosome cores. The sum of genome-wide epigenetic patterns is known as the epigenome. It is hypothesised that altered epigenetic marking is a means through which evidence of environmental exposures (including nutritional status and dietary exposure) is received and recorded by the genome. At least some of these epigenetic marks are remembered through multiple cell generations and their effects may be revealed in altered gene expression and cell function. Altered epigenetic marking allows plasticity of phenotype in a fixed genotype. Despite their identical genotypes, monozygotic twins show increasing epigenetic diversity with age and with divergent lifestyles. Differences in epigenetic markings may explain some inter-individual variation in disease risk and in response to nutritional interventions.
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Strategies for the acquisition of transcriptional and epigenetic information in single cells.
Li, Guang; Dzilic, Elda; Flores, Nick; Shieh, Alice; Wu, Sean M
2017-03-01
As the basic unit of living organisms, each single cell has unique molecular signatures and functions. Our ability to uncover the transcriptional and epigenetic signature of single cells has been hampered by the lack of tools to explore this area of research. The advent of microfluidic single cell technology along with single cell genome-wide DNA amplification methods had greatly improved our understanding of the expression variation in single cells. Transcriptional expression profile by multiplex qPCR or genome-wide RNA sequencing has enabled us to examine genes expression in single cells in different tissues. With the new tools, the identification of new cellular heterogeneity, novel marker genes, unique subpopulations, and spatial locations of each single cell can be acquired successfully. Epigenetic modifications for each single cell can also be obtained via similar methods. Based on single cell genome sequencing, single cell epigenetic information including histone modifications, DNA methylation, and chromatin accessibility have been explored and provided valuable insights regarding gene regulation and disease prognosis. In this article, we review the development of strategies to obtain single cell transcriptional and epigenetic data. Furthermore, we discuss ways in which single cell studies may help to provide greater understanding of the mechanisms of basic cardiovascular biology that will eventually lead to improvement in our ability to diagnose disease and develop new therapies.
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Single-cell dynamics of genome-nuclear lamina interactions.
Kind, Jop; Pagie, Ludo; Ortabozkoyun, Havva; Boyle, Shelagh; de Vries, Sandra S; Janssen, Hans; Amendola, Mario; Nolen, Leisha D; Bickmore, Wendy A; van Steensel, Bas
2013-03-28
The nuclear lamina (NL) interacts with hundreds of large genomic regions termed lamina associated domains (LADs). The dynamics of these interactions and the relation to epigenetic modifications are poorly understood. We visualized the fate of LADs in single cells using a "molecular contact memory" approach. In each nucleus, only ~30% of LADs are positioned at the periphery; these LADs are in intermittent molecular contact with the NL but remain constrained to the periphery. Upon mitosis, LAD positioning is not detectably inherited but instead is stochastically reshuffled. Contact of individual LADs with the NL is linked to transcriptional repression and H3K9 dimethylation in single cells. Furthermore, we identify the H3K9 methyltransferase G9a as a regulator of NL contacts. Collectively, these results highlight principles of the dynamic spatial architecture of chromosomes in relation to gene regulation. Copyright © 2013 Elsevier Inc. All rights reserved.
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Epigenetic silencing of ARRDC3 expression in basal-like breast cancer cells
NASA Astrophysics Data System (ADS)
Soung, Young Hwa; Pruitt, Kevin; Chung, Jun
2014-01-01
Arrestin domain-containing 3 (ARRDC3) is a tumor suppressor whose expression is either lost or suppressed in basal-like breast cancer (BLBC). However, the mechanism by which BLBC suppresses ARRDC3 expression is not established. Here, we show that expression of ARRDC3 in BLBC cells is suppressed at the transcriptional level. Suppression of ARRDC3 expression in BLBC cells involves epigenetic silencing as inhibitors of class III histone deacetylases (HDACs) significantly restores ARRDC3 levels in BLBC cells. SIRT2, among class III HDACs, plays a major role in epigenetic silencing of ARRDC3 in MDA-MB-231 cells. Acetylation levels of the ARRDC3 promoter in BLBC cells is significantly lower than that of other sub-types of BC cells. Chromatin immunopreciptitation analysis established SIRT2 binding at ARRDC3 promoter in BLBC cells. Our studies indicate that SIRT2 dependent epigenetic silencing of ARRDC3 is one of the important events that may contribute to the aggressive nature of BLBC cells.
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Peeters, Janneke G C; Vervoort, Stephin J; Tan, Sander C; Mijnheer, Gerdien; de Roock, Sytze; Vastert, Sebastiaan J; Nieuwenhuis, Edward E S; van Wijk, Femke; Prakken, Berent J; Creyghton, Menno P; Coffer, Paul J; Mokry, Michal; van Loosdregt, Jorg
2015-09-29
The underlying molecular mechanisms for many autoimmune diseases are poorly understood. Juvenile idiopathic arthritis (JIA) is an exceptionally well-suited model for studying autoimmune diseases due to its early onset and the possibility to analyze cells derived from the site of inflammation. Epigenetic profiling, utilizing primary JIA patient-derived cells, can contribute to the understanding of autoimmune diseases. With H3K27ac chromatin immunoprecipitation, we identified a disease-specific, inflammation-associated, typical enhancer and super-enhancer signature in JIA patient synovial-fluid-derived CD4(+) memory/effector T cells. RNA sequencing of autoinflammatory site-derived patient T cells revealed that BET inhibition, utilizing JQ1, inhibited immune-related super-enhancers and preferentially reduced disease-associated gene expression, including cytokine-related processes. Altogether, these results demonstrate the potential use of enhancer profiling to identify disease mediators and provide evidence for BET inhibition as a possible therapeutic approach for the treatment of autoimmune diseases. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
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DNMT1 is essential for mammary and cancer stem cell maintenance and tumorigenesis.
Pathania, Rajneesh; Ramachandran, Sabarish; Elangovan, Selvakumar; Padia, Ravi; Yang, Pengyi; Cinghu, Senthilkumar; Veeranan-Karmegam, Rajalakshmi; Arjunan, Pachiappan; Gnana-Prakasam, Jaya P; Sadanand, Fulzele; Pei, Lirong; Chang, Chang-Sheng; Choi, Jeong-Hyeon; Shi, Huidong; Manicassamy, Santhakumar; Prasad, Puttur D; Sharma, Suash; Ganapathy, Vadivel; Jothi, Raja; Thangaraju, Muthusamy
2015-04-24
Mammary stem/progenitor cells (MaSCs) maintain self-renewal of the mammary epithelium during puberty and pregnancy. DNA methylation provides a potential epigenetic mechanism for maintaining cellular memory during self-renewal. Although DNA methyltransferases (DNMTs) are dispensable for embryonic stem cell maintenance, their role in maintaining MaSCs and cancer stem cells (CSCs) in constantly replenishing mammary epithelium is unclear. Here we show that DNMT1 is indispensable for MaSC maintenance. Furthermore, we find that DNMT1 expression is elevated in mammary tumours, and mammary gland-specific DNMT1 deletion protects mice from mammary tumorigenesis by limiting the CSC pool. Through genome-scale methylation studies, we identify ISL1 as a direct DNMT1 target, hypermethylated and downregulated in mammary tumours and CSCs. DNMT inhibition or ISL1 expression in breast cancer cells limits CSC population. Altogether, our studies uncover an essential role for DNMT1 in MaSC and CSC maintenance and identify DNMT1-ISL1 axis as a potential therapeutic target for breast cancer treatment.
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NASA Astrophysics Data System (ADS)
Cortini, Ruggero; Barbi, Maria; Caré, Bertrand R.; Lavelle, Christophe; Lesne, Annick; Mozziconacci, Julien; Victor, Jean-Marc
2016-04-01
In higher organisms, all cells share the same genome, but every cell expresses only a limited and specific set of genes that defines the cell type. During cell division, not only the genome, but also the cell type is inherited by the daughter cells. This intriguing phenomenon is achieved by a variety of processes that have been collectively termed epigenetics: the stable and inheritable changes in gene expression patterns. This article reviews the extremely rich and exquisitely multiscale physical mechanisms that govern the biological processes behind the initiation, spreading, and inheritance of epigenetic states. These include not only the changes in the molecular properties associated with the chemical modifications of DNA and histone proteins, such as methylation and acetylation, but also less conventional changes, typically in the physics that governs the three-dimensional organization of the genome in cell nuclei. Strikingly, to achieve stability and heritability of epigenetic states, cells take advantage of many different physical principles, such as the universal behavior of polymers and copolymers, the general features of dynamical systems, and the electrostatic and mechanical properties related to chemical modifications of DNA and histones. By putting the complex biological literature in this new light, the emerging picture is that a limited set of general physical rules play a key role in initiating, shaping, and transmitting this crucial "epigenetic landscape." This new perspective not only allows one to rationalize the normal cellular functions, but also helps to understand the emergence of pathological states, in which the epigenetic landscape becomes dysfunctional.
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Epigenetics in Alzheimer's Disease: Perspective of DNA Methylation.
Qazi, Talal Jamil; Quan, Zhenzhen; Mir, Asif; Qing, Hong
2018-02-01
Research over the years has shown that causes of Alzheimer's disease are not well understood, but over the past years, the involvement of epigenetic mechanisms in the developing memory formation either under pathological or physiological conditions has become clear. The term epigenetics represents the heredity of changes in phenotype that are independent of altered DNA sequences. Different studies validated that cytosine methylation of genomic DNA decreases with age in different tissues of mammals, and therefore, the role of epigenetic factors in developing neurological disorders in aging has been under focus. In this review, we summarized and reviewed the involvement of different epigenetic mechanisms especially the DNA methylation in Alzheimer's disease (AD), late-onset Alzheimer's disease (LOAD), familial Alzheimer's disease (FAD), and autosomal dominant Alzheimer's disease (ADAD). Down to the minutest of details, we tried to discuss the methylation patterns like mitochondrial DNA methylation and ribosomal DNA (rDNA) methylation. Additionally, we mentioned some therapeutic approaches related to epigenetics, which could provide a potential cure for AD. Moreover, we reviewed some recent studies that validate DNA methylation as a potential biomarker and its role in AD. We hope that this review will provide new insights into the understanding of AD pathogenesis from the epigenetic perspective especially from the perspective of DNA methylation.
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Neuronal DNA Methyltransferases: Epigenetic Mediators between Synaptic Activity and Gene Expression?
Bayraktar, Gonca; Kreutz, Michael R.
2017-01-01
DNMT3A and 3B are the main de novo DNA methyltransferases (DNMTs) in the brain that introduce new methylation marks to non-methylated DNA in postmitotic neurons. DNA methylation is a key epigenetic mark that is known to regulate important cellular processes in neuronal development and brain plasticity. Accumulating evidence disclosed rapid and dynamic changes in DNA methylation of plasticity-relevant genes that are important for learning and memory formation. To understand how DNMTs contribute to brain function and how they are regulated by neuronal activity is a prerequisite for a deeper appreciation of activity-dependent gene expression in health and disease. This review discusses the functional role of de novo methyltransferases and in particular DNMT3A1 in the adult brain with special emphasis on synaptic plasticity, memory formation, and brain disorders. PMID:28513272
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Rahn, Elizabeth J; Guzman-Karlsson, Mikael C; David Sweatt, J
2013-10-01
Sensitization is a form of non-associative conditioning in which amplification of behavioral responses can occur following presentation of an aversive or noxious stimulus. Understanding the cellular and molecular underpinnings of sensitization has been an overarching theme spanning the field of learning and memory as well as that of pain research. In this review we examine how sensitization, both in the context of learning as well as pain processing, shares evolutionarily conserved behavioral, cellular/synaptic, and epigenetic mechanisms across phyla. First, we characterize the behavioral phenomenon of sensitization both in invertebrates and vertebrates. Particular emphasis is placed on long-term sensitization (LTS) of withdrawal reflexes in Aplysia following aversive stimulation or injury, although additional invertebrate models are also covered. In the context of vertebrates, sensitization of mammalian hyperarousal in a model of post-traumatic stress disorder (PTSD), as well as mammalian models of inflammatory and neuropathic pain is characterized. Second, we investigate the cellular and synaptic mechanisms underlying these behaviors. We focus our discussion on serotonin-mediated long-term facilitation (LTF) and axotomy-mediated long-term hyperexcitability (LTH) in reduced Aplysia systems, as well as mammalian spinal plasticity mechanisms of central sensitization. Third, we explore recent evidence implicating epigenetic mechanisms in learning- and pain-related sensitization. This review illustrates the fundamental and functional overlay of the learning and memory field with the pain field which argues for homologous persistent plasticity mechanisms in response to sensitizing stimuli or injury across phyla. Copyright © 2013 Elsevier Inc. All rights reserved.
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The role of epigenetic variation in the pathogenesis of systemic lupus erythematosus
2011-01-01
The focus of the present review is on the extent to which epigenetic alterations influence the development of systemic lupus erythematosus. Lupus is a systemic autoimmune disease characterized by the production of autoantibodies directed at nuclear self-antigens. A DNA methylation defect in CD4+ T cells has long been observed in idiopathic and drug-induced lupus. Recent studies utilizing high-throughput technologies have further characterized the nature of the DNA methylation defect in lupus CD4+ T cells. Emerging evidence in the literature is revealing an increasingly interconnected network of epigenetic dysregulation in lupus. Recent reports describe variable expression of a number of regulatory microRNAs in lupus CD4+ T cells, some of which govern the expression of DNA methyltransferase 1. While studies to date have revealed a significant role for epigenetic defects in the pathogenesis of lupus, the causal nature of epigenetic variation in lupus remains elusive. Future longitudinal epigenetic studies in lupus are therefore needed. PMID:22044622
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Syn, Genevieve; Blackwell, Jenefer M; Jamieson, Sarra E; Francis, Richard W
2018-01-01
Toxoplasma gondii uses epigenetic mechanisms to regulate both endogenous and host cell gene expression. To identify genes with putative epigenetic functions, we developed an in silico pipeline to interrogate the T. gondii proteome of 8313 proteins. Step 1 employs PredictNLS and NucPred to identify genes predicted to target eukaryotic nuclei. Step 2 uses GOLink to identify proteins of epigenetic function based on Gene Ontology terms. This resulted in 611 putative nuclear localised proteins with predicted epigenetic functions. Step 3 filtered for secretory proteins using SignalP, SecretomeP, and experimental data. This identified 57 of the 611 putative epigenetic proteins as likely to be secreted. The pipeline is freely available online, uses open access tools and software with user-friendly Perl scripts to automate and manage the results, and is readily adaptable to undertake any such in silico search for genes contributing to particular functions.
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Unexplored Potentials of Epigenetic Mechanisms of Plants and Animals—Theoretical Considerations
Seffer, Istvan; Nemeth, Zoltan; Hoffmann, Gyula; Matics, Robert; Seffer, A Gergely; Koller, Akos
2013-01-01
Morphological and functional changes of cells are important for adapting to environmental changes and associated with continuous regulation of gene expressions. Genes are regulated–in part–by epigenetic mechanisms resulting in alternating patterns of gene expressions throughout life. Epigenetic changes responding to the environmental and intercellular signals can turn on/off specific genes, but do not modify the DNA sequence. Most epigenetic mechanisms are evolutionary conserved in eukaryotic organisms, and several homologs of epigenetic factors are present in plants and animals. Moreover, in vitro studies suggest that the plant cytoplasm is able to induce a nuclear reassembly of the animal cell, whereas others suggest that the ooplasm is able to induce condensation of plant chromatin. Here, we provide an overview of the main epigenetic mechanisms regulating gene expression and discuss fundamental epigenetic mechanisms and factors functioning in both plants and animals. Finally, we hypothesize that animal genome can be reprogrammed by epigenetic factors from the plant protoplast. PMID:25512705
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Reyes-Aguirre, Luis I; Lamas, Monica
2016-01-01
Müller glia (MG) is the most abundant glial type in the vertebrate retina. Among its many functions, it is capable of responding to injury by dedifferentiating, proliferating, and differentiating into every cell types lost to damage. This regenerative ability is notoriously absent in mammals. We have previously reported that cultured mammalian MG undergoes a partial dedifferentiation, but fails to fully acquire a progenitor phenotype and differentiate into neurons. This might be explained by a mnemonic mechanism comprised by epigenetic traits, such as DNA methylation. To achieve a better understanding of this epigenetic memory, we studied the expression of pluripotency-associated genes, such as Oct4, Nanog , and Lin28 , which have been reported as necessary for regeneration in fish, at early times after NMDA-induced retinal injury in a mouse experimental model. We found that although Oct4 is expressed rapidly after damage (4 hpi), it is silenced at 24 hpi. This correlates with a significant decrease in the DNA methyltransferase Dnmt3b expression, which returns to basal levels at 24 hpi. By MS-PCR, we observed a decrease in Oct4 methylation levels at 4 and 12 hpi, before returning to a fully methylated state at 24 hpi. To demonstrate that these changes are restricted to MG, we separated these cells using a GLAST antibody coupled with magnetic beads. Finally, intravitreous administration of the DNA-methyltransferase inhibitor SGI-1027 induced Oct4 expression at 24 hpi in MG. Our results suggest that mammalian MG injury-induced dedifferentiation could be restricted by DNA methylation, which rapidly silences Oct4 expression, preventing multipotency acquisition.
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Reyes-Aguirre, Luis I.; Lamas, Monica
2016-01-01
Müller glia (MG) is the most abundant glial type in the vertebrate retina. Among its many functions, it is capable of responding to injury by dedifferentiating, proliferating, and differentiating into every cell types lost to damage. This regenerative ability is notoriously absent in mammals. We have previously reported that cultured mammalian MG undergoes a partial dedifferentiation, but fails to fully acquire a progenitor phenotype and differentiate into neurons. This might be explained by a mnemonic mechanism comprised by epigenetic traits, such as DNA methylation. To achieve a better understanding of this epigenetic memory, we studied the expression of pluripotency-associated genes, such as Oct4, Nanog, and Lin28, which have been reported as necessary for regeneration in fish, at early times after NMDA-induced retinal injury in a mouse experimental model. We found that although Oct4 is expressed rapidly after damage (4 hpi), it is silenced at 24 hpi. This correlates with a significant decrease in the DNA methyltransferase Dnmt3b expression, which returns to basal levels at 24 hpi. By MS-PCR, we observed a decrease in Oct4 methylation levels at 4 and 12 hpi, before returning to a fully methylated state at 24 hpi. To demonstrate that these changes are restricted to MG, we separated these cells using a GLAST antibody coupled with magnetic beads. Finally, intravitreous administration of the DNA-methyltransferase inhibitor SGI-1027 induced Oct4 expression at 24 hpi in MG. Our results suggest that mammalian MG injury-induced dedifferentiation could be restricted by DNA methylation, which rapidly silences Oct4 expression, preventing multipotency acquisition. PMID:27895551
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Pentoxifylline prevents post-traumatic stress disorder induced memory impairment.
Alzoubi, Karem H; Khabour, Omar F; Ahmed, Mohammed
2018-05-01
Posttraumatic stress disorder (PTSD) is a disabling prevalent and difficult-to-treat psychiatric disorder, which can develop after the exposure to severe traumatic events such as those occurring during wars and natural disasters. Pentoxifylline (PTX) is a potent antioxidant, which has an important role in prevention of cognitive dysfunctions. In the present study, the effect of PTX on memory impairment induced by PTSD was investigated using the rat animal model. PTSD-like behavior was induced in animals using a single-prolonged stress (SPS) rat model of PTSD (2 h restrain, 20 min forced swimming, 15 min rest, 1-2 min diethyl ether exposure). PTX was administered intraperitoneally at a dose of 100 mg/kg/day. Spatial learning and memory were assessed using the radial arm water maze (RAWM). Changes in oxidative stress biomarkers, brain derived neuroptrophic factor (BDNF), and epigenetics (histones) in the hippocampus following treatments were measured using enzymatic assays. The result revealed that SPS impaired both short- and long- term memory (P < 0.05). Use of PTX prevented memory impairment induced by SPS. Furthermore, PTX normalized SPS induced changes in the hippocampus GSH/GSSG ratio, activity of catalase, and glutathione peroxidase (GPx), BDNF, and certain histones levels. In conclusion, the SPS model of PTSD-like behavior induced memory impairment, whereas PTX prevented this impairment possibly through normalizing antioxidant mechanisms, BDNF and epigenetic changes in the hippocampus. Copyright © 2018 Elsevier Inc. All rights reserved.
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Epigenetic reprogramming in mammalian species after SCNT-based cloning.
Niemann, Heiner
2016-07-01
The birth of "Dolly," the first mammal cloned from an adult mammary epithelial cell, abolished the decades-old scientific dogma implying that a terminally differentiated cell cannot be reprogrammed into a pluripotent embryonic state. The most dramatic epigenetic reprogramming occurs in SCNT when the expression profile of a differentiated cell is abolished and a new embryo-specific expression profile, involving 10,000 to 12,000 genes, and thus, most genes of the entire genome is established, which drives embryonic and fetal development. The initial release from somatic cell epigenetic constraints is followed by establishment of post-zygotic expression patterns, X-chromosome inactivation, and adjustment of telomere length. Somatic cell nuclear transfer may be associated with a variety of pathologic changes of the fetal and placental phenotype in a proportion of cloned offspring, specifically in ruminants, that are thought to be caused by aberrant epigenetic reprogramming. Improvements in our understanding of this dramatic epigenetic reprogramming event will be instrumental in realizing the great potential of SCNT for basic research and for important agricultural and biomedical applications. Here, current knowledge on epigenetic reprogramming after use of SCNT in livestock is reviewed, with emphasis on gene-specific and global DNA methylation, imprinting, X-chromosome inactivation, and telomere length restoration in early development. Copyright © 2016 Elsevier Inc. All rights reserved.
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TALE-mediated epigenetic suppression of CDKN2A increases replication in human fibroblasts.
Bernstein, Diana L; Le Lay, John E; Ruano, Elena G; Kaestner, Klaus H
2015-05-01
Current strategies to alter disease-associated epigenetic modifications target ubiquitously expressed epigenetic regulators. This approach does not allow specific genes to be controlled in specific cell types; therefore, tools to selectively target epigenetic modifications in the desired cell type and strategies to more efficiently correct aberrant gene expression in disease are needed. Here, we have developed a method for directing DNA methylation to specific gene loci by conjugating catalytic domains of DNA methyltransferases (DNMTs) to engineered transcription activator-like effectors (TALEs). We demonstrated that these TALE-DNMTs direct DNA methylation specifically to the targeted gene locus in human cells. Further, we determined that minimizing direct nucleotide sequence repeats within the TALE moiety permits efficient lentivirus transduction, allowing easy targeting of primary cell types. Finally, we demonstrated that directed DNA methylation with a TALE-DNMT targeting the CDKN2A locus, which encodes the cyclin-dependent kinase inhibitor p16, decreased CDKN2A expression and increased replication of primary human fibroblasts, as intended. Moreover, overexpression of p16 in these cells reversed the proliferative phenotype, demonstrating the specificity of our epigenetic targeting. Together, our results demonstrate that TALE-DNMTs can selectively target specific genes and suggest that this strategy has potential application for the development of locus-specific epigenetic therapeutics.
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TALE-mediated epigenetic suppression of CDKN2A increases replication in human fibroblasts
Bernstein, Diana L.; Le Lay, John E.; Ruano, Elena G.; Kaestner, Klaus H.
2015-01-01
Current strategies to alter disease-associated epigenetic modifications target ubiquitously expressed epigenetic regulators. This approach does not allow specific genes to be controlled in specific cell types; therefore, tools to selectively target epigenetic modifications in the desired cell type and strategies to more efficiently correct aberrant gene expression in disease are needed. Here, we have developed a method for directing DNA methylation to specific gene loci by conjugating catalytic domains of DNA methyltransferases (DNMTs) to engineered transcription activator–like effectors (TALEs). We demonstrated that these TALE-DNMTs direct DNA methylation specifically to the targeted gene locus in human cells. Further, we determined that minimizing direct nucleotide sequence repeats within the TALE moiety permits efficient lentivirus transduction, allowing easy targeting of primary cell types. Finally, we demonstrated that directed DNA methylation with a TALE-DNMT targeting the CDKN2A locus, which encodes the cyclin-dependent kinase inhibitor p16, decreased CDKN2A expression and increased replication of primary human fibroblasts, as intended. Moreover, overexpression of p16 in these cells reversed the proliferative phenotype, demonstrating the specificity of our epigenetic targeting. Together, our results demonstrate that TALE-DNMTs can selectively target specific genes and suggest that this strategy has potential application for the development of locus-specific epigenetic therapeutics. PMID:25866970
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Fortress, Ashley M.; Kim, Jaekyoon; Poole, Rachel L.; Gould, Thomas J.
2014-01-01
Histone acetylation is essential for hippocampal memory formation in young adult rodents. Although dysfunctional histone acetylation has been associated with age-related memory decline in male rodents, little is known about whether histone acetylation is altered by aging in female rodents. In young female mice, the ability of 17β-estradiol (E2) to enhance object recognition memory consolidation requires histone H3 acetylation in the dorsal hippocampus. However, the extent to which histone acetylation is regulated by E2 in middle-aged females is unknown. The mnemonic benefits of E2 in aging females appear to be greatest in middle age, and so pinpointing the molecular mechanisms through which E2 enhances memory at this age could lead to the development of safer and more effective treatments for maintaining memory function without the side effects of current therapies. Here, we show that dorsal hippocampal infusion of E2 rapidly enhanced object recognition and spatial memory, and increased histone H3 acetylation in the dorsal hippocampus, while also significantly reducing levels of histone deacetylase (HDAC2 and HDAC3) proteins. E2 specifically increased histone H3 acetylation at Bdnf promoters pII and pIV in the dorsal hippocampus of both young and middle-aged mice, despite age-related decreases in pI and pIV acetylation. Furthermore, levels of mature BDNF and pro-BDNF proteins in the dorsal hippocampus were increased by E2 in middle-aged females. Together, these data suggest that the middle-aged female dorsal hippocampus remains epigenetically responsive to E2, and that E2 may enhance memory in middle-aged females via epigenetic regulation of Bdnf. PMID:25128537
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Chen, Kaifu; Chen, Zhong; Wu, Dayong; Zhang, Lili; Lin, Xueqiu; Su, Jianzhong; Rodriguez, Benjamin; Xi, Yuanxin; Xia, Zheng; Chen, Xi; Shi, Xiaobing; Wang, Qianben; Li, Wei
2016-01-01
Tumor suppressors are mostly defined by inactivating mutations in tumors, yet little is known about their epigenetic features in normal cells. Through integrative analysis of 1,134 genome-wide epigenetic profiles, mutations from >8,200 tumor-normal pairs, and our experimental data from clinical samples, we discovered broad H3K4me3 (wider than 4 kb) as the first epigenetic signature for tumor suppressors in normal cells. Broad H3K4me3 is associated with increased transcription elongation and enhancer activity together leading to exceptionally high gene expression, and is distinct from other broad epigenetic features, such as super-enhancers. Broad H3K4me3 conserved across normal cells may represent pan-cancer tumor suppressors, such as P53 and PTEN, whereas cell-type-specific broad H3K4me3 may indicate cell-identity genes and cell-type-specific tumor suppressors. Furthermore, widespread shortening of broad H3K4me3 in cancers is associated with repression of tumor suppressors. Together, the broad H3K4me3 epigenetic signature provides mutation-independent information for the discovery and characterization of novel tumor suppressors. PMID:26301496
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Jumonji/Arid1b (Jarid1b) protein modulates human esophageal cancer cell growth
KANO, YOSHIHIRO; KONNO, MASAMITSU; OHTA, KATSUYA; HARAGUCHI, NAOTSUGU; NISHIKAWA, SHIMPEI; KAGAWA, YOSHINORI; HAMABE, ATSUSHI; HASEGAWA, SHINICHIRO; OGAWA, HISATAKA; FUKUSUMI, TAKAHITO; NOGUCHI, YUKO; OZAKI, MIYUKI; KUDO, TOSHIHIRO; SAKAI, DAISUKE; SATOH, TAROH; ISHII, MASARU; MIZOHATA, EIICHI; INOUE, TAKESHI; MORI, MASAKI; DOKI, YUICHIRO; ISHII, HIDESHI
2013-01-01
Although esophageal cancer is highly heterogeneous and the involvement of epigenetic regulation of cancer stem cells is highly suspected, the biological significance of epigenetically modified molecules that regulate different subpopulations remains to be firmly established. Using esophageal cancer cells, we investigated the functional roles of the H3K4 demethylase Jumonji/Arid1b (Jarid1b) (Kdm5b/Plu-1/Rbp2-h1), an epigenetic factor that is required for continuous cell growth in melanoma. JARID1B knockdown resulted in the suppression of esophageal cancer cell growth, sphere formation and invasion ability and was associated with loss of epithelial marker expression. However, these inhibitory effects observed on tumor formation were reverted subsequent to subcutaneous inoculation of these cells into immune-deficient mice. These results indicated that JARID1B plays a role in maintaining cancer stem cells in the esophagus and justifies the rationale for studying the effects of continuous inhibition of this epigenetic factor in esophageal cancer. PMID:24649241
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Biophysical regulation of epigenetic state and cell reprogramming
NASA Astrophysics Data System (ADS)
Downing, Timothy L.; Soto, Jennifer; Morez, Constant; Houssin, Timothee; Fritz, Ashley; Yuan, Falei; Chu, Julia; Patel, Shyam; Schaffer, David V.; Li, Song
2013-12-01
Biochemical factors can help reprogram somatic cells into pluripotent stem cells, yet the role of biophysical factors during reprogramming is unknown. Here, we show that biophysical cues, in the form of parallel microgrooves on the surface of cell-adhesive substrates, can replace the effects of small-molecule epigenetic modifiers and significantly improve reprogramming efficiency. The mechanism relies on the mechanomodulation of the cells’ epigenetic state. Specifically, decreased histone deacetylase activity and upregulation of the expression of WD repeat domain 5 (WDR5)—a subunit of H3 methyltranferase—by microgrooved surfaces lead to increased histone H3 acetylation and methylation. We also show that microtopography promotes a mesenchymal-to-epithelial transition in adult fibroblasts. Nanofibrous scaffolds with aligned fibre orientation produce effects similar to those produced by microgrooves, suggesting that changes in cell morphology may be responsible for modulation of the epigenetic state. These findings have important implications in cell biology and in the optimization of biomaterials for cell-engineering applications.
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Bao, Siqin; Miyoshi, Naoki; Okamoto, Ikuhiro; Jenuwein, Thomas; Heard, Edith; Azim Surani, M
2005-08-01
The active and inactive X chromosomes have distinct epigenetic marks in somatic nuclei, which undergo reprogramming after transplantation into oocytes. We show that, despite the disappearance of Xist RNA coating in 30 min, the epigenetic memory of the inactive X persists with the precocious appearance of histone H3 trimethylation of lysine 27 (H3-3meK27), without the expected colocalization with Eed/Ezh2. Subsequently, Xist re-appears on the original inactive X, and the silent Xist on the active X undergoes re-activation, resulting in unusual biallelic Xist RNA domains. Despite this abnormal Xist expression pattern, colocalization of H3-3meK27 and Eed is thereafter confined to a single Xist domain, which is presumably on the original inactive X. These epigenetic events differ markedly from the kinetics of preferential paternal X inactivation in normal embryos. All the epigenetic marks on the X are apparently erased in the epiblast, suggesting that the oocyte and epiblast may have distinct properties for stepwise programming of the genome.
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Single cell and single molecule techniques for the analysis of the epigenome
NASA Astrophysics Data System (ADS)
Wallin, Christopher Benjamin
Epigenetic regulation is a critical biological process for the health and development of a cell. Epigenetic regulation is facilitated by covalent modifications to the underlying DNA and chromatin proteins. A fundamental understanding of these epigenetic modifications and their associated interactions at the molecular scale is necessary to explain phenomena including cellular identity, stem cell plasticity, and neoplastic transformation. It is widely known that abnormal epigenetic profiles have been linked to many diseases, most notably cancer. While the field of epigenetics has progressed rapidly with conventional techniques, significant advances remain to be made with respect to combinatoric analysis of epigenetic marks and single cell epigenetics. Therefore, in this dissertation, I will discuss our development of devices and methodologies to address these pertinent issues. First, we designed a preparatory polydimethylsiloxane (PDMS) microdevice for the extraction, purification, and stretching of human chromosomal DNA and chromatin from small cell populations down to a single cell. The valveless device captures cells by size exclusion within the micropillars, entraps the DNA or chromatin in the micropillars after cell lysis, purifies away the cellular debris, and fluorescently labels the DNA and/or chromatin all within a single reaction chamber. With the device, we achieve nearly 100% extraction efficiency of the DNA. The device is also used for in-channel immunostaining of chromatin followed by downstream single molecule chromatin analysis in nanochannels (SCAN). Second, using multi-color, time-correlated single molecule measurements in nanochannels, simultaneous coincidence detection of 2 epigenetic marks is demonstrated. Coincidence detection of 3 epigenetic marks is also established using a pulsed interleaved excitation scheme. With these two promising results, genome-wide quantification of epigenetic marks was pursued. Unfortunately, quantitative SCAN never materialized. Reasons for this, including poor signal to background, are explained in detail. Third, development of mobility-SCAN, an analytical technique for measuring and analyzing single molecules based on their fluorescent signature and their electrophoretic mobility in nanochannels is described. We use the technique to differentiate biomolecules from complex mixtures and derive parameters such as diffusion coefficients and effective charges. Finally, the device is used to detect binding interactions of various complexes similar to affinity capillary electrophoresis, but on a single molecule level. Fourth, we conclude by briefly discussing SCAN-sort, a technique to sort individual chromatin molecules based on their fluorescent emissions for further downstream analysis such as DNA sequencing. We demonstrate a 2-fold enrichment of chromatin from sorting and discuss possible system modifications for better performance in the future.
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Lindsay, Cameron; Seikaly, Hadi; Biron, Vincent L
2017-01-31
Epigenetic modifications are heritable changes in gene expression that do not directly alter DNA sequence. These modifications include DNA methylation, histone post-translational modifications, small and non-coding RNAs. Alterations in epigenetic profiles cause deregulation of fundamental gene expression pathways associated with carcinogenesis. The role of epigenetics in oropharyngeal squamous cell carcinoma (OPSCC) has recently been recognized, with implications for novel biomarkers, molecular diagnostics and chemotherapeutics. In this review, important epigenetic pathways in human papillomavirus (HPV) positive and negative OPSCC are summarized, as well as the potential clinical utility of this knowledge.This material has never been published and is not currently under evaluation in any other peer-reviewed publication.
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The various aspects of genetic and epigenetic toxicology: testing methods and clinical applications.
Ren, Ning; Atyah, Manar; Chen, Wan-Yong; Zhou, Chen-Hao
2017-05-22
Genotoxicity refers to the ability of harmful substances to damage genetic information in cells. Being exposed to chemical and biological agents can result in genomic instabilities and/or epigenetic alterations, which translate into a variety of diseases, cancer included. This concise review discusses, from both a genetic and epigenetic point of view, the current detection methods of different agents' genotoxicity, along with their basic and clinical relation to human cancer, chemotherapy, germ cells and stem cells.
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Ido, Yasuo
2016-07-01
Recent research in nutritional control of aging suggests that cytosolic increases in the reduced form of nicotinamide adenine dinucleotide and decreasing nicotinamide adenine dinucleotide metabolism plays a central role in controlling the longevity gene products sirtuin 1 (SIRT1), adenosine monophosphate-activated protein kinase (AMPK) and forkhead box O3 (FOXO3). High nutrition conditions, such as the diabetic milieu, increase the ratio of reduced to oxidized forms of cytosolic nicotinamide adenine dinucleotide through cascades including the polyol pathway. This redox change is associated with insulin resistance and the development of diabetic complications, and might be counteracted by insulin C-peptide. My research and others' suggest that the SIRT1-liver kinase B1-AMPK cascade creates positive feedback through nicotinamide adenine dinucleotide synthesis to help cells cope with metabolic stress. SIRT1 and AMPK can upregulate liver kinase B1 and FOXO3, key factors that help residential stem cells cope with oxidative stress. FOXO3 directly changes epigenetics around transcription start sites, maintaining the health of stem cells. 'Diabetic memory' is likely a result of epigenetic changes caused by high nutritional conditions, which disturb the quiescent state of residential stem cells and impair tissue repair. This could be prevented by restoring SIRT1-AMPK positive feedback through activating FOXO3. © 2016 The Author. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.
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Sun, Jin; Dong, Zhiwei; Zhang, Yang; He, Xiaoning; Fei, Dongdong; Jin, Fang; Yuan, Lin; Li, Bei; Jin, Yan
2017-07-12
Inflammatory microenvironment causes the change of epigenetic modification in periodontal ligament stem cells derived from periodontitis tissues (P-PDLSCs), which results in defective osteogenic differentiation compared to cells from healthy tissues. It's urgent to explore therapeutic strategies aimed at epigenetic targets associated with the regenerative ability of PDLSCs. Osthole, a small-molecule compound extracted from Chinese herbs, has been documented to promote osteogenesis and cell sheets formation of healthy PDLSCs. However, whether osthole shows same effect on P-PDLSCs and the mechanism of promotive effect is still unknown. The purpose of this study was to determine whether Osthole could restore defective osteogenic differentiation of P-PDLSCs via epigenetic modification. We demonstrated that 10 -7 Mol/L of Osthole was the best concentration for osteogenic differentiation and proliferation of P-PDLSCs. Mechanistically, we also found that Osthole upregulated MOZ and MORF, histone acetylases that specifically catalyze acetylation of Histone3 lisine9 (H3K9) and Histone3 lisine14 (H3K14), which are key regulators in osteogenic differentiation of P-PDLSCs. Furthermore, Osthole treatment improved cell sheet formation and enhanced the bone formation of PDLSC sheets in animal models of periodontitis. Our study suggests that Osthole is a promising drug to cure periodontitis via regulating epigenetic modification in cell sheets engineering.
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Dayeh, Tasnim; Ling, Charlotte
2015-10-01
β cell dysfunction is central to the development and progression of type 2 diabetes (T2D). T2D develops when β cells are not able to compensate for the increasing demand for insulin caused by insulin resistance. Epigenetic modifications play an important role in establishing and maintaining β cell identity and function in physiological conditions. On the other hand, epigenetic dysregulation can cause a loss of β cell identity, which is characterized by reduced expression of genes that are important for β cell function, ectopic expression of genes that are not supposed to be expressed in β cells, and loss of genetic imprinting. Consequently, this may lead to β cell dysfunction and impaired insulin secretion. Risk factors that can cause epigenetic dysregulation include parental obesity, an adverse intrauterine environment, hyperglycemia, lipotoxicity, aging, physical inactivity, and mitochondrial dysfunction. These risk factors can affect the epigenome at different time points throughout the lifetime of an individual and even before an individual is conceived. The plasticity of the epigenome enables it to change in response to environmental factors such as diet and exercise, and also makes the epigenome a good target for epigenetic drugs that may be used to enhance insulin secretion and potentially treat diabetes.
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Trained Memory of Human Uterine NK Cells Enhances Their Function in Subsequent Pregnancies.
Gamliel, Moriya; Goldman-Wohl, Debra; Isaacson, Batya; Gur, Chamutal; Stein, Natan; Yamin, Rachel; Berger, Michael; Grunewald, Myriam; Keshet, Eli; Rais, Yoach; Bornstein, Chamutal; David, Eyal; Jelinski, Adam; Eisenberg, Iris; Greenfield, Caryn; Ben-David, Arbel; Imbar, Tal; Gilad, Ronit; Haimov-Kochman, Ronit; Mankuta, David; Elami-Suzin, Matan; Amit, Ido; Hanna, Jacob H; Yagel, Simcha; Mandelboim, Ofer
2018-05-15
Natural killer cells (NKs) are abundant in the human decidua, regulating trophoblast invasion and angiogenesis. Several diseases of poor placental development are associated with first pregnancies, so we thus looked to characterize differences in decidual NKs (dNKs) in first versus repeated pregnancies. We discovered a population found in repeated pregnancies, which has a unique transcriptome and epigenetic signature, and is characterized by high expression of the receptors NKG2C and LILRB1. We named these cells Pregnancy Trained decidual NK cells (PTdNKs). PTdNKs have open chromatin around the enhancers of IFNG and VEGFA. Activation of PTdNKs led to increased production and secretion of IFN-γ and VEGFα, with the latter supporting vascular sprouting and tumor growth. The precursors of PTdNKs seem to be found in the endometrium. Because repeated pregnancies are associated with improved placentation, we propose that PTdNKs, which are present primarily in repeated pregnancies, might be involved in proper placentation. Copyright © 2018 Elsevier Inc. All rights reserved.
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Epigenetic Alterations in Cellular Immunity: New Insights into Autoimmune Diseases.
Wang, Zijun; Lu, Qianjin; Wang, Zhihui
2017-01-01
Epigenetic modification is an additional regulator in immune responses as the genome-wide profiling somehow fails to explain the sophisticated mechanisms in autoimmune diseases. The effect of epigenetic modifications on adaptive immunity derives from their regulations to induce a permissive or negative gene expression. Epigenetic events, such as DNA methylation, histone modifications and microRNAs (miRNAs) are often found in T cell activation, differentiation and commitment which are the major parts in cellular immunity. Recognizing the complexity of interactions between epigenetic mechanisms and immune disturbance in autoimmune diseases is essential for the exploration of efficient therapeutic targets. In this review, we summarize a list of studies that indicate the significance of dysregulated epigenetic modifications in autoimmune diseases while focusing on T cell immunity. © 2017 The Author(s)Published by S. Karger AG, Basel.
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Epigenetics in Adipose Tissue, Obesity, Weight Loss, and Diabetes12
Martínez, J. Alfredo; Milagro, Fermín I.; Claycombe, Kate J.; Schalinske, Kevin L.
2014-01-01
Given the role that diet and other environmental factors play in the development of obesity and type 2 diabetes, the implication of different epigenetic processes is being investigated. Although it is well known that external factors can cause cell type-dependent epigenetic changes, including DNA methylation, histone tail modifications, and chromatin remodeling, the regulation of these processes, the magnitude of the changes and the cell types in which they occur, the individuals more predisposed, and the more crucial stages of life remain to be elucidated. There is evidence that obese and diabetic people have a pattern of epigenetic marks different from nonobese and nondiabetic individuals. The main long-term goals in this field are the identification and understanding of the role of epigenetic marks that could be used as early predictors of metabolic risk and the development of drugs or diet-related treatments able to delay these epigenetic changes and even reverse them. But weight gain and insulin resistance/diabetes are influenced not only by epigenetic factors; different epigenetic biomarkers have also been identified as early predictors of weight loss and the maintenance of body weight after weight loss. The characterization of all the factors that are able to modify the epigenetic signatures and the determination of their real importance are hindered by the following factors: the magnitude of change produced by dietary and environmental factors is small and cumulative; there are great differences among cell types; and there are many factors involved, including age, with multiple interactions between them. PMID:24425725
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Epigenetics in adipose tissue, obesity, weight loss, and diabetes.
Martínez, J Alfredo; Milagro, Fermín I; Claycombe, Kate J; Schalinske, Kevin L
2014-01-01
Given the role that diet and other environmental factors play in the development of obesity and type 2 diabetes, the implication of different epigenetic processes is being investigated. Although it is well known that external factors can cause cell type-dependent epigenetic changes, including DNA methylation, histone tail modifications, and chromatin remodeling, the regulation of these processes, the magnitude of the changes and the cell types in which they occur, the individuals more predisposed, and the more crucial stages of life remain to be elucidated. There is evidence that obese and diabetic people have a pattern of epigenetic marks different from nonobese and nondiabetic individuals. The main long-term goals in this field are the identification and understanding of the role of epigenetic marks that could be used as early predictors of metabolic risk and the development of drugs or diet-related treatments able to delay these epigenetic changes and even reverse them. But weight gain and insulin resistance/diabetes are influenced not only by epigenetic factors; different epigenetic biomarkers have also been identified as early predictors of weight loss and the maintenance of body weight after weight loss. The characterization of all the factors that are able to modify the epigenetic signatures and the determination of their real importance are hindered by the following factors: the magnitude of change produced by dietary and environmental factors is small and cumulative; there are great differences among cell types; and there are many factors involved, including age, with multiple interactions between them.
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Kim, Joseph J; Moghe, Prabhas V
2018-06-14
This unit describes a protocol for acquiring and analyzing high-content super-resolution images of human stem cell nuclei for the characterization and classification of the cell differentiation paths based on distinct patterns of epigenetic mark organization. Here, we describe the cell culture, immunocytochemical labeling, super-resolution imaging parameters, and MATLAB-based quantitative image analysis approaches for monitoring human mesenchymal stem cells (hMSCs) and human induced pluripotent stem cells (hiPSCs) as the cells differentiate towards various lineages. Although this protocol uses specific cell types as examples, this approach could be easily extended to a variety of cell types and nuclear epigenetic and mechanosensitive biomarkers that are relevant to specific cell developmental scenarios. © 2018 by John Wiley & Sons, Inc. Copyright © 2018 John Wiley & Sons, Inc.
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A dermal HOX transcriptional program regulates site-specific epidermal fate
Rinn, John L.; Wang, Jordon K.; Allen, Nancy; Brugmann, Samantha A.; Mikels, Amanda J.; Liu, Helen; Ridky, Todd W.; Stadler, H. Scott; Nusse, Roel; Helms, Jill A.; Chang, Howard Y.
2008-01-01
Reciprocal epithelial–mesenchymal interactions shape site-specific development of skin. Here we show that site-specific HOX expression in fibroblasts is cell-autonomous and epigenetically maintained. The distal-specific gene HOXA13 is continually required to maintain the distal-specific transcriptional program in adult fibroblasts, including expression of WNT5A, a morphogen required for distal development. The ability of distal fibroblasts to induce epidermal keratin 9, a distal-specific gene, is abrogated by depletion of HOXA13, but rescued by addition of WNT5A. Thus, maintenance of appropriate HOX transcriptional program in adult fibroblasts may serve as a source of positional memory to differentially pattern the epithelia during homeostasis and regeneration. PMID:18245445
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A dermal HOX transcriptional program regulates site-specific epidermal fate.
Rinn, John L; Wang, Jordon K; Allen, Nancy; Brugmann, Samantha A; Mikels, Amanda J; Liu, Helen; Ridky, Todd W; Stadler, H Scott; Nusse, Roel; Helms, Jill A; Chang, Howard Y
2008-02-01
Reciprocal epithelial-mesenchymal interactions shape site-specific development of skin. Here we show that site-specific HOX expression in fibroblasts is cell-autonomous and epigenetically maintained. The distal-specific gene HOXA13 is continually required to maintain the distal-specific transcriptional program in adult fibroblasts, including expression of WNT5A, a morphogen required for distal development. The ability of distal fibroblasts to induce epidermal keratin 9, a distal-specific gene, is abrogated by depletion of HOXA13, but rescued by addition of WNT5A. Thus, maintenance of appropriate HOX transcriptional program in adult fibroblasts may serve as a source of positional memory to differentially pattern the epithelia during homeostasis and regeneration.
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Day, Troy
2016-04-01
Epigenetic inheritance is the transmission of nongenetic material such as gene expression levels, RNA and other biomolecules from parents to offspring. There is a growing realization that such forms of inheritance can play an important role in evolution. Bacteria represent a prime example of epigenetic inheritance because a large array of cellular components is transmitted to offspring, in addition to genetic material. Interestingly, there is an extensive and growing empirical literature showing that many bacteria can form 'persister' cells that are phenotypically resistant or tolerant to antibiotics, but most of these results are not interpreted within the context of epigenetic inheritance. Instead, persister cells are usually viewed as a genetically encoded bet-hedging strategy that has evolved in response to a fluctuating environment. Here I show, using a relatively simple model, that many of these empirical findings can be more simply understood as arising from a combination of epigenetic inheritance and cellular noise. I therefore suggest that phenotypic drug tolerance in bacteria might represent one of the best-studied examples of evolution under epigenetic inheritance. © 2016 John Wiley & Sons Ltd.
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2015-05-18
Department of Defense; Grant numbers: W81XWH-09-2-0044, W911NF-09-1-0298; Grant sponsor: Emory and Grady Memorial Hospital General Clinical Research...TERMS GWAS; PTSD; fMRI ; meQTL; epigenetic 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT Same as Report (SAR) 18. NUMBER OF PAGES 10...that contribute to this disorder. 2015 Wiley Periodicals, Inc. Key words: GWAS; PTSD; fMRI ; meQTL; epigenetic INTRODUCTION Although post-traumatic
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Gericke, G S
2010-05-01
Previous reports of specific patterns of increased fragility at common chromosomal fragile sites (CFS) found in association with certain neurobehavioural disorders did not attract attention at the time due to a shift towards molecular approaches to delineate neuropsychiatric disorder candidate genes. Links with miRNA, altered methylation and the origin of copy number variation indicate that CFS region characteristics may be part of chromatinomic mechanisms that are increasingly linked with neuroplasticity and memory. Current reports of large-scale double-stranded DNA breaks in differentiating neurons and evidence of ongoing DNA demethylation of specific gene promoters in adult hippocampus may shed new light on the dynamic epigenetic changes that are increasingly appreciated as contributing to long-term memory consolidation. The expression of immune recombination activating genes in key stress-induced memory regions suggests the adoption by the brain of this ancient pattern recognition and memory system to establish a structural basis for long-term memory through controlled chromosomal breakage at highly specific genomic regions. It is furthermore considered that these mechanisms for management of epigenetic information related to stress memory could be linked, in some instances, with the transfer of the somatically acquired information to the germline. Here, rearranged sequences can be subjected to further selection and possible eventual retrotranscription to become part of the more stable coding machinery if proven to be crucial for survival and reproduction. While linkage of cognitive memory with stress and fear circuitry and memory establishment through structural DNA modification is proposed as a normal process, inappropriate activation of immune-like genomic rearrangement processes through traumatic stress memory may have the potential to lead to undesirable activation of neuro-inflammatory processes. These theories could have a significant impact on the interpretation of risks posed by heredity and the environment and the search for neuropsychiatric candidate genes.
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Single-cell epigenomics: powerful new methods for understanding gene regulation and cell identity.
Clark, Stephen J; Lee, Heather J; Smallwood, Sébastien A; Kelsey, Gavin; Reik, Wolf
2016-04-18
Emerging single-cell epigenomic methods are being developed with the exciting potential to transform our knowledge of gene regulation. Here we review available techniques and future possibilities, arguing that the full potential of single-cell epigenetic studies will be realized through parallel profiling of genomic, transcriptional, and epigenetic information.
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Deciphering the Epigenetic Code in Embryonic and Dental Pulp Stem Cells
Bayarsaihan, Dashzeveg
2016-01-01
A close cooperation between chromatin states, transcriptional modulation, and epigenetic modifications is required for establishing appropriate regulatory circuits underlying self-renewal and differentiation of adult and embryonic stem cells. A growing body of research has established that the epigenome topology provides a structural framework for engaging genes in the non-random chromosomal interactions to orchestrate complex processes such as cell-matrix interactions, cell adhesion and cell migration during lineage commitment. Over the past few years, the functional dissection of the epigenetic landscape has become increasingly important for understanding gene expression dynamics in stem cells naturally found in most tissues. Adult stem cells of the human dental pulp hold great promise for tissue engineering, particularly in the skeletal and tooth regenerative medicine. It is therefore likely that progress towards pulp regeneration will have a substantial impact on the clinical research. This review summarizes the current state of knowledge regarding epigenetic cues that have evolved to regulate the pluripotent differentiation potential of embryonic stem cells and the lineage determination of developing dental pulp progenitors. PMID:28018144
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Cancer as a dysregulated epigenome allowing cellular growth advantage at the expense of the host
Timp, Winston; Feinberg, Andrew P.
2015-01-01
Although at the genetic level cancer is caused by diverse mutations, epigenetic modifications are characteristic of all cancers, from apparently normal precursor tissue to advanced metastatic disease, and these epigenetic modifications drive tumour cell heterogeneity. We propose a unifying model of cancer in which epigenetic dysregulation allows rapid selection for tumour cell survival at the expense of the host. Mechanisms involve both genetic mutations and epigenetic modifications that disrupt the function of genes that regulate the epigenome itself. Several exciting recent discoveries also point to a genome-scale disruption of the epigenome that involves large blocks of DNA hypomethylation, mutations of epigenetic modifier genes and alterations of heterochromatin in cancer (including large organized chromatin lysine modifications (LOCKs) and lamin-associated domains (LADs)), all of which increase epigenetic and gene expression plasticity. Our model suggests a new approach to cancer diagnosis and therapy that focuses on epigenetic dysregulation and has great potential for risk detection and chemoprevention. PMID:23760024
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Investigation of EZH2 pathways for novel epigenetic treatment strategies in oropharyngeal cancer.
Idris, Sherif; Lindsay, Cameron; Kostiuk, Morris; Andrews, Colin; Côté, David W J; O'Connell, Daniel A; Harris, Jeffrey; Seikaly, Hadi; Biron, Vincent L
2016-10-28
In recent decades, the incidence of oropharyngeal squamous cell carcinoma (OPSCC) has been rising worldwide as a result of increasing oncogenic human papillomavirus (HPV) infections in the oropharynx. EZH2 is an epigenetic regulatory protein associated with tumor aggressiveness and negative survival outcomes in several human cancers. We aimed to determine the role of EZH2 as a potential therapeutic epigenetic target in HPV-positive and negative OPSCC. The expression of EZH2 was measured by immunohistochemistry (IHC) and droplet digital PCR (ddPCR) in 2 HPV-positive and 2 HPV-negative cell lines. The cell lines were then cultured and treated with one of 3 EZH2 epigenetic inhibitors (3-deazaneplanocin A, GSK-343 and EPZ005687) or DMSO (control). Following 2, 4 and 7 days of treatment, cells were analyzed and compared by gene expression, cell survival and proliferation assays. EZH2 targeting resulted in greater inhibition of growth and survival in HPV-positive compared to HPV-negative cells lines. The expression profile of genes important in OPSCC also differed according to HPV-positivity for Ki67, CCND1, MET and PTEN/PIK3CA, but remained unchanged for EGFR, CDKN2A and p53. Inhibition of EZH2 has anti-tumorigenic effects on OPSCC cells in culture that is more pronounced in HPV-positive cell lines. EZH2 is a promising epigenetic target for the treatment of OPSCC.
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Buoncervello, Maria; Romagnoli, Giulia; Buccarelli, Mariachiara; Fragale, Alessandra; Toschi, Elena; Parlato, Stefania; Lucchetti, Donatella; Macchia, Daniele; Spada, Massimo; Canini, Irene; Sanchez, Massimo; Falchi, Mario; Musella, Martina; Biffoni, Mauro; Belardelli, Filippo; Capone, Imerio; Sgambato, Alessandro; Vitiani, Lucia Ricci; Gabriele, Lucia
2016-05-03
Epigenetic alterations, including dysregulated DNA methylation and histone modifications, govern the progression of colorectal cancer (CRC). Cancer cells exploit epigenetic regulation to control cellular pathways, including apoptotic and metastatic signals. Since aberrations in epigenome can be pharmacologically reversed by DNA methyltransferase and histone deacetylase inhibitors, epigenetics in combination with standard agents are currently envisaged as a new therapeutic frontier in cancer, expected to overcome drug resistance associated with current treatments. In this study, we challenged this idea and demonstrated that the combination of azacitidine and romidepsin with IFN-α owns a high therapeutic potential, targeting the most aggressive cellular components of CRC, such as metastatic cells and cancer stem cells (CSCs), via tight control of key survival and death pathways. Moreover, the antitumor efficacy of this novel pharmacological approach is associated with induction of signals of immunogenic cell death. Of note, a previously undisclosed key role of IFN-α in inducing both antiproliferative and pro-apoptotic effects on CSCs of CRC was also found. Overall, these findings open a new frontier on the suitability of IFN-α in association with epigenetics as a novel and promising therapeutic approach for CRC management.
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Buoncervello, Maria; Fragale, Alessandra; Toschi, Elena; Parlato, Stefania; Lucchetti, Donatella; Macchia, Daniele; Spada, Massimo; Canini, Irene; Sanchez, Massimo; Falchi, Mario; Musella, Martina; Biffoni, Mauro; Belardelli, Filippo; Capone, Imerio; Sgambato, Alessandro; Vitiani, Lucia Ricci; Gabriele, Lucia
2016-01-01
Epigenetic alterations, including dysregulated DNA methylation and histone modifications, govern the progression of colorectal cancer (CRC). Cancer cells exploit epigenetic regulation to control cellular pathways, including apoptotic and metastatic signals. Since aberrations in epigenome can be pharmacologically reversed by DNA methyltransferase and histone deacetylase inhibitors, epigenetics in combination with standard agents are currently envisaged as a new therapeutic frontier in cancer, expected to overcome drug resistance associated with current treatments. In this study, we challenged this idea and demonstrated that the combination of azacitidine and romidepsin with IFN-α owns a high therapeutic potential, targeting the most aggressive cellular components of CRC, such as metastatic cells and cancer stem cells (CSCs), via tight control of key survival and death pathways. Moreover, the antitumor efficacy of this novel pharmacological approach is associated with induction of signals of immunogenic cell death. Of note, a previously undisclosed key role of IFN-α in inducing both antiproliferative and pro-apoptotic effects on CSCs of CRC was also found. Overall, these findings open a new frontier on the suitability of IFN-α in association with epigenetics as a novel and promising therapeutic approach for CRC management. PMID:27028869
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Martos, Suzanne N; Tang, Wan-Yee; Wang, Zhibin
2015-07-01
Epigenetic mechanisms involving DNA methylation, histone modification, histone variants and nucleosome positioning, and noncoding RNAs regulate cell-, tissue-, and developmental stage-specific gene expression by influencing chromatin structure and modulating interactions between proteins and DNA. Epigenetic marks are mitotically inherited in somatic cells and may be altered in response to internal and external stimuli. The idea that environment-induced epigenetic changes in mammals could be inherited through the germline, independent of genetic mechanisms, has stimulated much debate. Many experimental models have been designed to interrogate the possibility of transgenerational epigenetic inheritance and provide insight into how environmental exposures influence phenotypes over multiple generations in the absence of any apparent genetic mutation. Unexpected molecular evidence has forced us to reevaluate not only our understanding of the plasticity and heritability of epigenetic factors, but of the stability of the genome as well. Recent reviews have described the difference between transgenerational and intergenerational effects; the two major epigenetic reprogramming events in the mammalian lifecycle; these two events making transgenerational epigenetic inheritance of environment-induced perturbations rare, if at all possible, in mammals; and mechanisms of transgenerational epigenetic inheritance in non-mammalian eukaryotic organisms. This paper briefly introduces these topics and mainly focuses on (1) transgenerational phenotypes and epigenetic effects in mammals, (2) environment-induced intergenerational epigenetic effects, and (3) the inherent difficulties in establishing a role for epigenetic inheritance in human environmental disease. Copyright © 2015 Elsevier Ltd. All rights reserved.
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Modulation of DNA methylation by human papillomavirus E6 and E7 oncoproteins in cervical cancer
Sen, Prakriti; Ganguly, Pooja; Ganguly, Niladri
2018-01-01
Human papillomaviruses (HPVs) are double stranded circular DNA viruses that infect cutaneous and mucosal epithelial cells. Almost 99% of cervical cancer has a HPV infection. The early oncoproteins E6 and E7 are important in this cellular transformation process. Epigenetic mechanisms have long been known to result in decisive alterations in DNA, leading to alterations in DNA-protein interactions, alterations in chromatin structure and compaction and significant alterations in gene expression. The enzymes responsible for these epigenetic modifications are DNA methyl transferases (DNMTs), histone acetylases and deacetylases. Epigenetics has an important role in cancer development by modifying the cellular micro environment. In this review, the authors discuss the role of HPV oncoproteins E6 and E7 in modulating the epigenetic mechanisms inside the host cell. The oncoproteins induce the expression of DNMTs which lead to aberrant DNA methylations and disruption of the normal epigenetic processes. The E7 oncoprotein may additionally directly bind and induce methyl transferase activity of the enzyme. These modulations lead to altered gene expression levels, particularly the genes involved in apoptosis, cell cycle and cell adhesion. In addition, the present review discusses how epigenetic mechanisms may be targeted for possible therapeutic interventions for HPV mediated cervical cancer. PMID:29285184
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Palomera-Sanchez, Zoraya; Watson, Gregory W; Wong, Carmen P; Beaver, Laura M; Williams, David E; Dashwood, Roderick H; Ho, Emily
2017-09-01
Androgen receptor (AR) is a transcription factor involved in normal prostate physiology and prostate cancer (PCa) development. 3,3'-Diindolylmethane (DIM) is a promising phytochemical agent against PCa that affects AR activity and epigenetic regulators in PCa cells. However, whether DIM suppresses PCa via epigenetic regulation of AR target genes is unknown. We assessed epigenetic regulation of AR target genes in LNCaP PCa cells and showed that DIM treatment led to epigenetic suppression of AR target genes involved in DNA repair (PARP1, MRE11, DNA-PK). Decreased expression of these genes was accompanied by an increase in repressive chromatin marks, loss of AR occupancy and EZH2 recruitment to their regulatory regions. Decreased DNA repair gene expression was associated with an increase in DNA damage (γH2Ax) and up-regulation of genomic repeat elements LINE1 and α-satellite. Our results suggest that DIM suppresses AR-dependent gene transcription through epigenetic modulation, leading to DNA damage and genome instability in PCa cells. Published by Elsevier Inc.
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Epigenetic Therapeutics: A New Weapon in the War Against Cancer.
Ahuja, Nita; Sharma, Anup R; Baylin, Stephen B
2016-01-01
The past 15 years have seen an explosion of discoveries related to the cellular regulation of phenotypes through epigenetic mechanisms. This regulation provides a software that packages DNA, without changing the primary base sequence, to establish heritable patterns of gene expression. In cancer, many aspects of the epigenome, controlled by DNA methylation, chromatin, and nucleosome positioning, are altered as one means by which tumor cells maintain abnormal states of self-renewal at the expense of normal maturation. Epigenetic and genetic abnormalities thus collaborate in cancer initiation and progression, as exemplified by frequent mutations in genes encoding proteins that control the epigenome. There is growing emphasis on using epigenetic therapies to reprogram neoplastic cells toward a normal state. Many agents targeting epigenetic regulation are under development and entering clinical trials. This review highlights the promise that epigenetic therapy, often in combination with other therapies, will become a potent tool for cancer management over the next decade.
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Epigenetics: the language of the cell?
Huang, Biao; Jiang, Cizhong; Zhang, Rongxin
2014-02-01
Epigenetics is one of the most rapidly developing fields of biological research. Breakthroughs in several technologies have enabled the possibility of genome-wide epigenetic research, for example the mapping of human genome-wide DNA methylation. In addition, with the development of various high-throughput and high-resolution sequencing technologies, a large number of functional noncoding RNAs have been identified. Massive studies indicated that these functional ncRNA also play an important role in epigenetics. In this review, we gain inspiration from the recent proposal of the ceRNAs hypothesis. This hypothesis proposes that miRNAs act as a language of communication. Accordingly, we further deduce that all of epigenetics may functionally acquire such a unique language characteristic. In summary, various epigenetic markers may not only participate in regulating cellular processes, but they may also act as the intracellular 'language' of communication and are involved in extensive information exchanges within cell.
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Chen, Kaifu; Chen, Zhong; Wu, Dayong; Zhang, Lili; Lin, Xueqiu; Su, Jianzhong; Rodriguez, Benjamin; Xi, Yuanxin; Xia, Zheng; Chen, Xi; Shi, Xiaobing; Wang, Qianben; Li, Wei
2015-10-01
Tumor suppressors are mostly defined by inactivating mutations in tumors, yet little is known about their epigenetic features in normal cells. Through integrative analysis of 1,134 genome-wide epigenetic profiles, mutations from >8,200 tumor-normal pairs and our experimental data from clinical samples, we discovered broad peaks for trimethylation of histone H3 at lysine 4 (H3K4me3; wider than 4 kb) as the first epigenetic signature for tumor suppressors in normal cells. Broad H3K4me3 is associated with increased transcription elongation and enhancer activity, which together lead to exceptionally high gene expression, and is distinct from other broad epigenetic features, such as super-enhancers. Genes with broad H3K4me3 peaks conserved across normal cells may represent pan-cancer tumor suppressors, such as TP53 and PTEN, whereas genes with cell type-specific broad H3K4me3 peaks may represent cell identity genes and cell type-specific tumor suppressors. Furthermore, widespread shortening of broad H3K4me3 peaks in cancers is associated with repression of tumor suppressors. Thus, the broad H3K4me3 epigenetic signature provides mutation-independent information for the discovery and characterization of new tumor suppressors.
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Niller, Hans Helmut; Wolf, Hans; Minarovits, Janos
2008-05-01
Epstein-Barr virus (EBV) is a human herpesvirus hiding in a latent form in memory B cells in the majority of the world population. Although, primary EBV infection is asymptomatic or causes a self-limiting disease, infectious mononucleosis, the virus is associated with a wide variety of neoplasms developing in immunosuppressed or immunodeficient individuals, but also in patients with an apparently intact immune system. In memory B cells, tumor cells, and lymphoblastoid cell lines (LCLs, transformed by EBV in vitro) the expression of the viral genes is highly restricted. There is no virus production (lytic viral replication associated with the expression of all viral genes) in tight latency. The expression of latent viral oncogenes and RNAs is under a strict epigenetic control via DNA methylation and histone modifications that results either in a complete silencing of the EBV genome in memory B cells, or in a cell-type dependent usage of latent promoters in tumor cells, germinal center B cells, and LCLs. Both the latent and lytic EBV proteins are potent immunogens and elicit vigorous B- and T-cell responses. In immunosuppressed and immunodeficient patients, or in individuals with a functional defect of EBV-specific T cells, lytic EBV replication is regularly activated and an increased viral load can be detected in the blood. Enhanced lytic replication results in new infection events and EBV-associated transformation events, and seems to be a risk factor both for malignant transformation and the development of autoimmune diseases. One may speculate that an increased load or altered presentation of a limited set of lytic or latent EBV proteins that cross-react with cellular antigens triggers and perpetuates the pathogenic processes that result in multiple sclerosis, systemic lupus erythematosus (SLE), and rheumatoid arthritis. In addition, in SLE patients EBV may cause defects of B-cell tolerance checkpoints because latent membrane protein 1, an EBV-encoded viral oncoprotein can induce BAFF, a B-cell activating factor that rescues self-reactive B cells and induces a lupus-like autoimmune disease in transgenic mice.
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DNA methylation-based measures of biological age: meta-analysis predicting time to death.
Chen, Brian H; Marioni, Riccardo E; Colicino, Elena; Peters, Marjolein J; Ward-Caviness, Cavin K; Tsai, Pei-Chien; Roetker, Nicholas S; Just, Allan C; Demerath, Ellen W; Guan, Weihua; Bressler, Jan; Fornage, Myriam; Studenski, Stephanie; Vandiver, Amy R; Moore, Ann Zenobia; Tanaka, Toshiko; Kiel, Douglas P; Liang, Liming; Vokonas, Pantel; Schwartz, Joel; Lunetta, Kathryn L; Murabito, Joanne M; Bandinelli, Stefania; Hernandez, Dena G; Melzer, David; Nalls, Michael; Pilling, Luke C; Price, Timothy R; Singleton, Andrew B; Gieger, Christian; Holle, Rolf; Kretschmer, Anja; Kronenberg, Florian; Kunze, Sonja; Linseisen, Jakob; Meisinger, Christine; Rathmann, Wolfgang; Waldenberger, Melanie; Visscher, Peter M; Shah, Sonia; Wray, Naomi R; McRae, Allan F; Franco, Oscar H; Hofman, Albert; Uitterlinden, André G; Absher, Devin; Assimes, Themistocles; Levine, Morgan E; Lu, Ake T; Tsao, Philip S; Hou, Lifang; Manson, JoAnn E; Carty, Cara L; LaCroix, Andrea Z; Reiner, Alexander P; Spector, Tim D; Feinberg, Andrew P; Levy, Daniel; Baccarelli, Andrea; van Meurs, Joyce; Bell, Jordana T; Peters, Annette; Deary, Ian J; Pankow, James S; Ferrucci, Luigi; Horvath, Steve
2016-09-28
Estimates of biological age based on DNA methylation patterns, often referred to as "epigenetic age", "DNAm age", have been shown to be robust biomarkers of age in humans. We previously demonstrated that independent of chronological age, epigenetic age assessed in blood predicted all-cause mortality in four human cohorts. Here, we expanded our original observation to 13 different cohorts for a total sample size of 13,089 individuals, including three racial/ethnic groups. In addition, we examined whether incorporating information on blood cell composition into the epigenetic age metrics improves their predictive power for mortality. All considered measures of epigenetic age acceleration were predictive of mortality (p≤8.2x10 -9 ) , independent of chronological age, even after adjusting for additional risk factors (p<5.4x10 -4 ) , and within the racial/ethnic groups that we examined (non-Hispanic whites, Hispanics, African Americans). Epigenetic age estimates that incorporated information on blood cell composition led to the smallest p-values for time to death (p=7.5x10 -43 ). Overall, this study a) strengthens the evidence that epigenetic age predicts all-cause mortality above and beyond chronological age and traditional risk factors, and b) demonstrates that epigenetic age estimates that incorporate information on blood cell counts lead to highly significant associations with all-cause mortality.
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Statistical Enrichment of Epigenetic States Around Triplet Repeats that Can Undergo Expansions
Essebier, Alexandra; Vera Wolf, Patricia; Cao, Minh Duc; Carroll, Bernard J.; Balasubramanian, Sureshkumar; Bodén, Mikael
2016-01-01
More than 30 human genetic diseases are linked to tri-nucleotide repeat expansions. There is no known mechanism that explains repeat expansions in full, but changes in the epigenetic state of the associated locus has been implicated in the disease pathology for a growing number of examples. A comprehensive comparative analysis of the genomic features associated with diverse repeat expansions has been lacking. Here, in an effort to decipher the propensity of repeats to undergo expansion and result in a disease state, we determine the genomic coordinates of tri-nucleotide repeat tracts at base pair resolution and computationally establish epigenetic profiles around them. Using three complementary statistical tests, we reveal that several epigenetic states are enriched around repeats that are associated with disease, even in cells that do not harbor expansion, relative to a carefully stratified background. Analysis of over one hundred cell types reveals that epigenetic states generally tend to vary widely between genic regions and cell types. However, there is qualified consistency in the epigenetic signatures of repeats associated with disease suggesting that changes to the chromatin and the DNA around an expanding repeat locus are likely to be similar. These epigenetic signatures may be exploited further to develop models that could explain the propensity of repeats to undergo expansions. PMID:27013954
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Race in an epigenetic time: thinking biology in the plural.
Meloni, Maurizio
2017-09-01
The notion that biological memories of environmental experiences can be embedded in the human genome and even transmitted transgenerationally is increasingly relevant in the postgenomic world, particularly in molecular epigenetics, where the genome is conceptualized as porous to environmental signals. In this article I discuss the current rethinking of race in epigenetic rather than genetic terms, emphasizing some of its paradoxical implications, especially for public policy. I claim in particular that: (i) if sociologists want to investigate race in a postgenomic world they should pay more attention to this novel plastic and biosocial view of race; and (ii) there are no reasons to believe that an epigenetic view will extinguish race, or that soft-inheritance claims will produce a less exclusionary discourse than genetics (hard heredity). Quite the opposite, the ground for a re-racialization of social debates and the reinforcement of biological boundaries between groups are highlighted in the article. © London School of Economics and Political Science 2017.
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The Emerging Role of Epigenetics in Stroke
Qureshi, Irfan A.; Mehler, Mark F.
2013-01-01
The transplantation of exogenous stem cells and the activation of endogenous neural stem and progenitor cells (NSPCs) are promising treatments for stroke. These cells can modulate intrinsic responses to ischemic injury and may even integrate directly into damaged neural networks. However, the neuroprotective and neural regenerative effects that can be mediated by these cells are limited and may even be deleterious. Epigenetic reprogramming represents a novel strategy for enhancing the intrinsic potential of the brain to protect and repair itself by modulating pathologic neural gene expression and promoting the recapitulation of seminal neural developmental processes. In fact, recent evidence suggests that emerging epigenetic mechanisms are critical for orchestrating nearly every aspect of neural development and homeostasis, including brain patterning, neural stem cell maintenance, neurogenesis and gliogenesis, neural subtype specification, and synaptic and neural network connectivity and plasticity. In this review, we survey the therapeutic potential of exogenous stem cells and endogenous NSPCs and highlight innovative technological approaches for designing, developing, and delivering epigenetic therapies for targeted reprogramming of endogenous pools of NSPCs, neural cells at risk, and dysfunctional neural networks to rescue and restore neurologic function in the ischemic brain. PMID:21403016
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The importance of detailed epigenomic profiling of different cell types within organs.
Stueve, Theresa Ryan; Marconett, Crystal N; Zhou, Beiyun; Borok, Zea; Laird-Offringa, Ite A
2016-06-01
The human body consists of hundreds of kinds of cells specified from a single genome overlaid with cell type-specific epigenetic information. Comprehensively profiling the body's distinct epigenetic landscapes will allow researchers to verify cell types used in regenerative medicine and to determine the epigenetic effects of disease, environmental exposures and genetic variation. Key marks/factors that should be investigated include regions of nucleosome-free DNA accessible to regulatory factors, histone marks defining active enhancers and promoters, DNA methylation levels, regulatory RNAs, and factors controlling the three-dimensional conformation of the genome. Here we use the lung to illustrate the importance of investigating an organ's purified cell epigenomes, and outline the challenges and promise of realizing a comprehensive catalog of primary cell epigenomes.
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Mitochondria link metabolism and epigenetics in haematopoiesis.
Schell, John C; Rutter, Jared
2017-05-31
Due to their varied metabolic and signalling roles, mitochondria are important in mediating cell behaviour. By altering mitochondrial function, two studies now identify metabolite-induced epigenetic changes that have profound effects on haematopoietic stem cell fate and function.
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Fragale, Alessandra; Romagnoli, Giulia; Licursi, Valerio; Buoncervello, Maria; Del Vecchio, Giorgia; Giuliani, Caterina; Parlato, Stefania; Leone, Celeste; De Angelis, Marta; Canini, Irene; Toschi, Elena; Belardelli, Filippo; Negri, Rodolfo; Capone, Imerio; Presutti, Carlo; Gabriele, Lucia
2017-07-01
Colorectal cancer results from the progressive accumulation of genetic and epigenetic alterations. IFN signaling defects play an important role in the carcinogenesis process, in which the inability of IFN transcription regulatory factors (IRF) to access regulatory sequences in IFN-stimulated genes (ISG) in tumors and in immune cells may be pivotal. We reported that low-dose combination of two FDA-approved epidrugs, azacytidine (A) and romidepsin (R), with IFNα2 (ARI) hampers the aggressiveness of both colorectal cancer metastatic and stem cells in vivo and triggers immunogenic cell death signals that stimulate dendritic cell (DC) function. Here, we investigated the molecular signals induced by ARI treatment and found that this drug combination increased the accessibility to regulatory sequences of ISGs and IRFs that were epigenetically silenced in both colorectal cancer cells and DCs. Likewise, specific ARI-induced histone methylation and acetylation changes marked epigenetically affected ISG promoters in both metastatic cancer cells and DCs. Analysis by ChIP-seq confirmed such ARI-induced epigenetically regulated IFN signature. The activation of this signal endowed DCs with a marked migratory capability. Our results establish a direct correlation between reexpression of silenced ISGs by epigenetic control and ARI anticancer activity and provide new knowledge for the development of innovative combined therapeutic strategies for colorectal cancer. Cancer Immunol Res; 5(7); 604-16. ©2017 AACR . ©2017 American Association for Cancer Research.
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Piazza, Rocco; Magistroni, Vera; Mogavero, Angela; Andreoni, Federica; Ambrogio, Chiara; Chiarle, Roberto; Mologni, Luca; Bachmann, Petra S; Lock, Richard B; Collini, Paola; Pelosi, Giuseppe; Gambacorti-Passerini, Carlo
2013-01-01
BIM is a proapoptotic member of the Bcl-2 family. Here, we investigated the epigenetic status of the BIM locus in NPM/ALK+ anaplastic large cell lymphoma (ALCL) cell lines and in lymph node biopsies from NPM/ALK+ ALCL patients. We show that BIM is epigenetically silenced in cell lines and lymph node specimens and that treatment with the deacetylase inhibitor trichostatin A restores the histone acetylation, strongly upregulates BIM expression, and induces cell death. BIM silencing occurs through recruitment of MeCP2 and the SIN3a/histone deacetylase 1/2 (HDAC1/2) corepressor complex. This event requires BIM CpG methylation/demethylation with 5-azacytidine that leads to detachment of the MeCP2 corepressor complex and reacetylation of the histone tails. Treatment with the ALK inhibitor PF2341066 or with an inducible shRNA targeting NPM/ALK does not restore BIM locus reacetylation; however, enforced expression of NPM/ALK in an NPM/ALK-negative cell line significantly increases the methylation at the BIM locus. This study demonstrates that BIM is epigenetically silenced in NPM/ALK-positive cells through recruitment of the SIN3a/HDAC1/2 corepressor complex and that NPM/ALK is dispensable to maintain BIM epigenetic silencing but is able to act as an inducer of BIM methylation. PMID:23633923
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Khan, Deena; Ahmed, S. Ansar
2015-01-01
Endocrine disrupting chemicals (EDC) abound in the environment since many compounds are released from chemical, agricultural, pharmaceutical, and consumer product industries. Many of the EDCs such as Bisphenol A (BPA) have estrogenic activity or interfere with endogenous sex hormones. Experimental studies have reported a positive correlation of BPA with reproductive toxicity, altered growth, and immune dysregulation. Although the precise relevance of these studies to the environmental levels is unclear, nevertheless, their potential health implications remain a concern. One possible mechanism by which BPA can alter genes is by regulating epigenetics, including microRNA, alteration of methylation, and histone acetylation. There is now wealth of information on BPA effects on non-lymphoid cells and by comparison, paucity of data on effects of BPA on the immune system. In this mini review, we will highlight the BPA regulation of estrogen receptor-mediated immune cell functions and in different inflammatory conditions. In addition, BPA-mediated epigenetic regulation of non-lymphoid cells is emphasized. We recognize that most of these studies are on non-lymphoid cells, and given that BPA also affects the immune system, it is plausible that BPA could have similar epigenetic regulation in immune cells. It is hoped that this review will stimulate studies in this area to ascertain whether or not BPA epigenetically regulates the cells of the immune system. PMID:26097467
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Memory loss in Alzheimer's disease
Jahn, Holger
2013-01-01
Loss of memory is among the first symptoms reported by patients suffering from Alzheimer's disease (AD) and by their caretakers. Working memory and long-term declarative memory are affected early during the course of the disease. The individual pattern of impaired memory functions correlates with parameters of structural or functional brain integrity. AD pathology interferes with the formation of memories from the molecular level to the framework of neural networks. The investigation of AD memory loss helps to identify the involved neural structures, such as the default mode network, the influence of epigenetic and genetic factors, such as ApoE4 status, and evolutionary aspects of human cognition. Clinically, the analysis of memory assists the definition of AD subtypes, disease grading, and prognostic predictions. Despite new AD criteria that allow the earlier diagnosis of the disease by inclusion of biomarkers derived from cerebrospinal fluid or hippocampal volume analysis, neuropsychological testing remains at the core of AD diagnosis. PMID:24459411
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Material Cues as Potent Regulators of Epigenetics and Stem Cell Function.
Crowder, Spencer W; Leonardo, Vincent; Whittaker, Thomas; Papathanasiou, Peter; Stevens, Molly M
2016-01-07
Biophysical signals act as potent regulators of stem cell function, lineage commitment, and epigenetic status. In recent years, synthetic biomaterials have been used to study a wide range of outside-in signaling events, and it is now well appreciated that material cues modulate the epigenome. Here, we review the role of extracellular signals in guiding stem cell behavior via epigenetic regulation, and we stress the role of physicochemical material properties as an often-overlooked modulator of intracellular signaling. We also highlight promising new research tools for ongoing interrogation of the stem cell-material interface. Copyright © 2016 Elsevier Inc. All rights reserved.
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Understanding genetics in neuroimaging.
Vasquez, Marina Lipkin; Renault, Ilana Zalcberg
2015-02-01
Gene expression is a process of DNA sequence reading into protein synthesis. In cases of problems in DNA repair/apoptosis mechanisms, cells accumulate genomic abnormalities and pass them through generations of cells. The accumulation of mutations causes diseases and even tumors. In addition to cancer, many other neurologic conditions have been associated with genetic mutations. Some trials are testing patients with epigenetic treatments. Epigenetic therapy must be used with caution because epigenetic processes and changes happen constantly in normal cells, giving rise to drug off-target effects. Scientists are making progress in specifically targeting abnormal cells with minimal damage to normal ones. Copyright © 2015. Published by Elsevier Inc.
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Meyer, Mark B.; Benkusky, Nancy A.; Sen, Buer; Rubin, Janet; Pike, J. Wesley
2016-01-01
Terminal differentiation of multipotent stem cells is achieved through a coordinated cascade of activated transcription factors and epigenetic modifications that drive gene transcription responsible for unique cell fate. Within the mesenchymal lineage, factors such as RUNX2 and PPARγ are indispensable for osteogenesis and adipogenesis, respectively. We therefore investigated genomic binding of transcription factors and accompanying epigenetic modifications that occur during osteogenic and adipogenic differentiation of mouse bone marrow-derived mesenchymal stem cells (MSCs). As assessed by ChIP-sequencing and RNA-sequencing analyses, we found that genes vital for osteogenic identity were linked to RUNX2, C/EBPβ, retinoid X receptor, and vitamin D receptor binding sites, whereas adipocyte differentiation favored PPARγ, retinoid X receptor, C/EBPα, and C/EBPβ binding sites. Epigenetic marks were clear predictors of active differentiation loci as well as enhancer activities and selective gene expression. These marrow-derived MSCs displayed an epigenetic pattern that suggested a default preference for the osteogenic pathway; however, these patterns were rapidly altered near the Adipoq, Cidec, Fabp4, Lipe, Plin1, Pparg, and Cebpa genes during adipogenic differentiation. Surprisingly, we found that these cells also exhibited an epigenetic plasticity that enabled them to trans-differentiate from adipocytes to osteoblasts (and vice versa) after commitment, as assessed by staining, gene expression, and ChIP-quantitative PCR analysis. The osteogenic default pathway may be subverted during pathological conditions, leading to skeletal fragility and increased marrow adiposity during aging, estrogen deficiency, and skeletal unloading. Taken together, our data provide an increased mechanistic understanding of the epigenetic programs necessary for multipotent differentiation of MSCs that may prove beneficial in the development of therapeutic strategies. PMID:27402842
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Nguyen, Van T. M.; Barozzi, Iros; Faronato, Monica; Lombardo, Ylenia; Steel, Jennifer H.; Patel, Naina; Darbre, Philippa; Castellano, Leandro; Győrffy, Balázs; Woodley, Laura; Meira, Alba; Patten, Darren K.; Vircillo, Valentina; Periyasamy, Manikandan; Ali, Simak; Frige, Gianmaria; Minucci, Saverio; Coombes, R. Charles; Magnani, Luca
2015-01-01
Endocrine therapies target the activation of the oestrogen receptor alpha (ERα) via distinct mechanisms, but it is not clear whether breast cancer cells can adapt to treatment using drug-specific mechanisms. Here we demonstrate that resistance emerges via drug-specific epigenetic reprogramming. Resistant cells display a spectrum of phenotypical changes with invasive phenotypes evolving in lines resistant to the aromatase inhibitor (AI). Orthogonal genomics analysis of reprogrammed regulatory regions identifies individual drug-induced epigenetic states involving large topologically associating domains (TADs) and the activation of super-enhancers. AI-resistant cells activate endogenous cholesterol biosynthesis (CB) through stable epigenetic activation in vitro and in vivo. Mechanistically, CB sparks the constitutive activation of oestrogen receptors alpha (ERα) in AI-resistant cells, partly via the biosynthesis of 27-hydroxycholesterol. By targeting CB using statins, ERα binding is reduced and cell invasion is prevented. Epigenomic-led stratification can predict resistance to AI in a subset of ERα-positive patients. PMID:26610607
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Epigenetic hierarchy governing Nestin expression.
Han, Dong Wook; Do, Jeong Tae; Araúzo-Bravo, Marcos J; Lee, Sung Ho; Meissner, Alexander; Lee, Hoon Taek; Jaenisch, Rudolf; Schöler, Hans R
2009-05-01
Nestin is an intermediate filament protein expressed specifically in neural stem cells and progenitor cells of the central nervous system. DNA demethylation and histone modifications are two types of epigenetic modifications working in a coordinate or synergistic manner to regulate the expression of various genes. This study investigated and elucidated the epigenetic regulation of Nestin gene expression during embryonic differentiation along the neural cell lineage. Nestin exhibits differential DNA methylation and histone acetylation patterns in Nestin-expressing and nonexpressing cells. In P19 embryonic carcinoma cells, activation of Nestin expression is mediated by both trichostatin A and 5-aza-2'-deoxycytidine treatment, concomitant with histone acetylation, but not with DNA demethylation. Nestin transcription is also mediated by treatment with retinoic acid, again in the absence of DNA demethylation. Thus, histone acetylation is sufficient to mediate the activation of Nestin transcription. This study proposed that the regulation of Nestin gene expression can be used as a model to study the epigenetic regulation of gene expression mediated by histone acetylation, but not by DNA demethylation.
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Morse, Sarah J; Butler, Anderson A; Davis, Robin L; Soller, Ian J; Lubin, Farah D
2015-04-01
A decline in long-term memory (LTM) formation is a common feature of the normal aging process, which corresponds with abnormal expression of memory-related genes in the aged hippocampus. Epigenetic modulation of chromatin structure is required for proper transcriptional control of genes, such as the brain-derived neurotrophic factor (Bdnf) and Zif268 in the hippocampus during the consolidation of new memories. Recently, the view has emerged that aberrant transcriptional regulation of memory-related genes may be reflective of an altered epigenetic landscape within the aged hippocampus, resulting in memory deficits with aging. Here, we found that baseline resting levels for tri-methylation of histone H3 at lysine 4 (H3K4me3) and acetylation of histone H3 at lysine 9 and 14 (H3K9,K14ac) were altered in the aged hippocampus as compared to levels in the hippocampus of young adult rats. Interestingly, object learning failed to increase activity-dependent H3K4me3 and di-methylation of histone H3 at lysine 9 (H3K9me2) levels in the hippocampus of aged adults as compared to young adults. Treatment with the LSD-1 histone demethylase inhibitor, t-PCP, increased baseline resting H3K4me3 and H3K9,K14ac levels in the young adult hippocampus, while young adult rats exhibited similar memory deficits as observed in aged rats. After environmental enrichment (EE), we found that object learning induced increases in H3K4me3 levels around the Bdnf, but not the Zif268, gene region in the aged hippocampus and rescued memory deficits in aged adults. Collectively, these results suggest that histone lysine methylation levels are abnormally regulated in the aged hippocampus and identify histone lysine methylation as a transcriptional mechanism by which EE may serve to restore memory formation with aging.
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Singh, Padmanabh; Konar, Arpita; Kumar, Ashish; Srivas, Sweta; Thakur, Mahendra K
2015-08-01
The amnesic potential of scopolamine is well manifested through synaptic plasticity gene expression changes and behavioral paradigms of memory impairment. However, the underlying mechanism remains obscure and consequently ideal therapeutic target is lacking. In this context, chromatin-modifying enzymes, which regulate memory gene expression changes, deserve major attention. Therefore, we analyzed the expression of chromatin-modifying enzymes and recovery potential of enzyme modulators in scopolamine-induced amnesia. Scopolamine administration drastically up-regulated DNA methyltransferases (DNMT1) and HDAC2 expression while CREB-binding protein (CBP), DNMT3a and DNMT3b remained unaffected. HDAC inhibitor sodium butyrate and DNMT inhibitor Aza-2'deoxycytidine recovered scopolamine-impaired hippocampal-dependent memory consolidation with concomitant increase in the expression of synaptic plasticity genes Brain-derived neurotrophic factor (BDNF) and Arc and level of histone H3K9 and H3K14 acetylation and decrease in DNA methylation level. Sodium butyrate showed more pronounced effect than Aza-2'deoxycytidine and their co-administration did not exhibit synergistic effect on gene expression. Taken together, we showed for the first time that scopolamine-induced up-regulation of chromatin-modifying enzymes, HDAC2 and DNMT1, leads to gene expression changes and consequent decline in memory consolidation. Our findings on the action of scopolamine as an epigenetic modulator can pave a path for ideal therapeutic targets. We propose the following putative pathway for scopolamine-mediated memory impairment; scopolamine up-regulates hippocampal DNMT1 and HDAC2 expression, induces methylation and deacetylation of BDNF and Arc promoter, represses gene expression and eventually impairs memory consolidation. On the other hand, Aza-2 and NaB inhibit DNMT1 and HDAC2 respectively, up-regulate BDNF and Arc expression and recover memory consolidation. We elucidate the action of scopolamine as an epigenetic modulator and hope that DNMT1 and HDAC2 would be ideal therapeutic targets for memory disorders. © 2015 International Society for Neurochemistry.
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Cancer Chemoprevention by Dietary Polyphenols: Promising Role for Epigenetics
Link, Alexander; Balaguer, Francesc; Goel, Ajay
2010-01-01
Epigenetics refers to heritable changes that are not encoded in the DNA sequence itself, but play an important role in the control of gene expression. In mammals, epigenetic mechanisms include changes in DNA methylation, histone modifications and non-coding RNAs. Although epigenetic changes are heritable in somatic cells, these modifications are also potentially reversible, which makes them attractive and promising avenues for tailoring cancer preventive and therapeutic strategies. Burgeoning evidence in the last decade has provided unprecedented clues that diet and environmental factors directly influence epigenetic mechanisms in humans. Dietary polyphenols from green tea, turmeric, soybeans, broccoli and others have shown to possess multiple cell-regulatory activities within cancer cells. More recently, we have begun to understand that some of the dietary polyphenols may exert their chemopreventive effects in part by modulating various components of the epigenetic machinery in humans. In this article, we first discuss the contribution of diet and environmental factors on epigenetic alterations; subsequently, we provide a comprehensive review of literature on the role of various dietary polyphenols. In particular, we summarize the current knowledge on a large number of dietary agents and their effects on DNA methylation, histone modifications and regulation of expression of non-coding miRNAs in various in vitro and in vivo models. We emphasize how increased understanding of the chemopreventive effects of dietary polyphenols on specific epigenetic alterations may provide unique and yet unexplored novel and highly effective chemopreventive strategies for reducing the health burden of cancer and other diseases in humans. PMID:20599773
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Dukowic-Schulze, Stefanie; Liu, Chang; Chen, Changbin
2018-01-01
DNA methylation and histone modifications are epigenetic changes on a DNA molecule that alter the three-dimensional (3D) structure locally as well as globally, impacting chromatin looping and packaging on a larger scale. Epigenetic marks thus inform higher-order chromosome organization and placement in the nucleus. Conventional epigenetic marks are joined by chromatin modifiers like cohesins, condensins and membrane-anchoring complexes to support particularly 3D chromosome organization. The most popular consequences of epigenetic modifications are gene expression changes, but chromatin modifications have implications beyond this, particularly in actively dividing cells and during sexual reproduction. In this opinion paper, we will focus on epigenetic mechanisms and chromatin modifications during meiosis as part of plant sexual reproduction where 3D management of chromosomes and re-organization of chromatin are defining features and prime tasks in reproductive cells, not limited to modulating gene expression. Meiotic chromosome organization, pairing and synapsis of homologous chromosomes as well as distribution of meiotic double-strand breaks and resulting crossovers are presumably highly influenced by epigenetic mechanisms. Special mobile small RNAs have been described in anthers, where these so-called phasiRNAs seem to direct DNA methylation in meiotic cells. Intriguingly, many of the mentioned developmental processes make use of epigenetic changes and small RNAs in a manner other than gene expression changes. Widening our approaches and opening our mind to thinking three-dimensionally regarding epigenetics in plant development holds high promise for new discoveries and could give us a boost for further knowledge.
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Ali, Dalia; Hamam, Rimi; Alfayez, Musaed; Kassem, Moustapha; Aldahmash, Abdullah
2016-01-01
The epigenetic mechanisms promoting lineage-specific commitment of human skeletal (mesenchymal or stromal) stem cells (hMSCs) into adipocytes or osteoblasts are still not fully understood. Herein, we performed an epigenetic library functional screen and identified several novel compounds, including abexinostat, which promoted adipocytic and osteoblastic differentiation of hMSCs. Using gene expression microarrays, chromatin immunoprecipitation for H3K9Ac combined with high-throughput DNA sequencing (ChIP-seq), and bioinformatics, we identified several key genes involved in regulating stem cell proliferation and differentiation that were targeted by abexinostat. Concordantly, ChIP-quantitative polymerase chain reaction revealed marked increase in H3K9Ac epigenetic mark on the promoter region of AdipoQ, FABP4, PPARγ, KLF15, CEBPA, SP7, and ALPL in abexinostat-treated hMSCs. Pharmacological inhibition of focal adhesion kinase (PF-573228) or insulin-like growth factor-1R/insulin receptor (NVP-AEW51) signaling exhibited significant inhibition of abexinostat-mediated adipocytic differentiation, whereas inhibition of WNT (XAV939) or transforming growth factor-β (SB505124) signaling abrogated abexinostat-mediated osteogenic differentiation of hMSCs. Our findings provide insight into the understanding of the relationship between the epigenetic effect of histone deacetylase inhibitors, transcription factors, and differentiation pathways governing adipocyte and osteoblast differentiation. Manipulating such pathways allows a novel use for epigenetic compounds in hMSC-based therapies and tissue engineering. Significance This unbiased epigenetic library functional screen identified several novel compounds, including abexinostat, that promoted adipocytic and osteoblastic differentiation of human skeletal (mesenchymal or stromal) stem cells (hMSCs). These data provide new insight into the understanding of the relationship between the epigenetic effect of histone deacetylase inhibitors, transcription factors, and differentiation pathways controlling adipocyte and osteoblast differentiation of hMSCs. Manipulating such pathways allows a novel use for epigenetic compounds in hMSC-based therapies for tissue engineering, bone disease, obesity, and metabolic-disorders. PMID:27194745
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Janczar, Szymon; Janczar, Karolina; Pastorczak, Agata; Harb, Hani; Paige, Adam J. W.; Zalewska-Szewczyk, Beata; Danilewicz, Marian; Mlynarski, Wojciech
2017-01-01
While cancer has been long recognized as a disease of the genome, the importance of epigenetic mechanisms in neoplasia was acknowledged more recently. The most active epigenetic marks are DNA methylation and histone protein modifications and they are involved in basic biological phenomena in every cell. Their role in tumorigenesis is stressed by recent unbiased large-scale studies providing evidence that several epigenetic modifiers are recurrently mutated or frequently dysregulated in multiple cancers. The interest in epigenetic marks is especially due to the fact that they are potentially reversible and thus druggable. In B-cell progenitor acute lymphoblastic leukemia (BCP-ALL) there is a relative paucity of reports on the role of histone protein modifications (acetylation, methylation, phosphorylation) as compared to acute myeloid leukemia, T-cell ALL, or other hematologic cancers, and in this setting chromatin modifications are relatively less well studied and reviewed than DNA methylation. In this paper, we discuss the biomarker associations and evidence for a driver role of dysregulated global and loci-specific histone marks, as well as mutations in epigenetic modifiers in BCP-ALL. Examples of chromatin modifiers recurrently mutated/disrupted in BCP-ALL and associated with disease outcomes include MLL1, CREBBP, NSD2, and SETD2. Altered histone marks and histone modifiers and readers may play a particular role in disease chemoresistance and relapse. We also suggest that epigenetic regulation of B-cell differentiation may have parallel roles in leukemogenesis. PMID:28054944
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Oliveras-Ferraros, Cristina; Vazquez-Martin, Alejandro; Menendez, Javier A
2010-10-01
Networks of oncogenes and tumor suppressor genes that control cancer cell proliferation also regulate stem cell renewal and possibly stem cell aging. Because (de)differentiation processes might dictate tumor cells to retrogress to a more stem-like state in response to aging-relevant epigenetic and/or environmental players, we recently envisioned that cultured human cancer cells might be used as reliable models to test the ability of antiaging interventions for promoting the initiation and maintenance of self-renewing divisions. Cancer cell lines naturally bearing undetectable amounts of stem/progenitor-like cell populations were continuously cultured in the presence of the caloric restriction mimetic metformin for several months. Microarray technology was employed to profile expression of genes related to the identification, growth, and differentiation of stem cells. Detection of functionally related gene groups using a pathway analysis package provided annotated genetic signatures over- and underexpressed in response to pharmacological mimicking of caloric restriction. By following this methodological approach, we recently obtained data fitting a model in which, in response to chronic impairment of cellular bioenergetics imposed by metformin-induced mitochondrial uncoupling as assessed by the phosphorylation state of cAMP-response element binding protein (CREB), tumor cells can retrogress from a differentiated state to a more CD44(+) stem-like primitive state epigenetically governed by the Polycomb-group suppressor BMI1-a crucial "stemness" gene involved in the epigenetic maintenance of adult stem cells. These findings might provide a novel molecular avenue to investigate if antiaging benefits from caloric restriction mimetics might relate to their ability to epigenetically reprogram stemness while prolonging the capacity of stem-like cell states to proliferate, differentiate, and replace mature cells in adult aging tissues.
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Gopinathan, Gokul; Kolokythas, Antonia
2013-01-01
Epigenetic mechanisms, such as histone modifications, play an active role in the differentiation and lineage commitment of mesenchymal stem cells. In the present study, epigenetic states and differentiation profiles of two odontogenic neural crest-derived intermediate progenitor populations were compared: dental pulp (DP) and dental follicle (DF). ChIP on chip assays revealed substantial H3K27me3-mediated repression of odontoblast lineage genes DSPP and dentin matrix protein 1 (DMP1) in DF cells, but not in DP cells. Mineralization inductive conditions caused steep increases of mineralization and patterning gene expression levels in DP cells when compared to DF cells. In contrast, mineralization induction resulted in a highly dynamic histone modification response in DF cells, while there was only a subdued effect in DP cells. Both DF and DP progenitors featured H3K4me3-active marks on the promoters of early mineralization genes RUNX2, MSX2, and DLX5, while OSX, IBSP, and BGLAP promoters were enriched for H3K9me3 or H3K27me3. Compared to DF cells, DP cells expressed higher levels of three pluripotency-associated genes, OCT4, NANOG, and SOX2. Finally, gene ontology comparison of bivalent marks unique for DP and DF cells highlighted cell–cell attachment genes in DP cells and neurogenesis genes in DF cells. In conclusion, the present study indicates that the DF intermediate odontogenic neural crest lineage is distinguished from its DP counterpart by epigenetic repression of DSPP and DMP1 genes and through dynamic histone enrichment responses to mineralization induction. Findings presented here highlight the crucial role of epigenetic regulatory mechanisms in the terminal differentiation of odontogenic neural crest lineages. PMID:23379639
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Emerging Trends in Epigenetic Regulation of Nutrient Deficiency Response in Plants.
Sirohi, Gunjan; Pandey, Bipin K; Deveshwar, Priyanka; Giri, Jitender
2016-03-01
Diverse environmental stimuli largely affect the ionic balance of soil, which have a direct effect on growth and crop yield. Details are fast emerging on the genetic/molecular regulators, at whole-genome levels, of plant responses to mineral deficiencies in model and crop plants. These genetic regulators determine the root architecture and physiological adaptations for better uptake and utilization of minerals from soil. Recent evidence also shows the potential roles of epigenetic mechanisms in gene regulation, driven by minerals imbalance. Mineral deficiency or sufficiency leads to developmental plasticity in plants for adaptation, which is preceded by a change in the pattern of gene expression. Notably, such changes at molecular levels are also influenced by altered chromatin structure and methylation patterns, or involvement of other epigenetic components. Interestingly, many of the changes induced by mineral deficiency are also inheritable in the form of epigenetic memory. Unravelling these mechanisms in response to mineral deficiency would further advance our understanding of this complex plant response. Further studies on such approaches may serve as an exciting interaction model of epigenetic and genetic regulations of mineral homeostasis in plants and designing strategies for crop improvement.
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An epigenetic biomarker of aging for lifespan and healthspan
Levine, Morgan E.; Lu, Ake T.; Quach, Austin; Chen, Brian H.; Assimes, Themistocles L.; Bandinelli, Stefania; Hou, Lifang; Baccarelli, Andrea A.; Stewart, James D.; Li, Yun; Whitsel, Eric A.; Wilson, James G; Reiner, Alex P; Aviv, Abraham; Lohman, Kurt; Liu, Yongmei; Ferrucci, Luigi
2018-01-01
Identifying reliable biomarkers of aging is a major goal in geroscience. While the first generation of epigenetic biomarkers of aging were developed using chronological age as a surrogate for biological age, we hypothesized that incorporation of composite clinical measures of phenotypic age that capture differences in lifespan and healthspan may identify novel CpGs and facilitate the development of a more powerful epigenetic biomarker of aging. Using an innovative two-step process, we develop a new epigenetic biomarker of aging, DNAm PhenoAge, that strongly outperforms previous measures in regards to predictions for a variety of aging outcomes, including all-cause mortality, cancers, healthspan, physical functioning, and Alzheimer's disease. While this biomarker was developed using data from whole blood, it correlates strongly with age in every tissue and cell tested. Based on an in-depth transcriptional analysis in sorted cells, we find that increased epigenetic, relative to chronological age, is associated with increased activation of pro-inflammatory and interferon pathways, and decreased activation of transcriptional/translational machinery, DNA damage response, and mitochondrial signatures. Overall, this single epigenetic biomarker of aging is able to capture risks for an array of diverse outcomes across multiple tissues and cells, and provide insight into important pathways in aging. PMID:29676998
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Soo, Benjamin P C; Tay, Julian; Ng, Shirelle; Ho, Steven C L; Yang, Yuansheng; Chao, Sheng-Hao
2017-08-01
Role of epigenetic regulation in the control of gene expression is well established. The impact of several epigenetic mechanisms, such as DNA methylation and histone acetylation, on recombinant protein production in mammalian cells has been investigated recently. Here we investigate the correlation between the selected epigenetic markers and five trastuzumab biosimilar-producing Chinese hamster ovary (CHO) cell lines in which the expression of trastuzumab is driven by human cytomegalovirus (HCMV) major immediate-early (MIE) promoter. We chose the producing clones in which transcription was the determinative step for the production of recombinant trastuzumab. We found that the abundance of trimethylation of histone 3 at lysine 4 (H3K4Me3) on the enhancer of HCMV MIE promoter correlated well with the relative titers of recombinant trastuzumab among the clones. Such close correlation was not observed between the recombinant protein and other epigenetic markers examined in our study. Our results demonstrate that the HCMV MIE enhancer-bound H3K4Me3 epigenetic marker may be used as the epigenetic indicator to predict the relative production of recombinant proteins between the producing CHO cell lines.
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Epigenetic Research in Cancer Epidemiology: Trends, Opportunities, and Challenges
Verma, Mukesh; Rogers, Scott; Divi, Rao L.; Schully, Sheri D.; Nelson, Stefanie; Su, L. Joseph; Ross, Sharon; Pilch, Susan; Winn, Deborah M.; Khoury, Muin J.
2014-01-01
Epigenetics is emerging as an important field in cancer epidemiology that promises to provide insights into gene regulation and facilitate cancer control throughout the cancer care continuum. Increasingly, investigators are incorporating epigenetic analysis into the studies of etiology and outcomes. To understand current progress and trends in the inclusion of epigenetics in cancer epidemiology, we evaluated the published literature and the National Cancer Institute (NCI) supported research grant awards in this field to identify trends in epigenetics research. We present a summary of the epidemiological studies in NCI’s grant portfolio (from January 2005 through December 2012) and in the scientific literature published during the same period, irrespective of support from NCI. Blood cells and tumor tissue were the most commonly used biospecimens in these studies, although buccal cells, cervical cells, sputum, and stool samples also were used. DNA methylation profiling was the focus of the majority of studies, but several studies also measured microRNA profiles. We illustrate here the current status of epidemiologic studies that are evaluating epigenetic changes in large populations. The incorporation of epigenomic assessments in cancer epidemiology studies has and is likely to continue to provide important insights into the field of cancer research. PMID:24326628
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Prieto, G. Aleph; Petrosyan, Arpine; Loertscher, Brad M.; Dieskau, André P.; Overman, Larry E.; Cotman, Carl W.
2016-01-01
An increasing number of studies show that an altered epigenetic landscape may cause impairments in regulation of learning and memory-related genes within the aged hippocampus, eventually resulting in cognitive deficits in the aged brain. One such epigenetic repressive mark is trimethylation of H3K9 (H3K9me3), which is typically implicated in gene silencing. Here, we identify, for the first time, an essential role for H3K9me3 and its histone methyl transferase (SUV39H1) in mediating hippocampal memory functions. Pharmacological inhibition of SUV39H1 using a novel and selective inhibitor decreased levels of H3K9me3 in the hippocampus of aged mice, and improved performance in the objection location memory and fear conditioning tasks and in a complex spatial environment learning task. The inhibition of SUV39H1 induced an increase in spine density of thin and stubby but not mushroom spines in the hippocampus of aged animals and increased surface GluR1 levels in hippocampal synaptosomes, a key index of spine plasticity. Furthermore, there were changes at BDNF exon I gene promoter, in concert with overall BDNF levels in the hippocampus of drug-treated animals compared with control animals. Together, these data demonstrate that SUV39H1 inhibition and the concomitant H3K9me3 downregulation mediate gene transcription in the hippocampus and reverse age-dependent deficits in hippocampal memory. SIGNIFICANCE STATEMENT Cognitive decline is a debilitating condition associated with not only neurodegenerative diseases but also aging in general. However, effective treatments have been slow to emerge so far. In this study, we demonstrate that epigenetic regulation of key synaptic proteins may be an underlying, yet reversible, cause of this decline. Our findings suggest that histone 3 trimethylation is a probable target for pharmacological intervention that can counteract cognitive decline in the aging brain. Finally, we provide support to the hypothesis that, by manipulating the enzyme that regulates H3K9me3 (using a newly developed specific inhibitor of SUV39H1), it is possible to alter the chromatin state of subjects and restore memory and synaptic function in the aging brain. PMID:27013689
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Li, Yuanyuan; Tollefsbol, Trygve O
2016-01-01
Aging is considered as one of the most important developmental processes in organisms and is closely associated with global deteriorations of epigenetic markers such as aberrant methylomic patterns. This altered epigenomic state, referred to ‘epigenetic drift’, reflects deficient maintenance of epigenetic marks and contributes to impaired cellular and molecular functions in aged cells. Epigenetic drift-induced abnormal changes during aging are scantily repaired by epigenetic modulators. This inflexibility in the aged epigenome may lead to an age-related decline in phenotypic plasticity at the cellular and molecular levels due to epigenetic drift. This perspective aims to provide novel concepts for understanding epigenetic effects on the aging process and to provide insights into epigenetic prevention and therapeutic strategies for age-related human disease. PMID:27882781
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How life changes itself: the Read-Write (RW) genome.
Shapiro, James A
2013-09-01
The genome has traditionally been treated as a Read-Only Memory (ROM) subject to change by copying errors and accidents. In this review, I propose that we need to change that perspective and understand the genome as an intricately formatted Read-Write (RW) data storage system constantly subject to cellular modifications and inscriptions. Cells operate under changing conditions and are continually modifying themselves by genome inscriptions. These inscriptions occur over three distinct time-scales (cell reproduction, multicellular development and evolutionary change) and involve a variety of different processes at each time scale (forming nucleoprotein complexes, epigenetic formatting and changes in DNA sequence structure). Research dating back to the 1930s has shown that genetic change is the result of cell-mediated processes, not simply accidents or damage to the DNA. This cell-active view of genome change applies to all scales of DNA sequence variation, from point mutations to large-scale genome rearrangements and whole genome duplications (WGDs). This conceptual change to active cell inscriptions controlling RW genome functions has profound implications for all areas of the life sciences. © 2013 Elsevier B.V. All rights reserved.
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DNMT1 is essential for mammary and cancer stem cell maintenance and tumorigenesis
Pathania, Rajneesh; Ramachandran, Sabarish; Elangovan, Selvakumar; Padia, Ravi; Yang, Pengyi; Cinghu, Senthilkumar; Veeranan-Karmegam, Rajalakshmi; Arjunan, Pachiappan; Gnana-Prakasam, Jaya P.; Fulzele, Sadanand; Pei, Lirong; Chang, Chang-Sheng; Choi, Hyeon; Shi, Huidong; Manicassamy, Santhakumar; Prasad, Puttur D.; Sharma, Suash; Ganapathy, Vadivel; Jothi, Raja; Thangaraju, Muthusamy
2015-01-01
Mammary stem/progenitor cells (MaSCs) maintain self-renewal of the mammary epithelium during puberty and pregnancy. DNA methylation provides a potential epigenetic mechanism for maintaining cellular memory during self-renewal. Although DNA methyltransferases (DNMTs) are dispensable for embryonic stem cell maintenance, their role in maintaining MaSCs and cancer stem cells (CSCs) in constantly replenishing mammary epithelium is unclear. Here we show that DNMT1 is indispensable for MaSC maintenance. Furthermore, we find that DNMT1 expression is elevated in mammary tumors, and mammary gland-specific DNMT1 deletion protects mice from mammary tumorigenesis by limiting the CSC pool. Through genome-scale methylation studies, we identify ISL1 as a direct DNMT1 target, hypermethylated and downregulated in mammary tumors and CSCs. DNMT inhibition or ISL1 expression in breast cancer cells limits CSC population. Altogether, our studies uncover an essential role for DNMT1 in MaSC and CSC maintenance and identify DNMT1-ISL1 axis as a potential therapeutic target for breast cancer treatment. PMID:25908435
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Pathogenic mechanisms of intracellular bacteria.
Niller, Hans Helmut; Masa, Roland; Venkei, Annamária; Mészáros, Sándor; Minarovits, Janos
2017-06-01
We wished to overview recent data on a subset of epigenetic changes elicited by intracellular bacteria in human cells. Reprogramming the gene expression pattern of various host cells may facilitate bacterial growth, survival, and spread. DNA-(cytosine C5)-methyltransferases of Mycoplasma hyorhinis targeting cytosine-phosphate-guanine (CpG) dinucleotides and a Mycobacterium tuberculosis methyltransferase targeting non-CpG sites methylated the host cell DNA and altered the pattern of gene expression. Gene silencing by CpG methylation and histone deacetylation, mediated by cellular enzymes, also occurred in M. tuberculosis-infected macrophages. M. tuberculosis elicited cell type-specific epigenetic changes: it caused increased DNA methylation in macrophages, but induced demethylation, deposition of euchromatic histone marks and activation of immune-related genes in dendritic cells. A secreted transposase of Acinetobacter baumannii silenced a cellular gene, whereas Mycobacterium leprae altered the epigenotype, phenotype, and fate of infected Schwann cells. The 'keystone pathogen' oral bacterium Porphyromonas gingivalis induced local DNA methylation and increased the level of histone acetylation in host cells. These epigenetic changes at the biofilm-gingiva interface may contribute to the development of periodontitis. Epigenetic regulators produced by intracellular bacteria alter the epigenotype and gene expression pattern of host cells and play an important role in pathogenesis.
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Ansari, Daniel; Urey, Carlos; Hilmersson, Katarzyna Said; Bauden, Monika P; Ek, Fredrik; Olsson, Roger; Andersson, Roland
2014-10-01
Mucin 4 (MUC4) has been linked to resistance to gemcitabine in pancreatic cancer cells. The aim of the present study was to assess whether epigenetic control of MUC4 expression can sensitize pancreatic cancer cells to gemcitabine treatment. A 76-member combined epigenetics and phosphatase small-molecule inhibitor library was screened for anti-proliferative activity against the MUC4(+) gemcitabine-resistant pancreatic cancer cell line Capan-1, followed by high-content screening of protein expression. Apicidin, a histone deacetylase inhibitor, showed the greatest anti-proliferative activity with a lethal dose 50 (LD50) value of 5.17 μM. Apicidin significantly reduced the expression of MUC4 and its transcription factor hepatocyte nuclear factor 4α. Combined treatment with a sub-therapeutic concentration of apicidin and gemcitabine synergistically inhibited growth of Capan-1 cells. Apicidin appears to be a novel anti-proliferative agent against pancreatic cancer cells that may reverse chemoresistance by epigenetically regulating MUC4 expression. Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.
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NASA Astrophysics Data System (ADS)
Yasuda, Kenji
2012-08-01
We have developed methods and systems of analyzing epigenetic information in cells to expand our understanding of how living systems are determined. Because cells are minimum units reflecting epigenetic information, which is considered to map the history of a parallel-processing recurrent network of biochemical reactions, their behaviors cannot be explained by considering only conventional deonucleotide (DNA) information-processing events. The role of epigenetic information on cells, which complements their genetic information, was inferred by comparing predictions from genetic information with cell behaviour observed under conditions chosen to reveal adaptation processes and community effects. A system of analyzing epigenetic information, on-chip cellomics technology, has been developed starting from the twin complementary viewpoints of cell regulation as an “algebraic” system (emphasis on temporal aspects) and as a “geometric” system (emphasis on spatial aspects) exploiting microfabrication technology and a reconstructive approach of cellular systems not only for single cell-based subjects such as Escherichia coli and macrophages but also for cellular networks like the community effect of cardiomyocytes and plasticity in neuronal networks. One of the most important contributions of this study was to be able to reconstruct the concept of a cell regulatory network from the “local” (molecules expressed at certain times and places) to the “global” (the cell as a viable, functioning system). Knowledge of epigenetic information, which we can control and change during cell lives, complements the genetic variety, and these two types of information are indispensable for living organisms. This new knowlege has the potential to be the basis of cell-based biological and medical fields such as those involving cell-based drug screening and the regeneration of organs from stem cells.
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Gómez, M. C.; Biancardi, M.N.; Jenkins, J.A.; Dumas, C.; Galiguis, J.; Wang, G.; Earle Pope, C.
2012-01-01
Somatic cell nuclear transfer offers the possibility of preserving endangered species including the black-footed cat, which is threatened with extinction. The effectiveness and efficiency of somatic cell nuclear transfer (SCNT) depends on a variety of factors, but 'inappropriate epigenetic reprogramming of the transplanted nucleus is the primary cause of the developmental failure of cloned embryos. Abnormal epigenetic events such as DNA methylation and histone modifications during SCNT perturb the expression of imprinted and pluripotent-related genes that, consequently, may result in foetal and neonatal abnormalities. We have demonstrated that pregnancies can be established after transfer of black-footed cat cloned embryos into domestic cat recipients, but none of the implanted embryos developed to term and the foetal failure has been associated to aberrant reprogramming in cloned embryos. There is growing evidence that modifying the epigenetic pattern of the chromatin template of both donor cells and reconstructed embryos with a combination of inhibitors of histone deacetylases and DNA methyltransferases results in enhanced gene reactivation and improved in vitro and in vivo developmental competence. Epigenetic modifications of the chromatin template of black-footed cat donor cells and reconstructed embryos with epigenetic-modifying compounds enhanced in vitro development, and regulated the expression of pluripotent genes, but these epigenetic modifications did not improve in vivo developmental competence.
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Charlet, Jessica; Tomari, Ayumi; Dallosso, Anthony R; Szemes, Marianna; Kaselova, Martina; Curry, Thomas J; Almutairi, Bader; Etchevers, Heather C; McConville, Carmel; Malik, Karim T A; Brown, Keith W
2017-04-01
Neuroblastoma is a childhood cancer in which many children still have poor outcomes, emphasising the need to better understand its pathogenesis. Despite recent genome-wide mutation analyses, many primary neuroblastomas do not contain recognizable driver mutations, implicating alternate molecular pathologies such as epigenetic alterations. To discover genes that become epigenetically deregulated during neuroblastoma tumorigenesis, we took the novel approach of comparing neuroblastomas to neural crest precursor cells, using genome-wide DNA methylation analysis. We identified 93 genes that were significantly differentially methylated of which 26 (28%) were hypermethylated and 67 (72%) were hypomethylated. Concentrating on hypermethylated genes to identify candidate tumor suppressor loci, we found the cell engulfment and adhesion factor gene MEGF10 to be epigenetically repressed by DNA hypermethylation or by H3K27/K9 methylation in neuroblastoma cell lines. MEGF10 showed significantly down-regulated expression in neuroblastoma tumor samples; furthermore patients with the lowest-expressing tumors had reduced relapse-free survival. Our functional studies showed that knock-down of MEGF10 expression in neuroblastoma cell lines promoted cell growth, consistent with MEGF10 acting as a clinically relevant, epigenetically deregulated neuroblastoma tumor suppressor gene. © 2016 The Authors. Molecular Carcinogenesis Published by Wiley Periodicals, Inc. © 2016 The Authors. Molecular Carcinogenesis Published by Wiley Periodicals, Inc.
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Charlet, Jessica; Tomari, Ayumi; Dallosso, Anthony R.; Szemes, Marianna; Kaselova, Martina; Curry, Thomas J.; Almutairi, Bader; Etchevers, Heather C.; McConville, Carmel; Malik, Karim T. A.
2016-01-01
Neuroblastoma is a childhood cancer in which many children still have poor outcomes, emphasising the need to better understand its pathogenesis. Despite recent genome‐wide mutation analyses, many primary neuroblastomas do not contain recognizable driver mutations, implicating alternate molecular pathologies such as epigenetic alterations. To discover genes that become epigenetically deregulated during neuroblastoma tumorigenesis, we took the novel approach of comparing neuroblastomas to neural crest precursor cells, using genome‐wide DNA methylation analysis. We identified 93 genes that were significantly differentially methylated of which 26 (28%) were hypermethylated and 67 (72%) were hypomethylated. Concentrating on hypermethylated genes to identify candidate tumor suppressor loci, we found the cell engulfment and adhesion factor gene MEGF10 to be epigenetically repressed by DNA hypermethylation or by H3K27/K9 methylation in neuroblastoma cell lines. MEGF10 showed significantly down‐regulated expression in neuroblastoma tumor samples; furthermore patients with the lowest‐expressing tumors had reduced relapse‐free survival. Our functional studies showed that knock‐down of MEGF10 expression in neuroblastoma cell lines promoted cell growth, consistent with MEGF10 acting as a clinically relevant, epigenetically deregulated neuroblastoma tumor suppressor gene. © 2016 The Authors. Molecular Carcinogenesis Published by Wiley Periodicals, Inc. PMID:27862318
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Florea, Ana-Maria
2013-01-01
Exposure of cells and organisms to stressors might result in epigenetic changes. Here it is shown that investigation of DNA methylation using pyrosequencing is an alternative for in vitro and in vivo toxicological testing of epigenetic effects induced by chemicals and drugs. An in vitro evaluation of global and CpG site specific DNA methylation upon treatment of cells with chemicals/drugs is shown. Bisulfite genomic sequencing of methylation controls showed high methylation of LINE1 in methylation positive control and low methylation in the negative controls. The CpG sites within the LINE1 element are methylated at different levels. In vitro cell cultures show a methylation level ranging from 56% to 49%. Cultures of drug resistant tumor cells show significant hypomethylation as compared with the originating nonresistant tumor cells. The in vitro testing of epigenetically active chemicals (5-methyl-2'-deoxycytidine and trichostatin A) revealed a significant change of LINE1 methylation status upon treatment, while specific CpG sites were more prone to demethylation than others (focal methylation). In conclusion, DNA methylation using pyrosequencing might be used not only for testing epigenetic toxins/drugs but also in risk assessment of drugs, food, and environmental relevant pollutants. PMID:24093099
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Epigenetic regulation of open chromatin in pluripotent stem cells
Kobayashi, Hiroshi; Kikyo, Nobuaki
2014-01-01
The recent progress in pluripotent stem cell research has opened new avenues of disease modeling, drug screening, and transplantation of patient-specific tissues that had been unimaginable until a decade ago. The central mechanism underlying pluripotency is epigenetic gene regulation; the majority of cell signaling pathways, both extracellular and cytoplasmic, eventually alter the epigenetic status of their target genes during the process of activating or suppressing the genes to acquire or maintain pluripotency. It has long been thought that the chromatin of pluripotent stem cells is globally open to enable the timely activation of essentially all genes in the genome during differentiation into multiple lineages. The current article reviews descriptive observations and the epigenetic machinery relevant to what is supposed to be globally open chromatin in pluripotent stem cells. This includes microscopic appearance, permissive gene transcription, chromatin remodeling complexes, histone modifications, DNA methylation, noncoding RNAs, dynamic movement of chromatin proteins, nucleosome accessibility and positioning, and long-range chromosomal interactions. Detailed analyses of each element, however, have revealed that the globally open chromatin hypothesis is not necessarily supported by some of the critical experimental evidence, such as genome-wide nucleosome accessibility and nucleosome positioning. Further understanding of the epigenetic gene regulation is expected to determine the true nature of the so-called globally open chromatin in pluripotent stem. PMID:24695097
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Decreased epigenetic age of PBMCs from Italian semi-supercentenarians and their offspring.
Horvath, Steve; Pirazzini, Chiara; Bacalini, Maria Giulia; Gentilini, Davide; Di Blasio, Anna Maria; Delledonne, Massimo; Mari, Daniela; Arosio, Beatrice; Monti, Daniela; Passarino, Giuseppe; De Rango, Francesco; D'Aquila, Patrizia; Giuliani, Cristina; Marasco, Elena; Collino, Sebastiano; Descombes, Patrick; Garagnani, Paolo; Franceschi, Claudio
2015-12-01
Given the dramatic increase in ageing populations, it is of great importance to understand the genetic and molecular determinants of healthy ageing and longevity. Semi-supercentenarians (subjects who reached an age of 105-109 years) arguably represent the gold standard of successful human ageing because they managed to avoid or postpone the onset of major age-related diseases. Relatively few studies have looked at epigenetic determinants of extreme longevity in humans. Here we test whether families with extreme longevity are epigenetically distinct from controls according to an epigenetic biomarker of ageing which is known as "epigenetic clock". We analyze the DNA methylation levels of peripheral blood mononuclear cells (PBMCs) from Italian families constituted of 82 semi-supercentenarians (mean age: 105.6 ± 1.6 years), 63 semi-supercentenarians' offspring (mean age: 71.8 ± 7.8 years), and 47 age-matched controls (mean age: 69.8 ± 7.2 years). We demonstrate that the offspring of semi-supercentenarians have a lower epigenetic age than age-matched controls (age difference=5.1 years, p=0.00043) and that centenarians are younger (8.6 years) than expected based on their chronological age. By contrast, no significant difference could be observed for estimated blood cell counts (such as naïve or exhausted cytotoxic T cells or helper T cells). Future studies will be needed to replicate these findings in different populations and to extend them to other tissues. Overall, our results suggest that epigenetic processes might play a role in extreme longevity and healthy human ageing.
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Decreased epigenetic age of PBMCs from Italian semi-supercentenarians and their offspring
Horvath, Steve; Pirazzini, Chiara; Bacalini, Maria Giulia; Gentilini, Davide; Di Blasio, Anna Maria; Delledonne, Massimo; Mari, Daniela; Arosio, Beatrice; Monti, Daniela; Passarino, Giuseppe; De Rango, Francesco; D'Aquila, Patrizia; Giuliani, Cristina; Marasco, Elena; Collino, Sebastiano; Descombes, Patrick; Garagnani, Paolo; Franceschi, Claudio
2015-01-01
Given the dramatic increase in ageing populations, it is of great importance to understand the genetic and molecular determinants of healthy ageing and longevity. Semi-supercentenarians (subjects who reached an age of 105-109 years) arguably represent the gold standard of successful human ageing because they managed to avoid or postpone the onset of major age-related diseases. Relatively few studies have looked at epigenetic determinants of extreme longevity in humans. Here we test whether families with extreme longevity are epigenetically distinct from controls according to an epigenetic biomarker of ageing which is known as “epigenetic clock”. We analyze the DNA methylation levels of peripheral blood mononuclear cells (PBMCs) from Italian families constituted of 82 semi-supercentenarians (mean age: 105.6 ± 1.6 years), 63 semi-supercentenarians' offspring (mean age: 71.8 ± 7.8 years), and 47 age-matched controls (mean age: 69.8 ± 7.2 years). We demonstrate that the offspring of semi-supercentenarians have a lower epigenetic age than age-matched controls (age difference=5.1 years, p=0.00043) and that centenarians are younger (8.6 years) than expected based on their chronological age. By contrast, no significant difference could be observed for estimated blood cell counts (such as naïve or exhausted cytotoxic T cells or helper T cells). Future studies will be needed to replicate these findings in different populations and to extend them to other tissues. Overall, our results suggest that epigenetic processes might play a role in extreme longevity and healthy human ageing. PMID:26678252
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Best, Thomas M.
2015-01-01
An increasing number of studies have proposed a strong correlation between reactive oxygen species (ROS)-induced oxidative stress (OS) and the pathogenesis of Alzheimer's disease (AD). With over five million people diagnosed in the United States alone, AD is the most common type of dementia worldwide. AD includes progressive neurodegeneration, followed by memory loss and reduced cognitive ability. Characterized by the formation of amyloid-beta (Aβ) plaques as a hallmark, the connection between ROS and AD is compelling. Analyzing the ROS response of essential proteins in the amyloidogenic pathway, such as amyloid-beta precursor protein (APP) and beta-secretase (BACE1), along with influential signaling programs of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and c-Jun N-terminal kinase (JNK), has helped visualize the path between OS and Aβ overproduction. In this review, attention will be paid to significant advances in the area of OS, epigenetics, and their influence on Aβ plaque assembly. Additionally, we aim to discuss available treatment options for AD that include antioxidant supplements, Asian traditional medicines, metal-protein-attenuating compounds, and histone modifying inhibitors. PMID:26543520
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Zuo, Li; Hemmelgarn, Benjamin T; Chuang, Chia-Chen; Best, Thomas M
2015-01-01
An increasing number of studies have proposed a strong correlation between reactive oxygen species (ROS)-induced oxidative stress (OS) and the pathogenesis of Alzheimer's disease (AD). With over five million people diagnosed in the United States alone, AD is the most common type of dementia worldwide. AD includes progressive neurodegeneration, followed by memory loss and reduced cognitive ability. Characterized by the formation of amyloid-beta (Aβ) plaques as a hallmark, the connection between ROS and AD is compelling. Analyzing the ROS response of essential proteins in the amyloidogenic pathway, such as amyloid-beta precursor protein (APP) and beta-secretase (BACE1), along with influential signaling programs of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and c-Jun N-terminal kinase (JNK), has helped visualize the path between OS and Aβ overproduction. In this review, attention will be paid to significant advances in the area of OS, epigenetics, and their influence on Aβ plaque assembly. Additionally, we aim to discuss available treatment options for AD that include antioxidant supplements, Asian traditional medicines, metal-protein-attenuating compounds, and histone modifying inhibitors.
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Epigenome analysis of pluripotent stem cells
Ricupero, Christopher L.; Swerdel, Mavis R.; Hart, Ronald P.
2015-01-01
Summary Mis-regulation of gene expression due to epigenetic abnormalities has been linked with complex genetic disorders, psychiatric illness and cancer. In addition, the dynamic epigenetic changes that occur in pluripotent stem cells are believed to impact regulatory networks essential for proper lineage development. Chromatin immunoprecipitation (ChIP) is a technique used to isolate and enrich chromatin fragments using antibodies against specific chromatin modifications, such as DNA binding proteins or covalent histone modifications. Until recently, many ChIP protocols required millions of cells for each immunoprecipitation. This severely limited analysis of rare cell populations or post-mitotic, differentiated cell lines. Here, we describe a low cell number ChIP protocol with next generation sequencing and analysis, that has the potential to uncover novel epigenetic regulatory pathways that were previously difficult or impossible to obtain. PMID:23546758
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Moody, Laura; Chen, Hong; Pan, Yuan-Xiang
2017-03-01
The perinatal period is a window of heightened plasticity that lays the groundwork for future anatomic, physiologic, and behavioral outcomes. During this time, maternal diet plays a pivotal role in the maturation of vital organs and the establishment of neuronal connections. However, when perinatal nutrition is either lacking in specific micro- and macronutrients or overloaded with excess calories, the consequences can be devastating and long lasting. The brain is particularly sensitive to perinatal insults, with several neurologic and psychiatric disorders having been linked to a poor in utero environment. Diseases characterized by learning and memory impairments, such as autism, schizophrenia, and Alzheimer disease, are hypothesized to be attributed in part to environmental factors, and evidence suggests that the etiology of these conditions may date back to very early life. In this review, we discuss the role of the early-life diet in shaping cognitive outcomes in offspring. We explore the endocrine and immune mechanisms responsible for these phenotypes and discuss how these systemic factors converge to change the brain's epigenetic landscape and regulate learning and memory across the lifespan. Through understanding the maternal programming of cognition, critical steps may be taken toward preventing and treating diseases that compromise learning and memory. © 2017 American Society for Nutrition.
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Epigenetic inactivation of TCF2 in ovarian cancer and various cancer cell lines
Terasawa, K; Toyota, M; Sagae, S; Ogi, K; Suzuki, H; Sonoda, T; Akino, K; Maruyama, R; Nishikawa, N; Imai, K; Shinomura, Y; Saito, T; Tokino, T
2006-01-01
Transcription factor 2 gene (TCF2) encodes hepatocyte nuclear factor 1β (HNF1β), a transcription factor associated with development and metabolism. Mutation of TCF2 has been observed in renal cell cancer, and by screening aberrantly methylated genes, we have now identified TCF2 as a target for epigenetic inactivation in ovarian cancer. TCF2 was methylated in 53% of ovarian cancer cell lines and 26% of primary ovarian cancers, resulting in loss of the gene's expression. TCF2 expression was restored by treating cells with a methyltransferase inhibitor, 5-aza-2′deoxycitidine (5-aza-dC). In addition, chromatin immunoprecipitation showed deacetylation of histone H3 in methylated cells and, when combined with 5-aza-dC, the histone deacetylase inhibitor trichostatin A synergistically induced TCF2 expression. Epigenetic inactivation of TCF2 was also seen in colorectal, gastric and pancreatic cell lines, suggesting general involvement of epigenetic inactivation of TCF2 in tumorigenesis. Restoration of TCF2 expression induced expression of HNF4α, a transcriptional target of HNF1β, indicating that epigenetic silencing of TCF2 leads to alteration of the hepatocyte nuclear factor network in tumours. These results suggest that TCF2 is involved in the development of ovarian cancers and may represent a useful target for their detection and treatment. PMID:16479257
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Noberini, Roberta; Osti, Daniela; Miccolo, Claudia; Richichi, Cristina; Lupia, Michela; Corleone, Giacomo; Hong, Sung-Pil; Colombo, Piergiuseppe; Pollo, Bianca; Fornasari, Lorenzo; Pruneri, Giancarlo; Magnani, Luca; Cavallaro, Ugo; Chiocca, Susanna; Minucci, Saverio; Pelicci, Giuliana; Bonaldi, Tiziana
2018-05-04
Histone post-translational modifications (PTMs) generate a complex combinatorial code that regulates gene expression and nuclear functions, and whose deregulation has been documented in different types of cancers. Therefore, the availability of relevant culture models that can be manipulated and that retain the epigenetic features of the tissue of origin is absolutely crucial for studying the epigenetic mechanisms underlying cancer and testing epigenetic drugs. In this study, we took advantage of quantitative mass spectrometry to comprehensively profile histone PTMs in patient tumor tissues, primary cultures and cell lines from three representative tumor models, breast cancer, glioblastoma and ovarian cancer, revealing an extensive and systematic rewiring of histone marks in cell culture conditions, which includes a decrease of H3K27me2/me3, H3K79me1/me2 and H3K9ac/K14ac, and an increase of H3K36me1/me2. While some changes occur in short-term primary cultures, most of them are instead time-dependent and appear only in long-term cultures. Remarkably, such changes mostly revert in cell line- and primary cell-derived in vivo xenograft models. Taken together, these results support the use of xenografts as the most representative models of in vivo epigenetic processes, suggesting caution when using cultured cells, in particular cell lines and long-term primary cultures, for epigenetic investigations.
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Noberini, Roberta; Osti, Daniela; Miccolo, Claudia; Richichi, Cristina; Lupia, Michela; Corleone, Giacomo; Hong, Sung-Pil; Colombo, Piergiuseppe; Pollo, Bianca; Fornasari, Lorenzo; Pruneri, Giancarlo; Magnani, Luca; Cavallaro, Ugo; Chiocca, Susanna; Minucci, Saverio; Pelicci, Giuliana; Bonaldi, Tiziana
2018-01-01
Abstract Histone post-translational modifications (PTMs) generate a complex combinatorial code that regulates gene expression and nuclear functions, and whose deregulation has been documented in different types of cancers. Therefore, the availability of relevant culture models that can be manipulated and that retain the epigenetic features of the tissue of origin is absolutely crucial for studying the epigenetic mechanisms underlying cancer and testing epigenetic drugs. In this study, we took advantage of quantitative mass spectrometry to comprehensively profile histone PTMs in patient tumor tissues, primary cultures and cell lines from three representative tumor models, breast cancer, glioblastoma and ovarian cancer, revealing an extensive and systematic rewiring of histone marks in cell culture conditions, which includes a decrease of H3K27me2/me3, H3K79me1/me2 and H3K9ac/K14ac, and an increase of H3K36me1/me2. While some changes occur in short-term primary cultures, most of them are instead time-dependent and appear only in long-term cultures. Remarkably, such changes mostly revert in cell line- and primary cell-derived in vivo xenograft models. Taken together, these results support the use of xenografts as the most representative models of in vivo epigenetic processes, suggesting caution when using cultured cells, in particular cell lines and long-term primary cultures, for epigenetic investigations. PMID:29618087
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Susanto, Johana M; Colvin, Emily K; Pinese, Mark; Chang, David K; Pajic, Marina; Mawson, Amanda; Caldon, C Elizabeth; Musgrove, Elizabeth A; Henshall, Susan M; Sutherland, Robert L; Biankin, Andrew V; Scarlett, Christopher J
2015-05-01
Despite incremental advances in the diagnosis and treatment for pancreatic cancer (PC), the 5‑year survival rate remains <5%. Novel therapies to increase survival and quality of life for PC patients are desperately needed. Epigenetic thera-peutic agents such as histone deacetylase inhibitors (HDACi) and DNA methyltransferase inhibitors (DNMTi) have demonstrated therapeutic benefits in human cancer. We assessed the efficacy of these epigenetic therapeutic agents as potential therapies for PC using in vitro and in vivo models. Treatment with HDACi [suberoylanilide hydroxamic acid (SAHA)] and DNMTi [5‑AZA‑2' deoxycytidine (5‑AZA‑dc)] decreased cell proliferation in MiaPaCa2 cells, and SAHA treatment, with or without 5‑AZA‑dc, resulted in higher cell death and lower DNA synthesis compared to 5‑AZA‑dc alone and controls (DMSO). Further, combination treatment with SAHA and 5‑AZA‑dc significantly increased expression of p21WAF1, leading to G1 arrest. Treatment with epigenetic agents delayed tumour growth in vivo, but did not decrease growth of established pancreatic tumours. In conclusion, these data demonstrate a potential role for epigenetic modifier drugs for the management of PC, specifically in the chemoprevention of PC, in combination with other chemotherapeutic agents.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Knipe, David M., E-mail: david_knipe@hms.harvard.edu
Herpes simplex virus (HSV) undergoes a lytic infection in epithelial cells and a latent infection in neuronal cells, and epigenetic mechanisms play a major role in the differential gene expression under the two conditions. HSV viron DNA is not associated with histones but is rapidly loaded with heterochromatin upon entry into the cell. Viral proteins promote reversal of the epigenetic silencing in epithelial cells while the viral latency-associated transcript promotes additional heterochromatin in neuronal cells. The cellular sensors that initiate the chromatinization of foreign DNA have not been fully defined. IFI16 and cGAS are both essential for innate sensing ofmore » HSV DNA, and new evidence shows how they work together to initiate innate signaling. IFI16 also plays a role in the heterochromatinization of HSV DNA, and this review will examine how IFI16 integrates epigenetic regulation and innate sensing of foreign viral DNA to show how these two responses are related. - Highlights: • HSV lytic and latent gene expression is regulated differentially by epigenetic processes. • The sensors of foreign DNA have not been defined fully. • IFI16 and cGAS cooperate to sense viral DNA in HSV-infected cells. • IFI16 plays a role in both innate sensing of HSV DNA and in restricting its expression.« less
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Epigenetic remodelling and dysregulation of DLGAP4 is linked with early-onset cerebellar ataxia
Minocherhomji, Sheroy; Hansen, Claus; Kim, Hyung-Goo; Mang, Yuan; Bak, Mads; Guldberg, Per; Papadopoulos, Nickolas; Eiberg, Hans; Doh, Gerald Dayebga; Møllgård, Kjeld; Hertz, Jens Michael; Nielsen, Jørgen E.; Ropers, Hans-Hilger; Tümer, Zeynep; Tommerup, Niels; Kalscheuer, Vera M.; Silahtaroglu, Asli
2014-01-01
Genome instability, epigenetic remodelling and structural chromosomal rearrangements are hallmarks of cancer. However, the coordinated epigenetic effects of constitutional chromosomal rearrangements that disrupt genes associated with congenital neurodevelopmental diseases are poorly understood. To understand the genetic–epigenetic interplay at breakpoints of chromosomal translocations disrupting CG-rich loci, we quantified epigenetic modifications at DLGAP4 (SAPAP4), a key post-synaptic density 95 (PSD95) associated gene, truncated by the chromosome translocation t(8;20)(p12;q11.23), co-segregating with cerebellar ataxia in a five-generation family. We report significant epigenetic remodelling of the DLGAP4 locus triggered by the t(8;20)(p12;q11.23) translocation and leading to dysregulation of DLGAP4 expression in affected carriers. Disruption of DLGAP4 results in monoallelic hypermethylation of the truncated DLGAP4 promoter CpG island. This induced hypermethylation is maintained in somatic cells of carriers across several generations in a t(8;20) dependent-manner however, is erased in the germ cells of the translocation carriers. Subsequently, chromatin remodelling of the locus-perturbed monoallelic expression of DLGAP4 mRNAs and non-coding RNAs in haploid cells having the translocation. Our results provide new mechanistic insight into the way a balanced chromosomal rearrangement associated with a neurodevelopmental disorder perturbs allele-specific epigenetic mechanisms at breakpoints leading to the deregulation of the truncated locus. PMID:24986922
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DNA methylation-based measures of biological age: meta-analysis predicting time to death
Chen, Brian H.; Marioni, Riccardo E.; Colicino, Elena; Peters, Marjolein J.; Ward-Caviness, Cavin K.; Tsai, Pei-Chien; Roetker, Nicholas S.; Just, Allan C.; Demerath, Ellen W.; Guan, Weihua; Bressler, Jan; Fornage, Myriam; Studenski, Stephanie; Vandiver, Amy R.; Moore, Ann Zenobia; Tanaka, Toshiko; Kiel, Douglas P.; Liang, Liming; Vokonas, Pantel; Schwartz, Joel; Lunetta, Kathryn L.; Murabito, Joanne M.; Bandinelli, Stefania; Hernandez, Dena G.; Melzer, David; Nalls, Michael; Pilling, Luke C.; Price, Timothy R.; Singleton, Andrew B.; Gieger, Christian; Holle, Rolf; Kretschmer, Anja; Kronenberg, Florian; Kunze, Sonja; Linseisen, Jakob; Meisinger, Christine; Rathmann, Wolfgang; Waldenberger, Melanie; Visscher, Peter M.; Shah, Sonia; Wray, Naomi R.; McRae, Allan F.; Franco, Oscar H.; Hofman, Albert; Uitterlinden, André G.; Absher, Devin; Assimes, Themistocles; Levine, Morgan E.; Lu, Ake T.; Tsao, Philip S.; Hou, Lifang; Manson, JoAnn E.; Carty, Cara L.; LaCroix, Andrea Z.; Reiner, Alexander P.; Spector, Tim D.; Feinberg, Andrew P.; Levy, Daniel; Baccarelli, Andrea; van Meurs, Joyce; Bell, Jordana T.; Peters, Annette; Deary, Ian J.; Pankow, James S.; Ferrucci, Luigi; Horvath, Steve
2016-01-01
Estimates of biological age based on DNA methylation patterns, often referred to as “epigenetic age”, “DNAm age”, have been shown to be robust biomarkers of age in humans. We previously demonstrated that independent of chronological age, epigenetic age assessed in blood predicted all-cause mortality in four human cohorts. Here, we expanded our original observation to 13 different cohorts for a total sample size of 13,089 individuals, including three racial/ethnic groups. In addition, we examined whether incorporating information on blood cell composition into the epigenetic age metrics improves their predictive power for mortality. All considered measures of epigenetic age acceleration were predictive of mortality (p≤8.2×10−9), independent of chronological age, even after adjusting for additional risk factors (p<5.4×10−4), and within the racial/ethnic groups that we examined (non-Hispanic whites, Hispanics, African Americans). Epigenetic age estimates that incorporated information on blood cell composition led to the smallest p-values for time to death (p=7.5×10−43). Overall, this study a) strengthens the evidence that epigenetic age predicts all-cause mortality above and beyond chronological age and traditional risk factors, and b) demonstrates that epigenetic age estimates that incorporate information on blood cell counts lead to highly significant associations with all-cause mortality. PMID:27690265
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Age-specific functional epigenetic changes in p21 and p16 in injury-activated satellite cells
Li, Ju; Han, Suhyoun; Cousin, Wendy; Conboy, Irina M.
2014-01-01
The regenerative capacity of muscle dramatically decreases with age because old muscle stem cells fail to proliferate in response to tissue damage. Here we uncover key age-specific differences underlying this proliferative decline: namely, the genetic loci of CDK inhibitors (CDKI) p21 and p16 are more epigenetically silenced in young muscle stem cells, as compared to old, both in quiescent cells and those responding to tissue injury. Interestingly, phosphorylated ERK (pERK) induced in these cells by ectopic FGF-2 is found in association with p21 and p16 promoters, and moreover, only in the old cells. Importantly, in the old satellite cells FGF-2/pERK silences p21 epigenetically and transcriptionally, which leads to reduced p21 protein levels and enhanced cell proliferation. In agreement with the epigenetic silencing of the loci, young muscle stem cells do not depend as much as old on ectopic FGF/pERK for their myogenic proliferation. In addition, other CDKIs, such asp15INK4B and p27KIP1, become elevated in satellite cells with age, confirming and explaining the profound regenerative defect of old muscle. This work enhances our understanding of tissue aging, promoting strategies for combating age-imposed tissue degeneration. PMID:25447026
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Sage, Cindy; Burgio, Ernesto
2018-01-01
Mobile phones and other wireless devices that produce electromagnetic fields (EMF) and pulsed radiofrequency radiation (RFR) are widely documented to cause potentially harmful health impacts that can be detrimental to young people. New epigenetic studies are profiled in this review to account for some neurodevelopmental and neurobehavioral changes due to exposure to wireless technologies. Symptoms of retarded memory, learning, cognition, attention, and behavioral problems have been reported in numerous studies and are similarly manifested in autism and attention deficit hyperactivity disorders, as a result of EMF and RFR exposures where both epigenetic drivers and genetic (DNA) damage are likely contributors. Technology benefits can be realized by adopting wired devices for education to avoid health risk and promote academic achievement. © 2017 The Authors. Child Development © 2017 Society for Research in Child Development, Inc.
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Fialova, Barbora; Luzna, Petra; Gursky, Jan; Langova, Katerina; Kolar, Zdenek; Trtkova, Katerina Smesny
2016-10-01
The androgen receptor (AR) plays an essential role in the development and progression of prostate cancer. Castration-resistant prostate cancer (CRPC) is a consequence of androgen deprivation therapy. Unchecked CRPC followed by metastasis is lethal. Some CRPCs show decreased AR gene expression due to epigenetic mechanisms such as DNA methylation and histone deacetylation. The aim of this study was to epigenetically modulate the methylated state of the AR gene leading to targeted demethylation and AR gene expression in androgen-independent human prostate cancer DU145 cell line, representing the CRPC model with very low or undetectable AR levels. The cell treatment was based on single and combined applications of two epigenetic inhibitors, sodium butyrate (NaB) as histone deacetylases inhibitor and 5'-Aza-2'-deoxycytidine (Aza-dC) as DNA methyltransferases inhibitor. We found that the Aza-dC in combination with NaB may help reduce the toxicity of higher NaB concentrations in cancer cells. In normal RWPE-1 cells and even stronger in cancer DU145 cells, the combined treatment induced both AR gene expression on the mRNA level and increased histone H4 acetylation in AR gene promoter. Also activation and maintenance of G2/M cell cycle arrest and better survival in normal RWPE-1 cells compared to cancer DU145 cells were observed after the treatments. These results imply the selective toxicity effect of both inhibitors used and their potentially more effective combined use in the epigenetic therapy of prostate cancer patients.
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Jointly characterizing epigenetic dynamics across multiple human cell types
An, Lin; Yue, Feng; Hardison, Ross C
2016-01-01
Advanced sequencing technologies have generated a plethora of data for many chromatin marks in multiple tissues and cell types, yet there is lack of a generalized tool for optimal utility of those data. A major challenge is to quantitatively model the epigenetic dynamics across both the genome and many cell types for understanding their impacts on differential gene regulation and disease. We introduce IDEAS, an integrative and discriminative epigenome annotation system, for jointly characterizing epigenetic landscapes in many cell types and detecting differential regulatory regions. A key distinction between our method and existing state-of-the-art algorithms is that IDEAS integrates epigenomes of many cell types simultaneously in a way that preserves the position-dependent and cell type-specific information at fine scales, thereby greatly improving segmentation accuracy and producing comparable annotations across cell types. PMID:27095202
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The Genetics and Epigenetics of Kidney Development
Patel, Sanjeevkumar R.; Dressler, Gregory R.
2013-01-01
The development of the mammalian kidney has been studied at the genetic, biochemical, and cell biological level for more than 40 years. As such, detailed mechanisms governing early patterning, cell lineages, and inductive interactions are well described. How genes interact to specify the renal epithelial cells of the nephrons and how this specification is relevant to maintaining normal renal function is discussed. Implicit in the development of the kidney are epigenetic mechanisms that mark renal cell types and connect certain developmental regulatory factors to chromatin modifications that control gene expression patterns and cellular physiology. In adults, such regulatory factors and their epigenetic pathways may function in regeneration and may be disturbed in disease processes. PMID:24011574
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Veigl, Martina L.; Morgan, William F.; Schwartz, Jeffrey L.
The low dose symposium thoughtfully addressed controversy of risk from low dose radiation exposure, hormesis and radon therapy. The stem cell symposium cogently considered the role of DNA damage and repair in hematopoietic stem cells underlying aging and malignancy and provocatively presented evidence that stem cells may have distinct morphologies and replicative properties, as well as special roles in cancer initiation. In the epigenetics symposium, studies illustrated the long range interaction of epigenetic mechanisms, the roles of CTCF and BORIS in region/specific regulation of epigenetic processes, the impact of DNA damage on epigenetic processes as well as links between epigeneticmore » mechanisms and early nutrition and bystander effects. This report shows the agenda and abstracts for this symposium.« less
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Concise Review: Epigenetic Regulation of Myogenesis in Health and Disease
Sincennes, Marie-Claude; Brun, Caroline E.
2016-01-01
Skeletal muscle regeneration is initiated by satellite cells, a population of adult stem cells that reside in the muscle tissue. The ability of satellite cells to self-renew and to differentiate into the muscle lineage is under transcriptional and epigenetic control. Satellite cells are characterized by an open and permissive chromatin state. The transcription factor Pax7 is necessary for satellite cell function. Pax7 is a nodal factor regulating the expression of genes associated with satellite cell growth and proliferation, while preventing differentiation. Pax7 recruits chromatin modifiers to DNA to induce expression of specific target genes involved in myogenic commitment following asymmetric division of muscle stem cells. Emerging evidence suggests that replacement of canonical histones with histone variants is an important regulatory mechanism controlling the ability of satellite cells and myoblasts to differentiate. Differentiation into the muscle lineage is associated with a global gene repression characterized by a decrease in histone acetylation with an increase in repressive histone marks. However, genes important for differentiation are upregulated by the specific action of histone acetyltransferases and other chromatin modifiers, in combination with several transcription factors, including MyoD and Mef2. Treatment with histone deacetylase (HDAC) inhibitors enhances muscle regeneration and is considered as a therapeutic approach in the treatment of muscular dystrophy. This review describes the recent findings on epigenetic regulation in satellite stem cells and committed myoblasts. The potential of epigenetic drugs, such as HDAC inhibitors, as well as their molecular mechanism of action in muscle cells, will be addressed. Significance This review summarizes recent findings concerning the epigenetic regulation of satellite cells in skeletal muscle. PMID:26798058
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Homosexuality via canalized sexual development: a testing protocol for a new epigenetic model.
Rice, William R; Friberg, Urban; Gavrilets, Sergey
2013-09-01
We recently synthesized and reinterpreted published studies to advance an epigenetic model for the development of homosexuality (HS). The model is based on epigenetic marks laid down in response to the XX vs. XY karyotype in embryonic stem cells. These marks boost sensitivity to testosterone in XY fetuses and lower it in XX fetuses, thereby canalizing sexual development. Our model predicts that a subset of these canalizing epigenetic marks stochastically carry over across generations and lead to mosaicism for sexual development in opposite-sex offspring--the homosexual phenotype being one such outcome. Here, we begin by outlining why HS has been under-appreciated as a commonplace phenomenon in nature, and how this trend is currently being reversed in the field of neurobiology. We next briefly describe our epigenetic model of HS, develop a set of predictions, and describe how epigenetic profiles of human stem cells can provide for a strong test of the model. © 2013 The Authors. Bioessays published by WILEY Periodicals, Inc.
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Homosexuality via canalized sexual development: A testing protocol for a new epigenetic model
Rice, William R; Friberg, Urban; Gavrilets, Sergey
2013-01-01
We recently synthesized and reinterpreted published studies to advance an epigenetic model for the development of homosexuality (HS). The model is based on epigenetic marks laid down in response to the XX vs. XY karyotype in embryonic stem cells. These marks boost sensitivity to testosterone in XY fetuses and lower it in XX fetuses, thereby canalizing sexual development. Our model predicts that a subset of these canalizing epigenetic marks stochastically carry over across generations and lead to mosaicism for sexual development in opposite-sex offspring – the homosexual phenotype being one such outcome. Here, we begin by outlining why HS has been under-appreciated as a commonplace phenomenon in nature, and how this trend is currently being reversed in the field of neurobiology. We next briefly describe our epigenetic model of HS, develop a set of predictions, and describe how epigenetic profiles of human stem cells can provide for a strong test of the model. PMID:23868698
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Epigenetics and maternal nutrition: nature v. nurture.
Simmons, Rebecca
2011-02-01
Under- and over-nutrition during pregnancy has been linked to the later development of diseases such as diabetes and obesity. Epigenetic modifications may be one mechanism by which exposure to an altered intrauterine milieu or metabolic perturbation may influence the phenotype of the organism much later in life. Epigenetic modifications of the genome provide a mechanism that allows the stable propagation of gene expression from one generation of cells to the next. This review highlights our current knowledge of epigenetic gene regulation and the evidence that chromatin remodelling and histone modifications play key roles in adipogenesis and the development of obesity. Epigenetic modifications affecting processes important to glucose regulation and insulin secretion have been described in the pancreatic β-cells and muscle of the intrauterine growth-retarded offspring, characteristics essential to the pathophysiology of type-2 diabetes. Epigenetic regulation of gene expression contributes to both adipocyte determination and differentiation in in vitro models. The contributions of histone acetylation, histone methylation and DNA methylation to the process of adipogenesis in vivo remain to be evaluated.
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EZH2: a pivotal regulator in controlling cell differentiation.
Chen, Ya-Huey; Hung, Mien-Chie; Li, Long-Yuan
2012-01-01
Epigenetic regulation plays an important role in stem cell self-renewal, maintenance and lineage differentiation. The epigenetic profiles of stem cells are related to their transcriptional signature. Enhancer of Zeste homlog 2 (EZH2), a catalytic subunit of epigenetic regulator Polycomb repressive complex 2 (PRC2), has been shown to be a key regulator in controlling cellular differentiation. EZH2 is a histone methyltransferase that not only methylates histone H3 on Lys 27 (H3K27me3) but also interacts with and recruits DNA methyltransferases to methylate CpG at certain EZH2 target genes to establish firm repressive chromatin structures, contributing to tumor progression and the regulation of development and lineage commitment both in embryonic stem cells (ESCs) and adult stem cells. In addition to its well-recognized epigenetic gene silencing function, EZH2 also directly methylates nonhistone targets such as the cardiac transcription factor, GATA4, resulting in attenuated GATA4 transcriptional activity and gene repression. This review addresses recent progress toward the understanding of the biological functions and regulatory mechanisms of EZH2 and its targets as well as their roles in stem cell maintenance and cell differentiation.
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Srivas, Sweta; Thakur, Mahendra K
2018-05-01
Epigenetic modifications through methylation of DNA and acetylation of histones modulate neuronal gene expression and regulate long-term memory. Earlier we demonstrated that scopolamine-induced decrease in memory consolidation is correlated with enhanced expression of hippocampal DNA methyltransferase 1 (DNMT1) and histone deacetylase 2 (HDAC2) in mice. DNMT1 and HDAC2 act together by recruiting a co-repressor complex and deacetylating the chromatin. The catalytic activity of HDACs is mainly dependent on its incorporation into multiprotein co-repressor complexes, among which SIN3A-HDAC2 co-repressor is widely studied to regulate synaptic plasticity. However, the involvement of co-repressor complex in regulating memory loss or amnesia is unexplored. This study examines the role of co-repressor SIN3A in scopolamine-induced amnesia through epigenetic changes in the hippocampus. Scopolamine treatment remarkably enhanced hippocampal SIN3A expression in mice. To prevent such increase in SIN3A expression, we used hippocampal infusion of SIN3A-siRNA and assessed the effect of SIN3A silencing on scopolamine-induced amnesia. Silencing of SIN3A in amnesic mice reduced the binding of HDAC2 at neuronal immediate early genes (IEGs) promoter, but did not change the expression of HDAC2. Furthermore, it increased acetylation of H3K9 and H3K14 at neuronal IEGs (Arc, Egr1, Homer1 and Narp) promoter, prevented scopolamine-induced down-regulation of IEGs and improved consolidation of memory during novel object recognition task. These findings together suggest that SIN3A has a critical role in regulation of synaptic plasticity and might act as a potential therapeutic target to rescue memory decline during amnesia and other neuropsychiatric pathologies. © 2018 International Society for Neurochemistry.
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Epigenetic regulation of gene expression in cancer: techniques, resources and analysis
Kagohara, Luciane T; Stein-O’Brien, Genevieve L; Kelley, Dylan; Flam, Emily; Wick, Heather C; Danilova, Ludmila V; Easwaran, Hariharan; Favorov, Alexander V; Qian, Jiang; Gaykalova, Daria A; Fertig, Elana J
2018-01-01
Abstract Cancer is a complex disease, driven by aberrant activity in numerous signaling pathways in even individual malignant cells. Epigenetic changes are critical mediators of these functional changes that drive and maintain the malignant phenotype. Changes in DNA methylation, histone acetylation and methylation, noncoding RNAs, posttranslational modifications are all epigenetic drivers in cancer, independent of changes in the DNA sequence. These epigenetic alterations were once thought to be crucial only for the malignant phenotype maintenance. Now, epigenetic alterations are also recognized as critical for disrupting essential pathways that protect the cells from uncontrolled growth, longer survival and establishment in distant sites from the original tissue. In this review, we focus on DNA methylation and chromatin structure in cancer. The precise functional role of these alterations is an area of active research using emerging high-throughput approaches and bioinformatics analysis tools. Therefore, this review also describes these high-throughput measurement technologies, public domain databases for high-throughput epigenetic data in tumors and model systems and bioinformatics algorithms for their analysis. Advances in bioinformatics data that combine these epigenetic data with genomics data are essential to infer the function of specific epigenetic alterations in cancer. These integrative algorithms are also a focus of this review. Future studies using these emerging technologies will elucidate how alterations in the cancer epigenome cooperate with genetic aberrations during tumor initiation and progression. This deeper understanding is essential to future studies with epigenetics biomarkers and precision medicine using emerging epigenetic therapies. PMID:28968850
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Ng, Laura J.; Cropley, Jennifer E.; Pickett, Hilda A.; Reddel, Roger R.; Suter, Catherine M.
2009-01-01
Tumours and immortalized cells avoid telomere attrition by using either the ribonucleoprotein enzyme telomerase or a recombination-based alternative lengthening of telomeres (ALT) mechanism. Available evidence from mice suggests that the epigenetic state of the telomere may influence the mechanism of telomere maintenance, but this has not been directly tested in human cancer. Here we investigated cytosine methylation directly adjacent to the telomere as a marker of the telomere's epigenetic state in a panel of human cell lines. We find that while ALT cells show highly heterogeneous patterns of subtelomeric methylation, subtelomeric regions in telomerase-positive cells invariably show denser methylation than normal cells, being almost completely methylated. When compared to matched normal and ALT cells, telomerase-positive cells also exhibit reduced levels of the telomeric repeat-containing-RNA (TERRA), whose transcription originates in the subtelomere. Our results are consistent with the notion that TERRA may inhibit telomerase: the heavy cytosine methylation we observe in telomerase-positive cells may reflect selection for TERRA silencing in order to facilitate telomerase activity at the telomere. These data suggest that the epigenetic differences between telomerase-positive and ALT cells may underlie the mechanism of telomere maintenance in human tumorigenesis and highlight the broad reaching consequences of epigenetic dysregulation in cancer. PMID:19129228
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Jensen, Taylor J.; Wozniak, Ryan J.; Arizona Cancer Center, University of Arizona, Tucson, AZ 85724
2009-02-15
Arsenic is a human carcinogen with exposure associated with cancer of the lung, skin, and bladder. Many potential mechanisms have been implicated as playing a role in the process of arsenical-induced malignancy including the perturbation of signaling pathways and aberrant epigenetic regulation. We initiated studies to examine the role of a member of the non-canonical WNT signaling pathway, WNT5A, in UROtsa cells and arsenite [URO-ASSC] and monomethylarsonous acid [URO-MSC] malignantly transformed variants. We present data herein that suggest that WNT5A is transcriptionally activated during arsenical-induced malignant transformation. This WNT5A transcriptional activation is correlated with the enrichment of permissive histone modificationsmore » and the reduction of repressive modifications in the WNT5A promoter region. The epigenetic activation of WNT5A expression and acetylation of its promoter remain after the removal of the arsenical, consistent with the maintenance of an anchorage independent growth phenotype in these cells. Additionally, treatment with epigenetic modifying drugs supports a functional role for these epigenetic marks in controlling gene expression. Reduction of WNT5A using lentiviral shRNA greatly attenuated the ability of these cells to grow in an anchorage independent fashion. Extension of our model into human bladder cancer cell lines indicates that each of the cell lines examined also express WNT5A. Taken together, these data suggest that the epigenetic remodeling of the WNT5A promoter is correlated with its transcriptional activation and this upregulation likely participates in arsenical-induced malignant transformation.« less
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Hutchins, Andrew Paul; Pei, Duanqing
Transposable elements (TEs) are mobile genomic sequences of DNA capable of autonomous and non-autonomous duplication. TEs have been highly successful, and nearly half of the human genome now consists of various families of TEs. Originally thought to be non-functional, these elements have been co-opted by animal genomes to perform a variety of physiological functions ranging from TE-derived proteins acting directly in normal biological functions, to innovations in transcription factor logic and influence on epigenetic control of gene expression. During embryonic development, when the genome is epigenetically reprogrammed and DNA-demethylated, TEs are released from repression and show embryonic stage-specific expression, and in human and mouse embryos, intact TE-derived endogenous viral particles can even be detected. A similar process occurs during the reprogramming of somatic cells to pluripotent cells: When the somatic DNA is demethylated, TEs are released from repression. In embryonic stem cells (ESCs), where DNA is hypomethylated, an elaborate system of epigenetic control is employed to suppress TEs, a system that often overlaps with normal epigenetic control of ESC gene expression. Finally, many long non-coding RNAs (lncRNAs) involved in normal ESC function and those assisting or impairing reprogramming contain multiple TEs in their RNA. These TEs may act as regulatory units to recruit RNA-binding proteins and epigenetic modifiers. This review covers how TEs are interlinked with the epigenetic machinery and lncRNAs, and how these links influence each other to modulate aspects of ESCs, embryogenesis, and somatic cell reprogramming.
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Adventures in hepatocarcinogenesis.
Pitot, Henry C
2007-01-01
Neoplasia is a heritably altered, relatively autonomous growth of tissue. Hepatocarcinogenesis, the pathogenesis of neoplasia in liver, as modeled in the rat exhibits three distinct, quantifiable stages: initiation, promotion, and progression. Simple mutations and/or epigenetic alterations may result in the irreversible stage of initiation. The stage of promotion results from selective enhancement of cell replication and selective inhibition of cellular apoptosis of initiated cells dependent on the genetic and/or epigenetic alterations of the latter. The irreversible stage of progression results from initial karyotypic alterations that evolve into greater degrees of genomic instability. The initial genomic alteration in the transition from promotion to progression may involve primarily epigenetic mechanisms driven by epigenetic and genetic alterations fixed during the stage of promotion.
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Epigenetics in adipose tissue, obesity, weight loss and diabetes
USDA-ARS?s Scientific Manuscript database
Given the role that the diet and other environmental factors play in the development of obesity and type 2 diabetes, the implication of different epigenetic processes is being investigated. Although it is well known that the environmental factors can cause cell type-dependent epigenetic changes, inc...
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Masuda, Muneyuki; Wakasaki, Takahiro; Toh, Satoshi
2016-01-01
Recent results of the Cancer Genome Atlas on head and neck squamous cell carcinoma (HNSCC) revealed that HNSCC lacked predominant gain-of-function mutations in oncogenes, whereas an essential role for epigenetics in oncogenesis has become apparent. In parallel, it has gained general acceptance that cancer is considered as complex adaptive system, which evolves responding environmental selective pressures. This somatic evolution appears to proceed concurrently with the acquisition of an atavistic pluripotent state (i.e., “stemness”), which is inducible by intrinsic epigenetic reprogramming program as demonstrated by induced pluripotent stem (iPS) cells. This Nobel prize-winning discovery has markedly accelerated and expanded cancer stem cell research from the point of epigenetic reprogramming. Taken together, we hypothesize that stress-triggered atavistic reprogramming (STAR) may be the major driving force of HNSCC evolution. In this perspective, we discuss the possible mechanisms of STAR in HNSCC, focusing on recent topics of epigenetic reprogramming in developmental and cancer cell biology. PMID:27429838
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Avitzour, Michal; Mor-Shaked, Hagar; Yanovsky-Dagan, Shira; Aharoni, Shira; Altarescu, Gheona; Renbaum, Paul; Eldar-Geva, Talia; Schonberger, Oshrat; Levy-Lahad, Ephrat; Epsztejn-Litman, Silvina; Eiges, Rachel
2014-01-01
Summary Fragile X syndrome (FXS) is the most common heritable form of cognitive impairment. It results from epigenetic silencing of the X-linked FMR1 gene by a CGG expansion in its 5′-untranslated region. Taking advantage of a large set of FXS-affected human embryonic stem cell (HESC) lines and isogenic subclones derived from them, we show that FMR1 hypermethylation commonly occurs in the undifferentiated state (six of nine lines, ranging from 24% to 65%). In addition, we demonstrate that hypermethylation is tightly linked with FMR1 transcriptional inactivation in undifferentiated cells, coincides with loss of H3K4me2 and gain of H3K9me3, and is unrelated to CTCF binding. Taken together, these results demonstrate that FMR1 epigenetic gene silencing takes place in FXS HESCs and clearly highlights the importance of examining multiple cell lines when investigating FXS and most likely other epigenetically regulated diseases. PMID:25418717
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Avitzour, Michal; Mor-Shaked, Hagar; Yanovsky-Dagan, Shira; Aharoni, Shira; Altarescu, Gheona; Renbaum, Paul; Eldar-Geva, Talia; Schonberger, Oshrat; Levy-Lahad, Ephrat; Epsztejn-Litman, Silvina; Eiges, Rachel
2014-11-11
Fragile X syndrome (FXS) is the most common heritable form of cognitive impairment. It results from epigenetic silencing of the X-linked FMR1 gene by a CGG expansion in its 5'-untranslated region. Taking advantage of a large set of FXS-affected human embryonic stem cell (HESC) lines and isogenic subclones derived from them, we show that FMR1 hypermethylation commonly occurs in the undifferentiated state (six of nine lines, ranging from 24% to 65%). In addition, we demonstrate that hypermethylation is tightly linked with FMR1 transcriptional inactivation in undifferentiated cells, coincides with loss of H3K4me2 and gain of H3K9me3, and is unrelated to CTCF binding. Taken together, these results demonstrate that FMR1 epigenetic gene silencing takes place in FXS HESCs and clearly highlights the importance of examining multiple cell lines when investigating FXS and most likely other epigenetically regulated diseases.
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Remote Memory and Cortical Synaptic Plasticity Require Neuronal CCCTC-Binding Factor (CTCF).
Kim, Somi; Yu, Nam-Kyung; Shim, Kyu-Won; Kim, Ji-Il; Kim, Hyopil; Han, Dae Hee; Choi, Ja Eun; Lee, Seung-Woo; Choi, Dong Il; Kim, Myung Won; Lee, Dong-Sung; Lee, Kyungmin; Galjart, Niels; Lee, Yong-Seok; Lee, Jae-Hyung; Kaang, Bong-Kiun
2018-05-30
The molecular mechanism of long-term memory has been extensively studied in the context of the hippocampus-dependent recent memory examined within several days. However, months-old remote memory maintained in the cortex for long-term has not been investigated much at the molecular level yet. Various epigenetic mechanisms are known to be important for long-term memory, but how the 3D chromatin architecture and its regulator molecules contribute to neuronal plasticity and systems consolidation is still largely unknown. CCCTC-binding factor (CTCF) is an 11-zinc finger protein well known for its role as a genome architecture molecule. Male conditional knock-out mice in which CTCF is lost in excitatory neurons during adulthood showed normal recent memory in the contextual fear conditioning and spatial water maze tasks. However, they showed remarkable impairments in remote memory in both tasks. Underlying the remote memory-specific phenotypes, we observed that female CTCF conditional knock-out mice exhibit disrupted cortical LTP, but not hippocampal LTP. Similarly, we observed that CTCF deletion in inhibitory neurons caused partial impairment of remote memory. Through RNA sequencing, we observed that CTCF knockdown in cortical neuron culture caused altered expression of genes that are highly involved in cell adhesion, synaptic plasticity, and memory. These results suggest that remote memory storage in the cortex requires CTCF-mediated gene regulation in neurons, whereas recent memory formation in the hippocampus does not. SIGNIFICANCE STATEMENT CCCTC-binding factor (CTCF) is a well-known 3D genome architectural protein that regulates gene expression. Here, we use two different CTCF conditional knock-out mouse lines and reveal, for the first time, that CTCF is critically involved in the regulation of remote memory. We also show that CTCF is necessary for appropriate expression of genes, many of which we found to be involved in the learning- and memory-related processes. Our study provides behavioral and physiological evidence for the involvement of CTCF-mediated gene regulation in the remote long-term memory and elucidates our understanding of systems consolidation mechanisms. Copyright © 2018 the authors 0270-6474/18/385042-11$15.00/0.
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Opiela, J; Samiec, M; Romanek, J
2017-07-15
Artificial epigenomic modulation of in vitro cultured mesenchymal stem cells (MSCs) by applying a non-selective HDAC inhibitor, termed TSA, can facilitate more epigenetic reprogramming of transcriptional activity of the somatic cell-descended nuclear genome in NT pig embryos. The results of the present investigation showed that TSA-dependent epigenomic modulation of nuclear donor MSCs highly affects both the in vitro developmental capability and the cytological quality of inter-species (porcine→bovine) cloned embryos. The developmental competences to reach the blastocyst stage among hybrid (porcine→bovine) nuclear-transferred embryos that had been reconstructed with bovine ooplasts and epigenetically modulated porcine MSCs were maintained at a relatively high level. These competences were higher than those noted in studies by other authors, but they were still decreased compared to those of intra-species (porcine) cloned embryos that had been reconstituted with porcine ooplasts and either the cell nuclei of epigenetically transformed MSCs or the cell nuclei of epigenetically non-transformed MSCs. In conclusion, MSCs undergoing TSA-dependent epigenetic transformation were used for the first time as a source of nuclear donor cells not only for inter-species somatic cell cloning in pigs but also for inter-species somatic cell cloning in other livestock species. Moreover, as a result of the current research, efficient sequential physicochemical activation of inter-species nuclear-transferred clonal cybrids derived from bovine ooplasm and porcine MSC nuclei was developed. Copyright © 2017 Elsevier Inc. All rights reserved.
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Romania, Paolo; Bertaina, Alice; Bracaglia, Giorgia; Locatelli, Franco; Fruci, Doriana; Rota, Rossella
2012-01-01
Gene expression control mediated by microRNAs and epigenetic remodeling of chromatin are interconnected processes often involved in feedback regulatory loops, which strictly guide proper tissue differentiation during embryonal development. Altered expression of microRNAs is one of the mechanisms leading to pathologic conditions, such as cancer. Several lines of evidence pointed to epigenetic alterations as responsible for aberrant microRNA expression in human cancers. Rhabdomyosarcoma and neuroblastoma are pediatric cancers derived from cells presenting features of skeletal muscle and neuronal precursors, respectively, blocked at different stages of differentiation. Consistently, tumor cells express tissue markers of origin but are unable to terminally differentiate. Several microRNAs playing a key role during tissue differentiation are often epigenetically downregulated in rhabdomyosarcoma and neuroblastoma and behave as tumor suppressors when re-expressed. Recently, inhibition of epigenetic modulators in adult tumors has provided encouraging results causing re-expression of anti-tumor master gene pathways. Thus, a similar approach could be used to correct the aberrant epigenetic regulation of microRNAs in rhabdomyosarcoma and neuroblastoma. The present review highlights the current insights on epigenetically deregulated microRNAs in rhabdomyosarcoma and neuroblastoma and their role in tumorigenesis and developmental pathways. The translational clinical implications and challenges regarding modulation of epigenetic chromatin remodeling/microRNAs interconnections are also discussed. PMID:23443118
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Ecker, Simone; Chen, Lu; Pancaldi, Vera; Bagger, Frederik O; Fernández, José María; Carrillo de Santa Pau, Enrique; Juan, David; Mann, Alice L; Watt, Stephen; Casale, Francesco Paolo; Sidiropoulos, Nikos; Rapin, Nicolas; Merkel, Angelika; Stunnenberg, Hendrik G; Stegle, Oliver; Frontini, Mattia; Downes, Kate; Pastinen, Tomi; Kuijpers, Taco W; Rico, Daniel; Valencia, Alfonso; Beck, Stephan; Soranzo, Nicole; Paul, Dirk S
2017-01-26
A healthy immune system requires immune cells that adapt rapidly to environmental challenges. This phenotypic plasticity can be mediated by transcriptional and epigenetic variability. We apply a novel analytical approach to measure and compare transcriptional and epigenetic variability genome-wide across CD14 + CD16 - monocytes, CD66b + CD16 + neutrophils, and CD4 + CD45RA + naïve T cells from the same 125 healthy individuals. We discover substantially increased variability in neutrophils compared to monocytes and T cells. In neutrophils, genes with hypervariable expression are found to be implicated in key immune pathways and are associated with cellular properties and environmental exposure. We also observe increased sex-specific gene expression differences in neutrophils. Neutrophil-specific DNA methylation hypervariable sites are enriched at dynamic chromatin regions and active enhancers. Our data highlight the importance of transcriptional and epigenetic variability for the key role of neutrophils as the first responders to inflammatory stimuli. We provide a resource to enable further functional studies into the plasticity of immune cells, which can be accessed from: http://blueprint-dev.bioinfo.cnio.es/WP10/hypervariability .
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Sungur, A Özge; Jochner, Magdalena C E; Harb, Hani; Kılıç, Ayşe; Garn, Holger; Schwarting, Rainer K W; Wöhr, Markus
2017-08-01
Autism spectrum disorder (ASD) is a class of neurodevelopmental disorders characterized by persistent deficits in social communication/interaction, together with restricted/repetitive patterns of behavior. ASD is among the most heritable neuropsychiatric conditions, and while available evidence points to a complex set of genetic factors, the SHANK gene family has emerged as one of the most promising candidates. Here, we assessed ASD-related phenotypes with particular emphasis on social behavior and cognition in Shank1 mouse mutants in comparison to heterozygous and wildtype littermate controls across development in both sexes. While social approach behavior was evident in all experimental conditions and social recognition was only mildly affected by genotype, Shank1 -/- null mutant mice were severely impaired in object recognition memory. This effect was particularly prominent in juveniles, not due to impairments in object discrimination, and replicated in independent mouse cohorts. At the neurobiological level, object recognition deficits were paralleled by increased brain-derived neurotrophic factor (BDNF) protein expression in the hippocampus of Shank1 -/- mice; yet BDNF levels did not differ under baseline conditions. We therefore investigated changes in the epigenetic regulation of hippocampal BDNF expression and detected an enrichment of histone H3 acetylation at the Bdnf promoter1 in Shank1 -/- mice, consistent with increased learning-associated BDNF. Together, our findings indicate that Shank1 deletions lead to an aberrant cognitive phenotype characterized by severe impairments in object recognition memory and increased hippocampal BDNF levels, possibly due to epigenetic modifications. This result supports the link between ASD and intellectual disability, and suggests epigenetic regulation as a potential therapeutic target. © 2017 Wiley Periodicals, Inc.
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Epigenetics and Therapeutic Targets Mediating Neuroprotection
Qureshi, Irfan A.; Mehler, Mark F.
2015-01-01
The rapidly evolving science of epigenetics is transforming our understanding of the nervous system in health and disease and holds great promise for the development of novel diagnostic and therapeutic approaches targeting neurological diseases. Increasing evidence suggests that epigenetic factors and mechanisms serve as important mediators of the pathogenic processes that lead to irrevocable neural injury and of countervailing homeostatic and regenerative responses. Epigenetics is, therefore, of considerable translational significance to the field of neuroprotection. In this brief review, we provide an overview of epigenetic mechanisms and highlight the emerging roles played by epigenetic processes in neural cell dysfunction and death and in resultant neuroprotective responses. PMID:26236020
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Epigenetics Mechanisms in Alzheimer’s disease
Mastroeni, Diego; Grover, Andrew; Delvaux, Elaine; Whiteside, Charisse; Coleman, Paul D.; Rogers, Joseph
2011-01-01
Epigenetic modifications help orchestrate sweeping developmental, aging, and disease-causing changes in phenotype by altering transcriptional activity in multiple genes spanning multiple biologic pathways. Although previous epigenetic research has focused primarily on dividing cells, particularly in cancer, recent studies have shown rapid, dynamic, and persistent epigenetic modifications in neurons that have significant neuroendocrine, neurophysiologic, and neurodegenerative consequences. Here, we provide a review of the major mechanisms for epigenetic modification and how they are reportedly altered in aging and Alzheimer’s disease (AD). Because of their reach across the genome, epigenetic mechanisms may provide a unique integrative framework for the pathologic diversity and complexity of AD. PMID:21482442
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Epigenetic Regulation by Sulforaphane: Opportunities for Breast and Prostate Cancer Chemoprevention.
Atwell, Lauren L; Beaver, Laura M; Shannon, Jackilen; Williams, David E; Dashwood, Roderick H; Ho, Emily
2015-04-01
Sulforaphane (SFN) is a phytochemical derived from cruciferous vegetables that has multiple molecular targets and anti-cancer properties. Researchers have demonstrated several chemopreventive benefits of SFN consumption, such as reductions in tumor growth, increases in cancer cell apoptosis, and disruption of signaling within tumor microenvironments both in vitro and in vivo . Emerging evidence indicates that SFN exerts several of its chemopreventive effects by altering epigenetic mechanisms. This review summarizes evidence of the impact of SFN on epigenetic events and how they relate to the chemopreventive effects of SFN observed in preclinical and clinical studies of breast and prostate cancers. Specific areas of focus include the role of SFN in the regulation of cell cycle, apoptosis, inflammation, antioxidant defense, and cancer cell signaling and their relationships to epigenetic mechanisms. Finally, remaining challenges and research needs for translating mechanistic work with SFN into human studies and clinical intervention trials are discussed.
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Single-cell multimodal profiling reveals cellular epigenetic heterogeneity.
Cheow, Lih Feng; Courtois, Elise T; Tan, Yuliana; Viswanathan, Ramya; Xing, Qiaorui; Tan, Rui Zhen; Tan, Daniel S W; Robson, Paul; Loh, Yuin-Han; Quake, Stephen R; Burkholder, William F
2016-10-01
Sample heterogeneity often masks DNA methylation signatures in subpopulations of cells. Here, we present a method to genotype single cells while simultaneously interrogating gene expression and DNA methylation at multiple loci. We used this targeted multimodal approach, implemented on an automated, high-throughput microfluidic platform, to assess primary lung adenocarcinomas and human fibroblasts undergoing reprogramming by profiling epigenetic variation among cell types identified through genotyping and transcriptional analysis.
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Chemical probes targeting epigenetic proteins: Applications beyond oncology
Ackloo, Suzanne; Brown, Peter J.; Müller, Susanne
2017-01-01
ABSTRACT Epigenetic chemical probes are potent, cell-active, small molecule inhibitors or antagonists of specific domains in a protein; they have been indispensable for studying bromodomains and protein methyltransferases. The Structural Genomics Consortium (SGC), comprising scientists from academic and pharmaceutical laboratories, has generated most of the current epigenetic chemical probes. Moreover, the SGC has shared about 4 thousand aliquots of these probes, which have been used primarily for phenotypic profiling or to validate targets in cell lines or primary patient samples cultured in vitro. Epigenetic chemical probes have been critical tools in oncology research and have uncovered mechanistic insights into well-established targets, as well as identify new therapeutic starting points. Indeed, the literature primarily links epigenetic proteins to oncology, but applications in inflammation, viral, metabolic and neurodegenerative diseases are now being reported. We summarize the literature of these emerging applications and provide examples where existing probes might be used. PMID:28080202
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Imani, Saber; Panahi, Yunes; Salimian, Jafar; Fu, Junjiang; Ghanei, Mostafa
2015-01-01
Sulfur mustard (SM, bis- (2-chloroethyl) sulphide) is a chemical warfare agent that causes DNA alkylation, protein modification and membrane damage. SM can trigger several molecular pathways involved in inflammation and oxidative stress, which cause cell necrosis and apoptosis, and loss of cells integrity and function. Epigenetic regulation of gene expression is a growing research topic and is addressed by DNA methylation, histone modification, chromatin remodeling, and noncoding RNAs expression. It seems SM can induce the epigenetic modifications that are translated into change in gene expression. Classification of epigenetic modifications long after exposure to SM would clarify its mechanism and paves a better strategy for the treatment of SM-affected patients. In this study, we review the key aberrant epigenetic modifications that have important roles in chronic obstructive pulmonary disease (COPD) and compared with mustard lung. PMID:26557960
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Sengupta, Deepanwita; Byrum, Stephanie D.; Avaritt, Nathan L.; Davis, Lauren; Shields, Bradley; Mahmoud, Fade; Reynolds, Matthew; Orr, Lisa M.; Mackintosh, Samuel G.; Shalin, Sara C.; Tackett, Alan J.
2016-01-01
Normal cell growth is characterized by a regulated epigenetic program that drives cellular activities such as gene transcription, DNA replication, and DNA damage repair. Perturbation of this epigenetic program can lead to events such as mis-regulation of gene transcription and diseases such as cancer. To begin to understand the epigenetic program correlated to the development of melanoma, we performed a novel quantitative mass spectrometric analysis of histone post-translational modifications mis-regulated in melanoma cell culture as well as patient tumors. Aggressive melanoma cell lines as well as metastatic melanoma were found to have elevated histone H3 Lys27 trimethylation (H3K27me3) accompanied by overexpressed methyltransferase EZH2 that adds the specific modification. The altered epigenetic program that led to elevated H3K27me3 in melanoma cell culture was found to directly silence transcription of the tumor suppressor genes RUNX3 and E-cadherin. The EZH2-mediated silencing of RUNX3 and E-cadherin transcription was also validated in advanced stage human melanoma tissues. This is the first study focusing on the detailed epigenetic mechanisms leading to EZH2-mediated silencing of RUNX3 and E-cadherin tumor suppressors in melanoma. This study underscores the utility of using high resolution mass spectrometry to identify mis-regulated epigenetic programs in diseases such as cancer, which could ultimately lead to the identification of biological markers for diagnostic and prognostic applications. PMID:26621846
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Cacci, Emanuele; Negri, Rodolfo; Biagioni, Stefano; Lupo, Giuseppe
2017-01-01
Neural stem/progenitor cell (NSPC) self-renewal and differentiation in the developing and the adult brain are controlled by extra-cellular signals and by the inherent competence of NSPCs to produce appropriate responses. Stage-dependent responsiveness of NSPCs to extrinsic cues is orchestrated at the epigenetic level. Epigenetic mechanisms such as DNA methylation, histone modifications and non-coding RNA-mediated regulation control crucial aspects of NSPC development and function, and are also implicated in pathological conditions. While their roles in the regulation of stem cell fate have been largely explored in pluripotent stem cell models, the epigenetic signature of NSPCs is also key to determine their multipotency as well as their progressive bias towards specific differentiation outcomes. Here we review recent developments in this field, focusing on the roles of histone methylation marks and the protein complexes controlling their deposition in NSPCs of the developing cerebral cortex and the adult subventricular zone. In this context, we describe how bivalent promoters, carrying antagonistic epigenetic modifications, feature during multiple steps of neural development, from neural lineage specification to neuronal differentiation. Furthermore, we discuss the emerging cross-talk between epigenetic regulators and microRNAs, and how the interplay between these different layers of regulation can finely tune the expression of genes controlling NSPC maintenance and differentiation. In particular, we highlight recent advances in the identification of astrocyte-enriched microRNAs and their function in cell fate choices of NSPCs differentiating towards glial lineages.
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Epigenetic regulation of neuroblastoma development.
Durinck, Kaat; Speleman, Frank
2018-05-01
In recent years, technological advances have enabled a detailed landscaping of the epigenome and the mechanisms of epigenetic regulation that drive normal cell function, development and cancer. Rather than merely a structural entity to support genome compaction, we now look at chromatin as a very dynamic and essential constellation that is actively participating in the tight orchestration of transcriptional regulation as well as DNA replication and repair. The unique feature of chromatin flexibility enabling fast switches towards more or less restricted epigenetic cellular states is, not surprisingly, intimately connected to cancer development and treatment resistance, and the central role of epigenetic alterations in cancer is illustrated by the finding that up to 50% of all mutations across cancer entities affect proteins controlling the chromatin status. We summarize recent insights into epigenetic rewiring underlying neuroblastoma (NB) tumor formation ranging from changes in DNA methylation patterns and mutations in epigenetic regulators to global effects on transcriptional regulatory circuits that involve key players in NB oncogenesis. Insights into the disruption of the homeostatic epigenetic balance contributing to developmental arrest of sympathetic progenitor cells and subsequent NB oncogenesis are rapidly growing and will be exploited towards the development of novel therapeutic strategies to increase current survival rates of patients with high-risk NB.
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Olsen, Ansgar S.; Sarras, Michael P.; Leontovich, Alexey; Intine, Robert V.
2012-01-01
Metabolic memory (MM) is the phenomenon whereby diabetes complications persist and progress after glycemic recovery is achieved. Here, we present data showing that MM is heritable and that the transmission correlates with hyperglycemia-induced DNA hypomethylation and aberrant gene expression. Streptozocin was used to induce hyperglycemia in adult zebrafish, and then, following streptozocin withdrawal, a recovery phase was allowed to reestablish a euglycemic state. Blood glucose and serum insulin returned to physiological levels during the first 2 weeks of the recovery phase as a result of pancreatic β-cell regeneration. In contrast, caudal fin regeneration and skin wound healing remained impaired to the same extent as in diabetic fish, and this impairment was transmissible to daughter cell tissue. Daughter tissue that was never exposed to hyperglycemia, but was derived from tissue that was, did not accumulate AGEs or exhibit increased levels of oxidative stress. However, CpG island methylation and genome-wide microarray expression analyses revealed the persistence of hyperglycemia-induced global DNA hypomethylation that correlated with aberrant gene expression for a subset of loci in this daughter tissue. Collectively, the data presented here implicate the epigenetic mechanism of DNA methylation as a potential contributor to the MM phenomenon. PMID:22228713
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Epigenetic Induction of EGR-1 Expression by the Amyloid Precursor Protein during Exposure to Novelty
Hendrickx, Aurélie; Pierrot, Nathalie; Tasiaux, Bernadette; Schakman, Olivier; Brion, Jean-Pierre; Kienlen-Campard, Pascal; De Smet, Charles; Octave, Jean-Noël
2013-01-01
Following transcriptome comparison of primary cultures isolated from brain of mice expressing or not the amyloid precursor protein APP, we found transcription of the EGR-1 gene to be regulated by APP. In primary cultures of cortical neurons, APP significantly down regulated EGR-1 expression at both mRNA and protein levels in a γ-secretase independent manner. The intracellular domain of APP did not interact with EGR-1 gene promoter, but enrichment of acetylated histone H4 at the EGR-1 promoter region was measured in APP-/- neurons, as well as in brain of APP-/- mice, in which increase in EGR-1 expression was also measured. These results argue for an important function of APP in the epigenetic regulation of EGR-1 gene transcription both in vitro and in vivo. In APP-/- mice, constitutive overexpression of EGR-1 in brain impaired epigenetic induction of this early transcriptional regulator during exposure to novelty. Altogether, these results indicate an important function of APP in the epigenetic regulation of the transcription of EGR-1, known to be important for memory formation. PMID:24066134
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Epigenetic regulation of oligodendrocyte identity
Liu, Jia; Casaccia, Patrizia
2010-01-01
The interplay of transcription factors and epigenetic modifiers, including histone modifications, DNA methylation and microRNAs during development is essential for the acquisition of specific cell fates. Here we review the epigenetic “programming” of stem cells into oligodendrocytes, by analyzing three sequential stages of lineage progression. The first transition from pluripotent stem cell to neural precursor is characterized by repression of pluripotency genes and restriction of the lineage potential to the neural fate. The second transition from multipotential precursor to oligodendrocyte progenitor is associated with the progressive loss of plasticity and the repression of neuronal and astrocytic genes. The last step of differentiation of oligodendrocyte progenitors into myelin-forming cells is defined by a model of de-repression of myelin genes. PMID:20227775
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Veazey, Kylee J; Muller, Daria; Golding, Michael C
2013-01-01
Exposure to alcohol significantly alters the developmental trajectory of progenitor cells and fundamentally compromises tissue formation (i.e., histogenesis). Emerging research suggests that ethanol can impair mammalian development by interfering with the execution of molecular programs governing differentiation. For example, ethanol exposure disrupts cellular migration, changes cell-cell interactions, and alters growth factor signaling pathways. Additionally, ethanol can alter epigenetic mechanisms controlling gene expression. Normally, lineage-specific regulatory factors (i.e., transcription factors) establish the transcriptional networks of each new cell type; the cell's identity then is maintained through epigenetic alterations in the way in which the DNA encoding each gene becomes packaged within the chromatin. Ethanol exposure can induce epigenetic changes that do not induce genetic mutations but nonetheless alter the course of fetal development and result in a large array of patterning defects. Two crucial enzyme complexes--the Polycomb and Trithorax proteins--are central to the epigenetic programs controlling the intricate balance between self-renewal and the execution of cellular differentiation, with diametrically opposed functions. Prenatal ethanol exposure may disrupt the functions of these two enzyme complexes, altering a crucial aspect of mammalian differentiation. Characterizing the involvement of Polycomb and Trithorax group complexes in the etiology of fetal alcohol spectrum disorders will undoubtedly enhance understanding of the role that epigenetic programming plays in this complex disorder.
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Adi Harel, S; Bossel Ben-Moshe, N; Aylon, Y; Bublik, D R; Moskovits, N; Toperoff, G; Azaiza, D; Biagoni, F; Fuchs, G; Wilder, S; Hellman, A; Blandino, G; Domany, E; Oren, M
2015-01-01
MicroRNAs (miRs) regulate a variety of cellular processes, and their impaired expression is involved in cancer. Silencing of tumor-suppressive miRs in cancer can occur through epigenetic modifications, including DNA methylation and histone deacetylation. We performed comparative miR profiling on cultured lung cancer cells before and after treatment with 5′aza-deoxycytidine plus Trichostatin A to reverse DNA methylation and histone deacetylation, respectively. Several tens of miRs were strongly induced by such ‘epigenetic therapy'. Two representatives, miR-512-5p (miR-512) and miR-373, were selected for further analysis. Both miRs were secreted in exosomes. Re-expression of both miRs augmented cisplatin-induced apoptosis and inhibited cell migration; miR-512 also reduced cell proliferation. TEAD4 mRNA was confirmed as a direct target of miR-512; likewise, miR-373 was found to target RelA and PIK3CA mRNA directly. Our results imply that miR-512 and miR-373 exert cell-autonomous and non-autonomous tumor-suppressive effects in lung cancer cells, where their re-expression may benefit epigenetic cancer therapy. PMID:25591738
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Epigenetic Heterogeneity of B-Cell Lymphoma: DNA Methylation, Gene Expression and Chromatin States
Hopp, Lydia; Löffler-Wirth, Henry; Binder, Hans
2015-01-01
Mature B-cell lymphoma is a clinically and biologically highly diverse disease. Its diagnosis and prognosis is a challenge due to its molecular heterogeneity and diverse regimes of biological dysfunctions, which are partly driven by epigenetic mechanisms. We here present an integrative analysis of DNA methylation and gene expression data of several lymphoma subtypes. Our study confirms previous results about the role of stemness genes during development and maturation of B-cells and their dysfunction in lymphoma locking in more proliferative or immune-reactive states referring to B-cell functionalities in the dark and light zone of the germinal center and also in plasma cells. These dysfunctions are governed by widespread epigenetic effects altering the promoter methylation of the involved genes, their activity status as moderated by histone modifications and also by chromatin remodeling. We identified four groups of genes showing characteristic expression and methylation signatures among Burkitt’s lymphoma, diffuse large B cell lymphoma, follicular lymphoma and multiple myeloma. These signatures are associated with epigenetic effects such as remodeling from transcriptionally inactive into active chromatin states, differential promoter methylation and the enrichment of targets of transcription factors such as EZH2 and SUZ12. PMID:26371046
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Kuang, Haixue; Tang, Zhenqiu; Zhang, Chengyue; Wang, Zhibin; Li, Wenji; Yang, Chunjuan; Wang, Qiuhong; Yang, Bingyou; Kong, Ah-Ng
2017-01-01
Nuclear factor erythroid-2 related factor 2 (Nrf2) is a vital transcription factor that regulates the anti-oxidative defense system. Previous reports suggested that the expression of the Nrf2 gene can be regulated by epigenetic modifications. The potential epigenetic effect of taxifolin (TAX), a potent cancer chemopreventive agent, in skin cancer chemoprotection is unknown. In this study, we investigated how Nrf2 is epigenetically regulated by TAX in JB6 P+ cells. TAX was found to inhibit the 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced colony formation of JB6 P+ cells. TAX induced antioxidant response element (ARE)-luciferase activity in HepG2-C8 cells and up-regulated mRNA and protein levels of Nrf2 and its downstream genes heme oxygenase-1 (HO-1) and NAD(P)H quinone oxidoreductase 1 (NQO1), in JB6 P+ cells. Furthermore, bisulfite genomic sequencing revealed that TAX treatment reduces the methylation level of the first 15 CpGs sites in the Nrf2 promoter. Western blotting showed that TAX inhibits the expression levels of DNA methyltransferase (DNMT) and histone deacetylase (HDAC) proteins. In summary, our results revealed that TAX can induce expression of Nrf2 and its downstream target genes in JB6 P+ cells by CpG demethylation. These finding suggest that TAX may exhibit a skin cancer preventive effect by activating Nrf2 via an epigenetic pathway. PMID:28714938
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Genetic and epigenetic instability of stem cells.
Rajamani, Karthyayani; Li, Yuan-Sheng; Hsieh, Dean-Kuo; Lin, Shinn-Zong; Harn, Horng-Jyh; Chiou, Tzyy-Wen
2014-01-01
Recently, research on stem cells has been receiving an increasing amount of attention, both for its advantages and disadvantages. Genetic and epigenetic instabilities among stem cells have been a recurring obstacle to progress in regenerative medicine using stem cells. Various reports have stated that these instabilities can transform stem cells when transferred in vivo and thus have the potential to develop tumors. Previous research has shown that various extrinsic and intrinsic factors can contribute to the stability of stem cells. The extrinsic factors include growth supplements, growth factors, oxygen tension, passage technique, and cryopreservation. Controlling these factors based on previous reports may assist researchers in developing strategies for the production and clinical application of "safe" stem cells. On the other hand, the intrinsic factors can be unpredictable and uncontrollable; therefore, to ensure the successful use of stem cells in regenerative medicine, it is imperative to develop and implement appropriate strategies and technique for culturing stem cells and to confirm the genetic and epigenetic safety of these stem cells before employing them in clinical trials.
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Epigenetic Effects of Environmental Chemicals Bisphenol A and Phthalates
Singh, Sher; Li, Steven Shoei-Lung
2012-01-01
The epigenetic effects on DNA methylation, histone modification, and expression of non-coding RNAs (including microRNAs) of environmental chemicals such as bisphenol A (BPA) and phthalates have expanded our understanding of the etiology of human complex diseases such as cancers and diabetes. Multiple lines of evidence from in vitro and in vivo models have established that epigenetic modifications caused by in utero exposure to environmental toxicants can induce alterations in gene expression that may persist throughout life. Epigenetics is an important mechanism in the ability of environmental chemicals to influence health and disease, and BPA and phthalates are epigenetically toxic. The epigenetic effect of BPA was clearly demonstrated in viable yellow mice by decreasing CpG methylation upstream of the Agouti gene, and the hypomethylating effect of BPA was prevented by maternal dietary supplementation with a methyl donor like folic acid or the phytoestrogen genistein. Histone H3 was found to be trimethylated at lysine 27 by BPA effect on EZH2 in a human breast cancer cell line and mice. BPA exposure of human placental cell lines has been shown to alter microRNA expression levels, and specifically, miR-146a was strongly induced by BPA treatment. In human breast cancer MCF7 cells, treatment with the phthalate BBP led to demethylation of estrogen receptor (ESR1) promoter-associated CpG islands, indicating that altered ESR1 mRNA expression by BBP is due to aberrant DNA methylation. Maternal exposure to phthalate DEHP was also shown to increase DNA methylation and expression levels of DNA methyltransferases in mouse testis. Further, some epigenetic effects of BPA and phthalates in female rats were found to be transgenerational. Finally, the available new technologies for global analysis of epigenetic alterations will provide insight into the extent and patterns of alterations between human normal and diseased tissues. In vitro models such as human embryonic stem cells may be extremely useful in bettering the understanding of epigenetic effects on human development, health and disease, because the formation of embryoid bodies in vitro is very similar to the early stage of embryogenesis. PMID:22949852
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Epigenetic effects of environmental chemicals bisphenol A and phthalates.
Singh, Sher; Li, Steven Shoei-Lung
2012-01-01
The epigenetic effects on DNA methylation, histone modification, and expression of non-coding RNAs (including microRNAs) of environmental chemicals such as bisphenol A (BPA) and phthalates have expanded our understanding of the etiology of human complex diseases such as cancers and diabetes. Multiple lines of evidence from in vitro and in vivo models have established that epigenetic modifications caused by in utero exposure to environmental toxicants can induce alterations in gene expression that may persist throughout life. Epigenetics is an important mechanism in the ability of environmental chemicals to influence health and disease, and BPA and phthalates are epigenetically toxic. The epigenetic effect of BPA was clearly demonstrated in viable yellow mice by decreasing CpG methylation upstream of the Agouti gene, and the hypomethylating effect of BPA was prevented by maternal dietary supplementation with a methyl donor like folic acid or the phytoestrogen genistein. Histone H3 was found to be trimethylated at lysine 27 by BPA effect on EZH2 in a human breast cancer cell line and mice. BPA exposure of human placental cell lines has been shown to alter microRNA expression levels, and specifically, miR-146a was strongly induced by BPA treatment. In human breast cancer MCF7 cells, treatment with the phthalate BBP led to demethylation of estrogen receptor (ESR1) promoter-associated CpG islands, indicating that altered ESR1 mRNA expression by BBP is due to aberrant DNA methylation. Maternal exposure to phthalate DEHP was also shown to increase DNA methylation and expression levels of DNA methyltransferases in mouse testis. Further, some epigenetic effects of BPA and phthalates in female rats were found to be transgenerational. Finally, the available new technologies for global analysis of epigenetic alterations will provide insight into the extent and patterns of alterations between human normal and diseased tissues. In vitro models such as human embryonic stem cells may be extremely useful in bettering the understanding of epigenetic effects on human development, health and disease, because the formation of embryoid bodies in vitro is very similar to the early stage of embryogenesis.
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Li, Bing; Su, Trent; Ferrari, Roberto; Li, Jing-Yu; Kurdistani, Siavash K
2014-02-01
The cellular epigenetic landscape changes as pluripotent stem cells differentiate to somatic cells or when differentiated cells transform to a cancerous state. These epigenetic changes are commonly correlated with differences in gene expression. Whether active DNA replication is also associated with distinct chromatin environments in these developmentally and phenotypically diverse cell types has not been known. Here, we used BrdU-seq to map active DNA replication loci in human embryonic stem cells (hESCs), normal primary fibroblasts and a cancer cell line, and correlated these maps to the epigenome. In all cell lines, the majority of BrdU peaks were enriched in euchromatin and at DNA repetitive elements, especially at microsatellite repeats, and coincided with previously determined replication origins. The most prominent BrdU peaks were shared between all cells but a sizable fraction of the peaks were specific to each cell type and associated with cell type-specific genes. Surprisingly, the BrdU peaks that were common to all cell lines were associated with H3K18ac, H3K56ac, and H4K20me1 histone marks only in hESCs but not in normal fibroblasts or cancer cells. Depletion of the histone acetyltransferases for H3K18 and H3K56 dramatically decreased the number and intensity of BrdU peaks in hESCs. Our data reveal a unique epigenetic signature that distinguishes active replication loci in hESCs from normal somatic or malignant cells.
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Shaikhibrahim, Zaki; Lindstrot, Andreas; Ochsenfahrt, Jacqueline; Fuchs, Kerstin; Wernert, Nicolas
2013-01-01
Epigenetic changes have been suggested to drive prostate cancer (PCa) development and progression. Therefore, in this study, we aimed to identify novel epigenetics-related genes in PCa tissues, and to examine their expression in metastatic PCa cell lines. We analyzed the expression of epigenetics-related genes via a clustering analysis based on gene function in moderately and poorly differentiated PCa glands compared to normal glands of the peripheral zone (prostate proper) from PCa patients using Whole Human Genome Oligo Microarrays. Our analysis identified 12 epigenetics-related genes with a more than 2-fold increase or decrease in expression and a p-value <0.01. In modera-tely differentiated tumors compared to normal glands of the peripheral zone, we found the genes, TDRD1, IGF2, DICER1, ADARB1, HILS1, GLMN and TRIM27, to be upregulated, whereas TNRC6A and DGCR8 were found to be downregulated. In poorly differentiated tumors, we found TDRD1, ADARB and RBM3 to be upregulated, whereas DGCR8, PIWIL2 and BC069781 were downregulated. Our analysis of the expression level for each gene in the metastatic androgen-sensitive VCaP and LNCaP, and -insensitive PC3 and DU-145 PCa cell lines revealed differences in expression among the cell lines which may reflect the different biological properties of each cell line, and the potential role of each gene at different metastatic sites. The novel epigenetics-related genes that we identified in primary PCa tissues may provide further insight into the role that epigenetic changes play in PCa. Moreover, some of the genes that we identified may play important roles in primary PCa and metastasis, in primary PCa only, or in metastasis only. Follow-up studies are required to investigate the functional role and the role that the expression of these genes play in the outcome and progression of PCa using tissue microarrays.
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2017-01-01
The locus coeruleus is connected to the dorsal hippocampus via strong fiber projections. It becomes activated after arousal and novelty, whereupon noradrenaline is released in the hippocampus. Noradrenaline from the locus coeruleus is involved in modulating the encoding, consolidation, retrieval, and reversal of hippocampus-based memory. Memory storage can be modified by the activation of the locus coeruleus and subsequent facilitation of hippocampal long-term plasticity in the forms of long-term depression and long-term potentiation. Recent evidence indicates that noradrenaline and dopamine are coreleased in the hippocampus from locus coeruleus terminals, thus fostering neuromodulation of long-term synaptic plasticity and memory. Noradrenaline is an inductor of epigenetic modifications regulating transcriptional control of synaptic long-term plasticity to gate the endurance of memory storage. In conclusion, locus coeruleus activation primes the persistence of hippocampus-based long-term memory. PMID:28695015
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Avramova, Zoya
2015-07-01
Drought, salinity, extreme temperature variations, pathogen and herbivory attacks are recurring environmental stresses experienced by plants throughout their life. To survive repeated stresses, plants provide responses that may be different from their response during the first encounter with the stress. A different response to a similar stress represents the concept of 'stress memory'. A coordinated reaction at the organismal, cellular and gene/genome levels is thought to increase survival chances by improving the plant's tolerance/avoidance abilities. Ultimately, stress memory may provide a mechanism for acclimation and adaptation. At the molecular level, the concept of stress memory indicates that the mechanisms responsible for memory-type transcription during repeated stresses are not based on repetitive activation of the same response pathways activated by the first stress. Some recent advances in the search for transcription 'memory factors' are discussed with an emphasis on super-induced dehydration stress memory response genes in Arabidopsis. © 2015 The Author The Plant Journal © 2015 John Wiley & Sons Ltd.
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Epigenetic Alterations in Epstein-Barr Virus-Associated Diseases.
Niller, Hans Helmut; Banati, Ferenc; Salamon, Daniel; Minarovits, Janos
2016-01-01
Latent Epstein-Bar virus genomes undergo epigenetic modifications which are dependent on the respective tissue type and cellular phenotype. These define distinct viral epigenotypes corresponding with latent viral gene expression profiles. Viral Latent Membrane Proteins 1 and 2A can induce cellular DNA methyltransferases, thereby influencing the methylation status of the viral and cellular genomes. Therefore, not only the viral genomes carry epigenetic modifications, but also the cellular genomes adopt major epigenetic alterations upon EBV infection. The distinct cellular epigenotypes of EBV-infected cells differ from the epigenotypes of their normal counterparts. In Burkitt lymphoma (BL), nasopharyngeal carcinoma (NPC) and EBV-associated gastric carcinoma (EBVaGC) significant changes in the host cell methylome with a strong tendency towards CpG island hypermethylation are observed. Hypermethylated genes unique for EBVaGC suggest the existence of an EBV-specific "epigenetic signature". Contrary to the primary malignancies carrying latent EBV genomes, lymphoblastoid cells (LCs) established by EBV infection of peripheral B cells in vitro are characterized by a massive genome-wide demethylation and a significant decrease and redistribution of heterochromatic histone marks. Establishing complete epigenomes of the diverse EBV-associated malignancies shall clarify their similarities and differences and further clarify the contribution of EBV to the pathogenesis, especially for the epithelial malignancies, NPC and EBVaGC.
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DNA methylation, microRNAs, and their crosstalk as potential biomarkers in hepatocellular carcinoma
Anwar, Sumadi Lukman; Lehmann, Ulrich
2014-01-01
Epigenetic alterations have been identified as a major characteristic in human cancers. Advances in the field of epigenetics have contributed significantly in refining our knowledge of molecular mechanisms underlying malignant transformation. DNA methylation and microRNA expression are epigenetic mechanisms that are widely altered in human cancers including hepatocellular carcinoma (HCC), the third leading cause of cancer related mortality worldwide. Both DNA methylation and microRNA expression patterns are regulated in developmental stage specific-, cell type specific- and tissue-specific manner. The aberrations are inferred in the maintenance of cancer stem cells and in clonal cell evolution during carcinogenesis. The availability of genome-wide technologies for DNA methylation and microRNA profiling has revolutionized the field of epigenetics and led to the discovery of a number of epigenetically silenced microRNAs in cancerous cells and primary tissues. Dysregulation of these microRNAs affects several key signalling pathways in hepatocarcinogenesis suggesting that modulation of DNA methylation and/or microRNA expression can serve as new therapeutic targets for HCC. Accumulative evidence shows that aberrant DNA methylation of certain microRNA genes is an event specifically found in HCC which correlates with unfavorable outcomes. Therefore, it can potentially serve as a biomarker for detection as well as for prognosis, monitoring and predicting therapeutic responses in HCC. PMID:24976726
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Epigenetic Alterations in Human Papillomavirus-Associated Cancers
Song, Christine; McLaughlin-Drubin, Margaret E.
2017-01-01
Approximately 15–20% of human cancers are caused by viruses, including human papillomaviruses (HPVs). Viruses are obligatory intracellular parasites and encode proteins that reprogram the regulatory networks governing host cellular signaling pathways that control recognition by the immune system, proliferation, differentiation, genomic integrity, and cell death. Given that key proteins in these regulatory networks are also subject to mutation in non-virally associated diseases and cancers, the study of oncogenic viruses has also been instrumental to the discovery and analysis of many fundamental cellular processes, including messenger RNA (mRNA) splicing, transcriptional enhancers, oncogenes and tumor suppressors, signal transduction, immune regulation, and cell cycle control. More recently, tumor viruses, in particular HPV, have proven themselves invaluable in the study of the cancer epigenome. Epigenetic silencing or de-silencing of genes can have cellular consequences that are akin to genetic mutations, i.e., the loss and gain of expression of genes that are not usually expressed in a certain cell type and/or genes that have tumor suppressive or oncogenic activities, respectively. Unlike genetic mutations, the reversible nature of epigenetic modifications affords an opportunity of epigenetic therapy for cancer. This review summarizes the current knowledge on epigenetic regulation in HPV-infected cells with a focus on those elements with relevance to carcinogenesis. PMID:28862667
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Jacobsen, Mette J.; Mentzel, Caroline M. Junker; Olesen, Ann Sofie; Huby, Thierry; Jørgensen, Claus B.; Barrès, Romain; Fredholm, Merete
2016-01-01
Obesity is associated with immunological perturbations that contribute to insulin resistance. Epigenetic mechanisms can control immune functions and have been linked to metabolic complications, although their contribution to insulin resistance still remains unclear. In this study, we investigated the link between metabolic dysfunction and immune alterations with the epigenetic signature in leukocytes in a porcine model of obesity. Global DNA methylation of circulating leukocytes, adipose tissue leukocyte trafficking, and macrophage polarisation were established by flow cytometry. Adipose tissue inflammation and metabolic function were further characterised by quantification of metabolites and expression levels of genes associated with obesity and inflammation. Here we show that obese pigs showed bigger visceral fat pads, higher levels of circulating LDL cholesterol, and impaired glucose tolerance. These changes coincided with impaired metabolism, sustained macrophages infiltration, and increased inflammation in the adipose tissue. Those immune alterations were linked to global DNA hypermethylation in both B-cells and T-cells. Our results provide novel insight into the possible contribution of immune cell epigenetics into the immunological disturbances observed in obesity. The dramatic changes in the transcriptomic and epigenetic signature of circulating lymphocytes reinforce the concept that epigenetic processes participate in the increased immune cell activation and impaired metabolic functions in obesity. PMID:26798656
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A two-step process for epigenetic inheritance in Arabidopsis
Blevins, Todd; Pontvianne, Frédéric; Cocklin, Ross; Podicheti, Ram; Chandrasekhara, Chinmayi; Yerneni, Satwica; Braun, Chris; Lee, Brandon; Rusch, Doug; Mockaitis, Keithanne; Tang, Haixu; Pikaard, Craig S.
2014-01-01
Summary In Arabidopsis, multisubunit RNA polymerases IV and V orchestrate RNA-directed DNA methylation (RdDM) and transcriptional silencing, but what identifies the loci to be silenced is unclear. We show that heritable silent locus identity at a specific subset of RdDM targets requires HISTONE DEACETYLASE 6 (HDA6) acting upstream of Pol IV recruitment and siRNA biogenesis. At these loci, epigenetic memory conferring silent locus identity is erased in hda6 mutants such that restoration of HDA6 activity cannot restore siRNA biogenesis or silencing. Silent locus identity is similarly lost in mutants for the cytosine maintenance methyltransferase, MET1. By contrast, pol IV or pol V mutants disrupt silencing without erasing silent locus identity, allowing restoration of Pol IV or Pol V function to restore silencing. Collectively, these observations indicate that silent locus specification and silencing are separable steps that together account for epigenetic inheritance of the silenced state. PMID:24657166
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A histone methylation network regulates transgenerational epigenetic memory in C. elegans
Greer, Eric L.; Beese-Sims, Sara E.; Brookes, Emily; Spadafora, Ruggero; Zhu, Yun; Rothbart, Scott B.; Aristizábal-Corrales, David; Chen, Shuzhen; Badeaux, Aimee I.; Jin, Qiuye; Wang, Wei; Strahl, Brian D.; Colaiácovo, Monica P.; Shi, Yang
2014-01-01
Summary How epigenetic information is transmitted from generation to generation remains largely unknown. Deletion of the C. elegans Histone H3 lysine 4 dimethyl (H3K4me2) demethylase spr-5 leads to inherited accumulation of the euchromatic H3K4me2 mark and progressive decline in fertility. Here we identified multiple chromatin-modifying factors, including novel H3K4me1/me2 and H3K9me3 methyltransferases, an H3K9me3 demethylase and an H3K9me reader, which either suppress or accelerate the progressive transgenerational phenotypes of spr-5 mutant worms. Our findings uncover a network of chromatin regulators that control the trans-generational flow of epigenetic information, and suggest that the balance between euchromatic H3K4 and heterochromatic H3K9 methylation regulates trans-generational effects on fertility. PMID:24685137
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USDA-ARS?s Scientific Manuscript database
DNA methylation is an epigenetic mechanism central to the development and maintenance of complex mammalian tissues, but our understanding of its role in intestinal development is limited. We used whole genome bisulfite sequencing, and found that differentiation of mouse colonic intestinal stem cell...
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Regulation of object recognition and object placement by ovarian sex steroid hormones
Tuscher, Jennifer J.; Fortress, Ashley M.; Kim, Jaekyoon; Frick, Karyn M.
2014-01-01
The ovarian hormones 17β-estradiol (E2) and progesterone (P4) are potent modulators of hippocampal memory formation. Both hormones have been demonstrated to enhance hippocampal memory by regulating the cellular and molecular mechanisms thought to underlie memory formation. Behavioral neuroendocrinologists have increasingly used the object recognition and object placement (object location) tasks to investigate the role of E2 and P4 in regulating hippocampal memory formation in rodents. These one-trial learning tasks are ideal for studying acute effects of hormone treatments on different phases of memory because they can be administered during acquisition (pre-training), consolidation (post-training), or retrieval (pre-testing). This review synthesizes the rodent literature testing the effects of E2 and P4 on object recognition (OR) and object placement (OP), and the molecular mechanisms in the hippocampus supporting memory formation in these tasks. Some general trends emerge from the data. Among gonadally intact females, object memory tends to be best when E2 and P4 levels are elevated during the estrous cycle, pregnancy, and in middle age. In ovariectomized females, E2 given before or immediately after testing generally enhances OR and OP in young and middle-aged rats and mice, although effects are mixed in aged rodents. Effects of E2 treatment on OR 7and OP memory consolidation can be mediated by both classical estrogen receptors (ERα and ERβ), and depend on glutamate receptors (NMDA, mGluR1) and activation of numerous cell signaling cascades (e.g., ERK, PI3K/Akt, mTOR) and epigenetic processes (e.g., histone H3 acetylation, DNA methylation). Acute P4 treatment given immediately after training also enhances OR and OP in young and middle-aged ovariectomized females by activating similar cell signaling pathways as E2 (e.g., ERK, mTOR). The few studies that have administered both hormones in combination suggest that treatment can enhance OR and OP, but that effects are highly dependent on factors such as dose and timing of administration. In addition to providing more detail on these general conclusions, this review will discuss directions for future avenues of research into the hormonal regulation of object memory. PMID:25131507
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Cellular and epigenetic drivers of stem cell ageing.
Ermolaeva, Maria; Neri, Francesco; Ori, Alessandro; Rudolph, K Lenhard
2018-06-01
Adult tissue stem cells have a pivotal role in tissue maintenance and regeneration throughout the lifespan of multicellular organisms. Loss of tissue homeostasis during post-reproductive lifespan is caused, at least in part, by a decline in stem cell function and is associated with an increased incidence of diseases. Hallmarks of ageing include the accumulation of molecular damage, failure of quality control systems, metabolic changes and alterations in epigenome stability. In this Review, we discuss recent evidence in support of a novel concept whereby cell-intrinsic damage that accumulates during ageing and cell-extrinsic changes in ageing stem cell niches and the blood result in modifications of the stem cell epigenome. These cumulative epigenetic alterations in stem cells might be the cause of the deregulation of developmental pathways seen during ageing. In turn, they could confer a selective advantage to mutant and epigenetically drifted stem cells with altered self-renewal and functions, which contribute to the development of ageing-associated organ dysfunction and disease.
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With Gottlieb beyond Gottlieb: The Role of Epigenetics in Psychobiological Development
ERIC Educational Resources Information Center
Lux, Vanessa
2013-01-01
The emerging field of molecular epigenetics studies relatively stable changes in genetic activity that are not due to changes in the DNA sequence. Initial research results indicate a functional role for epigenetic mechanisms in neuron development and neuronal cell function. However, concepts that integrate these findings in an overall theory of…
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The Art of Interpreting Epigenetic Activity | Center for Cancer Research
Even though all the cells of the human body share a common genomic blueprint, epigenetic activity such as DNA methylation, introduces molecular diversity that results in functionally and biologically different cellular constituents. In cancers, this ability of epigenetic activity to introduce molecular diversity is emerging as a powerful classifier of biological aggressiveness.
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Genetic and epigenetic variation in the lineage specification of regulatory T cells
Arvey, Aaron; van der Veeken, Joris; Plitas, George; Rich, Stephen S; Concannon, Patrick; Rudensky, Alexander Y
2015-01-01
Regulatory T (Treg) cells, which suppress autoimmunity and other inflammatory states, are characterized by a distinct set of genetic elements controlling their gene expression. However, the extent of genetic and associated epigenetic variation in the Treg cell lineage and its possible relation to disease states in humans remain unknown. We explored evolutionary conservation of regulatory elements and natural human inter-individual epigenetic variation in Treg cells to identify the core transcriptional control program of lineage specification. Analysis of single nucleotide polymorphisms in core lineage-specific enhancers revealed disease associations, which were further corroborated by high-resolution genotyping to fine map causal polymorphisms in lineage-specific enhancers. Our findings suggest that a small set of regulatory elements specify the Treg lineage and that genetic variation in Treg cell-specific enhancers may alter Treg cell function contributing to polygenic disease. DOI: http://dx.doi.org/10.7554/eLife.07571.001 PMID:26510014
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Past, present, and future of epigenetics applied to livestock breeding
González-Recio, Oscar; Toro, Miguel A.; Bach, Alex
2015-01-01
This article reviews the concept of Lamarckian inheritance and the use of the term epigenetics in the field of animal genetics. Epigenetics was first coined by Conrad Hal Waddington (1905–1975), who derived the term from the Aristotelian word epigenesis. There exists some controversy around the word epigenetics and its broad definition. It includes any modification of the expression of genes due to factors other than mutation in the DNA sequence. This involves DNA methylation, post-translational modification of histones, but also linked to regulation of gene expression by non-coding RNAs, genome instabilities or any other force that could modify a phenotype. There is little evidence of the existence of transgenerational epigenetic inheritance in mammals, which may commonly be confounded with environmental forces acting simultaneously on an individual, her developing fetus and the germ cell lines of the latter, although it could have an important role in the cellular energetic status of cells. Finally, we review some of the scarce literature on the use of epigenetics in animal breeding programs. PMID:26442117
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Guerrero-Bosagna, Carlos; Savenkova, Marina; Haque, Md. Muksitul; Nilsson, Eric; Skinner, Michael K.
2013-01-01
Environmental toxicants have been shown to induce the epigenetic transgenerational inheritance of adult onset disease, including testis disease and male infertility. The current study was designed to determine the impact of an altered sperm epigenome on the subsequent development of an adult somatic cell (Sertoli cell) that influences the onset of a specific disease (male infertility). A gestating female rat (F0 generation) was exposed to the agriculture fungicide vinclozolin during gonadal sex determination and then the subsequent F3 generation progeny used for the isolation of Sertoli cells and assessment of testis disease. As previously observed, enhanced spermatogenic cell apoptosis was observed. The Sertoli cells provide the physical and nutritional support for the spermatogenic cells. Over 400 genes were differentially expressed in the F3 generation control versus vinclozolin lineage Sertoli cells. A number of specific cellular pathways were identified to be transgenerationally altered. One of the key metabolic processes affected was pyruvate/lactate production that is directly linked to spermatogenic cell viability. The Sertoli cell epigenome was also altered with over 100 promoter differential DNA methylation regions (DMR) modified. The genomic features and overlap with the sperm DMR were investigated. Observations demonstrate that the transgenerational sperm epigenetic alterations subsequently alters the development of a specific somatic cell (Sertoli cell) epigenome and transcriptome that correlates with adult onset disease (male infertility). The environmentally induced epigenetic transgenerational inheritance of testis disease appears to be a component of the molecular etiology of male infertility. PMID:23555832
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Matsukura, Hiroshi, E-mail: hmatsukura.epi@mri.tmd.ac.jp; Aisaki, Ken-ichi; Igarashi, Katsuhide
2011-08-26
Highlights: {yields} Genistein (GEN) is a phytoestrogen found in soy products. {yields} GEN demethylated/unsilenced the steroidogenic factor 1 gene in endometrial tissue. {yields} GEN thus altered mRNA expression in uteri of ovariectomized (OVX) mice. {yields} A high-resolution melting assay was used to screen for epigenetic change. {yields} We isolated an endometrial cell clone that was epigenetically modulated by GEN. -- Abstract: It has recently been demonstrated that genistein (GEN), a phytoestrogen in soy products, is an epigenetic modulator in various types of cells; but its effect on endometrium has not yet been determined. We investigated the effects of GEN onmore » mouse uterine cells, in vivo and in vitro. Oral administration of GEN for 1 week induced mild proliferation of the endometrium in ovariectomized (OVX) mice, which was accompanied by the induction of steroidogenic factor 1 (SF-1) gene expression. GEN administration induced demethylation of multiple CpG sites in the SF-1 promoter; these sites are extensively methylated and thus silenced in normal endometrium. The GEN-mediated promoter demethylation occurred predominantly on the luminal side, as opposed to myometrium side, indicating that the epigenetic change was mainly shown in regenerated cells. Primary cultures of endometrial stromal cell colonies were screened for GEN-mediated alterations of DNA methylation by a high-resolution melting (HRM) method. One out of 20 colony-forming cell clones showed GEN-induced demethylation of SF-1. This clone exhibited a high proliferation capacity with continuous colony formation activity through multiple serial clonings. We propose that only a portion of endometrial cells are capable of receiving epigenetic modulation by GEN.« less
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Zhang, Shirong; Wu, Kan; Feng, Jianguo; Wu, Zhibing; Deng, Qinghua; Guo, Chao; Xia, Bing; Zhang, Jing; Huang, Haixiu; Zhu, Lucheng; Zhang, Ke; Shen, Binghui; Chen, Xufeng; Ma, Shenglin
2016-10-18
Metastasis is the reason for most cancer death, and a crucial primary step for cancer metastasis is invasion of the surrounding tissue, which may be initiated by some rare tumor cells that escape the heterogeneous primary tumor. In this study, we isolated invasive subpopulations of cancer cells from human non-small cell lung cancer (NSCLC) H460 and H1299 cell lines, and determined the gene expression profiles and the responses of these invasive cancer cells to treatments of ionizing radiation and chemotherapeutic agents. The subpopulation of highly invasive NSCLC cells showed epigenetic signatures of epithelial-mesenchymal transition, cancer cell stemness, increased DNA damage repair and cell survival signaling. We also investigated the epigenetic therapy potential of suberoylanilide hydroxamic acid (SAHA) on invasive cancer cells, and found that SAHA suppresses cancer cell invasiveness and sensitizes cancer cells to treatments of IR and chemotherapeutic agents. Our results provide guidelines for identification of metastatic predictors and for clinical management of NSCLC. This study also suggests a beneficial clinical potential of SAHA as a chemotherapeutic agent for NSCLC patients.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Vaid, Mudit; Prasad, Ram; Singh, Tripti
Grape seed proanthocyanidins (GSPs) have been shown to have anti-skin carcinogenic effects in in vitro and in vivo models. However, the precise epigenetic molecular mechanisms remain unexplored. This study was designed to investigate whether GSPs reactivate silenced tumor suppressor genes following epigenetic modifications in skin cancer cells. For this purpose, A431 and SCC13 human squamous cell carcinoma cell lines were used as in vitro models. The effects of GSPs on DNA methylation, histone modifications and tumor suppressor gene expressions were studied in these cell lines using enzyme activity assays, western blotting, dot-blot analysis and real-time polymerase chain reaction (RT-PCR). Wemore » found that treatment of A431 and SCC13 cells with GSPs decreased the levels of: (i) global DNA methylation, (ii) 5-methylcytosine, (iii) DNA methyltransferase (DNMT) activity and (iv) messenger RNA (mRNA) and protein levels of DNMT1, DNMT3a and DNMT3b in these cells. Similar effects were noted when these cancer cells were treated identically with 5-aza-2′-deoxycytidine, an inhibitor of DNA methylation. GSPs decreased histone deacetylase activity, increased levels of acetylated lysines 9 and 14 on histone H3 (H3-Lys 9 and 14) and acetylated lysines 5, 12 and 16 on histone H4, and reduced the levels of methylated H3-Lys 9. Further, GSP treatment resulted in re-expression of the mRNA and proteins of silenced tumor suppressor genes, RASSF1A, p16{sup INK4a} and Cip1/p21. Together, this study provides a new insight into the epigenetic mechanisms of GSPs and may have significant implications for epigenetic therapy in the treatment/prevention of skin cancers in humans. -- Highlights: ►Epigenetic modulations have been shown to have a role in cancer risk. ►Proanthocyanidins decrease the levels of DNA methylation and histone deacetylation. ►Proanthocyanidins inhibit histone deacetylase activity in skin cancer cells. ►Proanthocyanidins reactivate tumor suppressor genes in skin cancer cells. ►Grape seed proanthocyanidins can prevent skin cancer through epigenetic modulation.« less
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Iriyama, Chisako; Tomita, Akihiro, E-mail: atomita@med.nagoya-u.ac.jp; Hoshino, Hideaki
2012-03-23
Highlights: Black-Right-Pointing-Pointer Circulating DNAs (CDs) can be used to detect genetic/epigenetic abnormalities in MDS. Black-Right-Pointing-Pointer Epigenetic changes can be detected more sensitively when using plasma DNA than PBMNC. Black-Right-Pointing-Pointer Mutation ratio in CDs may reflect the ratio in stem cell population in bone marrow. Black-Right-Pointing-Pointer Using CDs can be a safer alternate strategy compared to bone marrow aspiration. -- Abstract: Myelodysplastic syndrome (MDS) is a hematopoietic stem cell disorder. Several genetic/epigenetic abnormalities are deeply associated with the pathogenesis of MDS. Although bone marrow (BM) aspiration is a common strategy to obtain MDS cells for evaluating their genetic/epigenetic abnormalities, BM aspirationmore » is difficult to perform repeatedly to obtain serial samples because of pain and safety concerns. Here, we report that circulating cell-free DNAs from plasma and serum of patients with MDS can be used to detect genetic/epigenetic abnormalities. The plasma DNA concentration was found to be relatively high in patients with higher blast cell counts in BM, and accumulation of DNA fragments from mono-/di-nucleosomes was confirmed. Using serial peripheral blood (PB) samples from patients treated with hypomethylating agents, global methylation analysis using bisulfite pyrosequencing was performed at the specific CpG sites of the LINE-1 promoter. The results confirmed a decrease of the methylation percentage after treatment with azacitidine (days 3-9) using DNAs from plasma, serum, and PB mono-nuclear cells (PBMNC). Plasma DNA tends to show more rapid change at days 3 and 6 compared with serum DNA and PBMNC. Furthermore, the TET2 gene mutation in DNAs from plasma, serum, and BM cells was quantitated by pyrosequencing analysis. The existence ratio of mutated genes in plasma and serum DNA showed almost equivalent level with that in the CD34+/38- stem cell population in BM. These data suggest that genetic/epigenetic analyses using PB circulating DNA can be a safer and painless alternative to using BM cells.« less
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Preethi, Jayakumar; Singh, Hemant K.; Rajan, Koilmani E.
2016-01-01
Bacopa monniera extract (CDRI-08; BME) has been known to improve learning and memory, and understanding the molecular mechanisms may help to know its specificity. We investigated whether the BME treatment alters the methylation status of reelin and brain-derived neurotropic factor (BDNF) to enhance the memory through the interaction of N-methyl-D-aspartate receptor (NMDAR) with synaptic proteins. Rat pups were subjected to novel object recognition test following daily oral administration of BME (80 mg/kg) in 0.5% gum acacia (per-orally, p.o.; PND 15–29)/three doses of 5-azacytidine (5-azaC; 3.2 mg/kg) in 0.9% saline (intraperitoneally, i.p.) on PND-30. After the behavioral test, methylation status of reelin, BDNF and activation of NMDAR, and its interactions with synaptic proteins were tested. Rat pups treated with BME/5-azaC showed higher discrimination towards novel objects than with old objects during testing. Further, we observed an elevated level of unmethylated DNA in reelin and BDNF promoter region. Up-regulated reelin along with the splice variant of apolipoprotein E receptor 2 (ApoER 2, ex 19) form a cluster and activate NMDAR through disabled adopter protein-1 (DAB1) to enhance BDNF. Observed results suggest that BME regulate reelin epigenetically, which might enhance NMDAR interactions with synaptic proteins and induction of BDNF. These changes may be linked with improved novel object recognition memory. PMID:27445807
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Tomizawa, H; Matsuzawa, D; Ishii, D; Matsuda, S; Kawai, K; Mashimo, Y; Sutoh, C; Shimizu, E
2015-03-01
DNA methylation is one of the essential factors in the control of gene expression. Alteration of the DNA methylation pattern has been linked to various neurological, behavioral and neurocognitive dysfunctions. Recent studies have pointed out the importance of epigenetics in brain development and functions including learning and memory. Nutrients related to one-carbon metabolism are known to play important roles in the maintenance of genomic DNA methylation. Previous studies have shown that the long-term administration of a diet lacking essential one-carbon nutrients such as methionine, choline and folic acid (methyl donors) caused global DNA hypermethylation in the brain. Therefore, the long-term feeding of a methyl-donor-deficient diet may cause abnormal brain development including learning and memory. To confirm this hypothesis, 3-week-old mice were maintained on a folate-, methionine- and choline-deficient (FMCD) or control (CON) diet for 3 weeks. We found that the methyl-donor deficiency impaired both novel object recognition and fear extinction after 3 weeks of treatment. The FMCD group showed spontaneous recovery of fear that differed from that in CON. In addition, we found decreased Gria1 gene expression and specific CpG hypermethylation of the Gria1 promoter region in the FMCD hippocampus. Our data suggest that a chronic dietary lack of methyl donors in the developmental period affects learning, memory and gene expressions in the hippocampus. © 2015 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.
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Steinritz, Dirk; Schmidt, Annette; Balszuweit, Frank; Thiermann, Horst; Simons, Thilo; Striepling, Enno; Bölck, Birgit; Bloch, Wilhelm
2016-02-26
Victims that were exposed to the chemical warfare agent sulfur mustard (SM) suffer from chronic dermal and ocular lesions, severe pulmonary problems and cancer development. It has been proposed that epigenetic perturbations might be involved in that process but this has not been investigated so far. In this study, we investigated epigenetic modulations in vitro using early endothelial cells (EEC) that were exposed to different SM concentrations (0.5, 1.0, 23.5 and 50μM). A comprehensive analysis of 78 genes related to epigenetic pathways (i.e., DNA-methylation and post-translational histone modifications) was performed. Moreover, we analyzed global DNA methylation in vitro in EEC after SM exposure as a maker for epigenetic modulations and in vivo using human skin samples that were obtained from a patient 1 year after an accidently exposure to pure SM. SM exposure resulted in a complex regulation pattern of epigenetic modulators which was accompanied by a global increase of DNA methylation in vitro. Examination of the SM exposed human skin samples also revealed a significant increase of global DNA methylation in vivo, underlining the biological relevance of our findings. Thus, we demonstrated for the first time that SM affects epigenetic pathways and causes epigenetic modulations both in vivo and in vitro. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
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Shen, Siming; Casaccia-Bonnefil, Patrizia
2008-01-01
The role of epigenetics in modulating gene expression in the development of organs and tissues and in disease states is becoming increasingly evident. Epigenetics refers to the several mechanisms modulating inheritable changes in gene expression that are independent of modifications of the primary DNA sequence and include post-translational modifications of nucleosomal histones, changes in DNA methylation, and the role of microRNA. This review focuses on the epigenetic regulation of gene expression in oligodendroglial lineage cells. The biological effects that post-translational modifications of critical residues in the N-terminal tails of nucleosomal histones have on oligodendroglial cells are reviewed, and the implications for disease and repair are critically discussed. PMID:17999198
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Applications of alignment-free methods in epigenomics.
Pinello, Luca; Lo Bosco, Giosuè; Yuan, Guo-Cheng
2014-05-01
Epigenetic mechanisms play an important role in the regulation of cell type-specific gene activities, yet how epigenetic patterns are established and maintained remains poorly understood. Recent studies have supported a role of DNA sequences in recruitment of epigenetic regulators. Alignment-free methods have been applied to identify distinct sequence features that are associated with epigenetic patterns and to predict epigenomic profiles. Here, we review recent advances in such applications, including the methods to map DNA sequence to feature space, sequence comparison and prediction models. Computational studies using these methods have provided important insights into the epigenetic regulatory mechanisms.
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Epigenetic Mistakes in Neurodevelopmental Disorders.
Mastrototaro, Giuseppina; Zaghi, Mattia; Sessa, Alessandro
2017-04-01
Epigenetics is the array of the chromatin modifications that customize in cell-, stage-, or condition-specific manner the information encloses in plain DNA molecules. Increasing evidences suggest the importance of epigenetic mechanisms for development and maintenance of central nervous system. In fact, a large number of newly discovered genetic causes of neurodevelopmental disorders such as intellectual disability, autism spectrum disorders, and many other syndromes are mutations within genes encoding for chromatin remodeling enzymes. Here, we review recent findings on the epigenetic origin of human diseases, with emphasis on disorders that affect development of the nervous system, and discuss novel therapeutic avenues that target epigenetic mechanisms.
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Intratumoral heterogeneity of the epigenome
Song, Jun S.; Costello, Joseph F.
2016-01-01
Investigation into intratumoral heterogeneity (ITH) of the epigenome is in a formative stage. The patterns of tumor evolution inferred from epigenetic ITH and genetic ITH are remarkably similar, suggesting widespread co-dependency of these disparate mechanisms. The biological and clinical relevance of epigenetic ITH are becoming more apparent. Rare tumor cells with unique and reversible epigenetic states may drive drug resistance, and the degree of epigenetic ITH at diagnosis may predict patient outcome. This perspective presents these current concepts and clinical implications of epigenetic ITH, and the experimental and computational techniques at the forefront of ITH exploration. PMID:27070699
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Epigenetic restriction of embryonic cell lineage fate by methylation of Elf5
Ng, Ray Kit; Dean, Wendy; Dawson, Claire; Lucifero, Diana; Madeja, Zofia; Reik, Wolf; Hemberger, Myriam
2008-01-01
Mouse ES cells can differentiate into all three germ layers of the embryo but are generally excluded from the trophoblast lineage. Here we show that ES cells deficient in DNA methylation can differentiate efficiently into trophoblast derivatives. In a genome-wide screen we identify the transcription factor Elf5 as methylated and repressed in ES cells, and hypomethylated and expressed in TS and methylation-deficient ES cells. Elf5 creates a positive feedback loop with TS cell determinants Cdx2 and Eomes that is restricted to the trophoblast lineage by epigenetic regulation of Elf5. Importantly, the late-acting function of Elf5 allows initial plasticity and regulation in the early blastocyst. Thus, Elf5 acts downstream of initial lineage determination as a gatekeeper to reinforce commitment to the trophoblast lineage, or to abort this pathway in epiblast cells. This epigenetic restriction of cell lineage fate provides a molecular mechanism for Waddington’s concept of canalization of developmental pathways. PMID:18836439
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Bistability, epigenetics, and bet-hedging in bacteria.
Veening, Jan-Willem; Smits, Wiep Klaas; Kuipers, Oscar P
2008-01-01
Clonal populations of microbial cells often show a high degree of phenotypic variability under homogeneous conditions. Stochastic fluctuations in the cellular components that determine cellular states can cause two distinct subpopulations, a property called bistability. Phenotypic heterogeneity can be readily obtained by interlinking multiple gene regulatory pathways, effectively resulting in a genetic logic-AND gate. Although switching between states can occur within the cells' lifetime, cells can also pass their cellular state over to the next generation by a mechanism known as epigenetic inheritance and thus perpetuate the phenotypic state. Importantly, heterogeneous populations can demonstrate increased fitness compared with homogeneous populations. This suggests that microbial cells employ bet-hedging strategies to maximize survival. Here, we discuss the possible roles of interlinked bistable networks, epigenetic inheritance, and bet-hedging in bacteria.
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The many faces of REST oversee epigenetic programming of neuronal genes.
Ballas, Nurit; Mandel, Gail
2005-10-01
Nervous system development relies on a complex signaling network to engineer the orderly transitions that lead to the acquisition of a neural cell fate. Progression from the non-neuronal pluripotent stem cell to a restricted neural lineage is characterized by distinct patterns of gene expression, particularly the restriction of neuronal gene expression to neurons. Concurrently, cells outside the nervous system acquire and maintain a non-neuronal fate that permanently excludes expression of neuronal genes. Studies of the transcriptional repressor REST, which regulates a large network of neuronal genes, provide a paradigm for elucidating the link between epigenetic mechanisms and neurogenesis. REST orchestrates a set of epigenetic modifications that are distinct between non-neuronal cells that give rise to neurons and those that are destined to remain as nervous system outsiders.
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Translational epigenetics: clinical approaches to epigenome therapeutics for cancer.
Selcuklu, S Duygu; Spillane, Charles
2008-01-01
Cancer epigenetics research is now entering an exciting phase of translational epigenetics whereby novel epigenome therapeutics is being developed for application in clinical settings. Epigenetics refers to all heritable and potentially reversible changes in gene or genome functioning that occurs without altering the nucleotide sequence of the DNA. A range of different epigenetic "marks" can activate or repress gene expression. While epigenetic alterations are associated with most cancers, epigenetic dysregulation can also have a causal role in cancer etiology. Epigenetically disrupted stem or progenitor cells could have an early role in neoplastic transformations, while perturbance of epigenetic regulatory mechanisms controlling gene expression in cancer-relevant pathways will also be a contribution factor. The reversibility of epigenetic marks provides the possibility that the activity of key cancer genes and pathways can be regulated as a therapeutic approach. The growing availability of a range of chemical agents which can affect epigenome functioning has led to a range of epigenetic-therapeutic approaches for cancer and intense interest in the development of second-generation epigenetic drugs (epi-drugs) which would have greater specificity and efficacy in clinical settings. The latest developments in this exciting arena of translational cancer epigenetics were presented at a recent conference on "Epigenetics and New Therapies in Cancer" at the Spanish National Cancer Research Center (CNIO), Spain.
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ERK/MAPK Regulates Hippocampal Histone Phosphorylation Following Contextual Fear Conditioning
ERIC Educational Resources Information Center
Levenson, Jonathan M.; Sweatt, J. David; Chwang, Wilson B.; O'Riordan, Kenneth J.
2006-01-01
Long-term memory formation is regulated by many distinct molecular mechanisms that control gene expression. An emerging model for effecting a stable, coordinated pattern of gene transcription involves epigenetic tagging through modifications of histones or DNA. In this study, we investigated the regulation of histone phosphorylation in the…
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Chacon, Jessica Ann; Schutsky, Keith; Powell, Daniel J
2016-11-14
Genomic destabilizers, such as radiation and chemotherapy, and epigenetic modifiers are used for the treatment of cancer due to their apoptotic effects on the aberrant cells. However, these therapies may also induce widespread changes within the immune system and cancer cells, which may enable tumors to avoid immune surveillance and escape from host anti-tumor immunity. Genomic destabilizers can induce immunogenic death of tumor cells, but also induce upregulation of immune inhibitory ligands on drug-resistant cells, resulting in tumor progression. While administration of immunomodulatory antibodies that block the interactions between inhibitory receptors on immune cells and their ligands on tumor cells can mediate cancer regression in a subset of treated patients, it is crucial to understand how genomic destabilizers alter the immune system and malignant cells, including which inhibitory molecules, receptors and/or ligands are upregulated in response to genotoxic stress. Knowledge gained in this area will aid in the rational design of trials that combine genomic destabilizers, epigenetic modifiers and immunotherapeutic agents that may be synergized to improve clinical responses and prevent tumor escape from the immune system. Our review article describes the impact genomic destabilizers, such as radiation and chemotherapy, and epigenetic modifiers have on anti-tumor immunity and the tumor microenvironment. Although genomic destabilizers cause DNA damage on cancer cells, these therapies can also have diverse effects on the immune system, promote immunogenic cell death or survival and alter the cancer cell expression of immune inhibitor molecules.
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Induced Pluripotent Stem (iPS) Cells in Dentistry: A Review
Malhotra, Neeraj
2016-01-01
iPS cells are derived from somatic cells via transduction and expression of selective transcription factors. Both viral-integrating (like retroviral) and non-integrating (like, mRNA or protein-based) techniques are available for the production of iPS cells. In the field of dentistry, iPS cells have been derived from stem cells of apical papilla, dental pulp stem cells, and stem cells from exfoliated deciduous teeth, gingival and periodontal ligament fibroblasts, and buccal mucosa fibroblasts. iPS cells have the potential to differentiate into all derivatives of the 3 primary germ layers i.e. ectoderm, endoderm, and mesoderm. They are autogeneically accessible, and can produce patient-specific or disease-specific cell lines without the issue of ethical controversy. They have been successfully tested to produce mesenchymal stem cells-like cells, neural crest-like cells, ameloblasts-like cells, odontoblasts-like cells, and osteoprogenitor cells. These cells can aid in regeneration of periodontal ligament, alveolar bone, cementum, dentin-pulp complex, as well as possible Biotooth formation. However certain key issues like, epigenetic memory of iPS cells, viral-transduction, tumorgenesis and teratoma formation need to be overcome, before they can be successfully used in clinical practice. The article discusses the sources, pros and cons, and current applications of iPS cells in dentistry with an emphasis on encountered challenges and their solutions. PMID:27572712
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The inactive X chromosome is epigenetically unstable and transcriptionally labile in breast cancer.
Chaligné, Ronan; Popova, Tatiana; Mendoza-Parra, Marco-Antonio; Saleem, Mohamed-Ashick M; Gentien, David; Ban, Kristen; Piolot, Tristan; Leroy, Olivier; Mariani, Odette; Gronemeyer, Hinrich; Vincent-Salomon, Anne; Stern, Marc-Henri; Heard, Edith
2015-04-01
Disappearance of the Barr body is considered a hallmark of cancer, although whether this corresponds to genetic loss or to epigenetic instability and transcriptional reactivation is unclear. Here we show that breast tumors and cell lines frequently display major epigenetic instability of the inactive X chromosome, with highly abnormal 3D nuclear organization and global perturbations of heterochromatin, including gain of euchromatic marks and aberrant distributions of repressive marks such as H3K27me3 and promoter DNA methylation. Genome-wide profiling of chromatin and transcription reveal modified epigenomic landscapes in cancer cells and a significant degree of aberrant gene activity from the inactive X chromosome, including several genes involved in cancer promotion. We demonstrate that many of these genes are aberrantly reactivated in primary breast tumors, and we further demonstrate that epigenetic instability of the inactive X can lead to perturbed dosage of X-linked factors. Taken together, our study provides the first integrated analysis of the inactive X chromosome in the context of breast cancer and establishes that epigenetic erosion of the inactive X can lead to the disappearance of the Barr body in breast cancer cells. This work offers new insights and opens up the possibility of exploiting the inactive X chromosome as an epigenetic biomarker at the molecular and cytological levels in cancer. © 2015 Chaligné et al.; Published by Cold Spring Harbor Laboratory Press.
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Landscaping the epigenetic landscape of cancer.
Aranda-Anzaldo, Armando; Dent, Myrna A R
2018-06-08
Waddington's epigenetic landscape was introduced in biology for understanding the complex process of metazoan development in an accessible fashion. The epigenetic landscape concept implies the coupling of cell differentiation and tissue/organ morphogenesis under a simple visual metaphor or analogy with significant heuristic value. Yet in recent times the epigenetic landscape has been reduced to an illustration device just for cell differentiation thus diminishing its explanatory power and heuristic value. On the other hand, the current mainstream in cancer research is concentrated on the search for proximate causes but not on achieving a deeper understanding of the phenomenon. Nevertheless an emerging alternative perspective that understands cancer as a problem related to tissue/organ morphology and structural organization is getting wider attention. Within such a perspective here we present and discuss a historically restored, non-reductionist, version of the epigenetic landscape that when applied to the problem of cancer improves our understanding of it as a common biological phenomenon resulting from the uncoupling of morphogenesis and cell differentiation as a consequence of the progressive erosion of the epigenetic landscape. The following discussion aims at finding a general framework, not dependent on proximate causes, for understanding the phenomenon of cancer and suggests new research strategies on this problem but away from the current emphasis on the putative genetic causes of cancer. Copyright © 2018 Elsevier Ltd. All rights reserved.
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Epigenetic Therapy for Friedreich Ataxia
Soragni, Elisabetta; Miao, Wenyan; Iudicello, Marco; Jacoby, David; De Mercanti, Stefania; Clerico, Marinella; Longo, Filomena; Piga, Antonio; Ku, Sherman; Campau, Erica; Du, Jintang; Penalver, Pablo; Rai, Myriam; Madara, Joseph C.; Nazor, Kristopher; O’Connor, Melinda; Maximov, Anton; Loring, Jeanne F.; Pandolfo, Massimo; Durelli, Luca; Gottesfeld, Joel M.; Rusche, James R.
2015-01-01
Objective To investigate whether a histone deacetylase inhibitor (HDACi) would be effective in an in vitro model for the neurodegenerative disease Friedreich ataxia (FRDA) and to evaluate safety and surrogate markers of efficacy in a phase I clinical trial in patients. Methods We used a human FRDA neuronal cell model, derived from patient induced pluripotent stem cells, to determine the efficacy of a 2-aminobenzamide HDACi (109) as a modulator of FXN gene expression and chromatin histone modifications. FRDA patients were dosed in 4 cohorts, ranging from 30mg/day to 240mg/day of the formulated drug product of HDACi 109, RG2833. Patients were monitored for adverse effects as well as for increases in FXN mRNA, frataxin protein, and chromatin modification in blood cells. Results In the neuronal cell model, HDACi 109/RG2833 increases FXN mRNA levels and frataxin protein, with concomitant changes in the epigenetic state of the gene. Chromatin signatures indicate that histone H3 lysine 9 is a key residue for gene silencing through methylation and reactivation through acetylation, mediated by the HDACi. Drug treatment in FRDA patients demonstrated increased FXN mRNA and H3 lysine 9 acetylation in peripheral blood mononuclear cells. No safety issues were encountered. Interpretation Drug exposure inducing epigenetic changes in neurons in vitro is comparable to the exposure required in patients to see epigenetic changes in circulating lymphoid cells and increases in gene expression. These findings provide a proof of concept for the development of an epigenetic therapy for this fatal neurological disease. PMID:25159818
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Epigenetic modulation of dental pulp stem cells: implications for regenerative endodontics.
Duncan, H F; Smith, A J; Fleming, G J P; Cooper, P R
2016-05-01
Dental pulp stem cells (DPSCs) offer significant potential for use in regenerative endodontics, and therefore, identifying cellular regulators that control stem cell fate is critical to devising novel treatment strategies. Stem cell lineage commitment and differentiation are regulated by an intricate range of host and environmental factors of which epigenetic influence is considered vital. Epigenetic modification of DNA and DNA-associated histone proteins has been demonstrated to control cell phenotype and regulate the renewal and pluripotency of stem cell populations. The activities of the nuclear enzymes, histone deacetylases, are increasingly being recognized as potential targets for pharmacologically inducing stem cell differentiation and dedifferentiation. Depending on cell maturity and niche in vitro, low concentration histone deacetylase inhibitor (HDACi) application can promote dedifferentiation of several post-natal and mouse embryonic stem cell populations and conversely increase differentiation and accelerate mineralization in DPSC populations, whilst animal studies have shown an HDACi-induced increase in stem cell marker expression during organ regeneration. Notably, both HDAC and DNA methyltransferase inhibitors have also been demonstrated to dramatically increase the reprogramming of somatic cells to induced pluripotent stem cells (iPSCs) for use in regenerative therapeutic procedures. As the regulation of cell fate will likely remain the subject of intense future research activity, this review aims to describe the current knowledge relating to stem cell epigenetic modification, focusing on the role of HDACi on alteration of DPSC phenotype, whilst presenting the potential for therapeutic application as part of regenerative endodontic regimens. © 2015 International Endodontic Journal. Published by John Wiley & Sons Ltd.
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Royston, Kendra J; Paul, Bidisha; Nozell, Susan; Rajbhandari, Rajani; Tollefsbol, Trygve O
2018-07-01
Little is known about the effects of combinatorial dietary compounds on the regulation of epigenetic mechanisms involved in breast cancer prevention. The human diet consists of a multitude of components, and there is a need to elucidate how certain compounds interact in collaboration. Withaferin A (WA), found in the Indian winter cherry and documented as a DNA methyltransferase (DNMT) inhibitor, and sulforaphane (SFN), a well-known histone deacetylase (HDAC) inhibitor found in cruciferous vegetables, are two epigenetic modifying compounds that have only recently been studied in conjunction. The use of DNMT and HDAC inhibitors to reverse the malignant expression of certain genes in breast cancer has shown considerable promise. Previously, we found that SFN + WA synergistically promote breast cancer cell death. Herein, we determined that these compounds inhibit cell cycle progression from S to G2 phase in MDA-MB-231 and MCF-7 breast cancer. Furthermore, we demonstrate that this unique combination of epigenetic modifying compounds down-regulates the levels of Cyclin D1 and CDK4, and pRB; conversely, the levels of E2F mRNA and tumor suppressor p21 are increased independently of p53. We find these events coincide with an increase in unrestricted histone methylation. We propose SFN + WA-induced breast cancer cell death is attributed, in part, to epigenetic modifications that result in the modulated expression of key genes responsible for the regulation of cancer cell senescence. Copyright © 2018 Elsevier Inc. All rights reserved.
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Epigenetic regulation of EFEMP1 in prostate cancer: biological relevance and clinical potential
Almeida, Mafalda; Costa, Vera L; Costa, Natália R; Ramalho-Carvalho, João; Baptista, Tiago; Ribeiro, Franclim R; Paulo, Paula; Teixeira, Manuel R; Oliveira, Jorge; Lothe, Ragnhild A; Lind, Guro E; Henrique, Rui; Jerónimo, Carmen
2014-01-01
Epigenetic alterations are common in prostate cancer (PCa) and seem to contribute decisively to its initiation and progression. Moreover, aberrant promoter methylation is a promising biomarker for non-invasive screening. Herein, we sought to characterize EFEMP1 as biomarker for PCa, unveiling its biological relevance in prostate carcinogenesis. Microarray analyses of treated PCa cell lines and primary tissues enabled the selection of differentially methylated genes, among which EFEMP1 was further validated by MSP and bisulfite sequencing. Assessment of biomarker performance was accomplished by qMSP. Expression analysis of EFEMP1 and characterization of histone marks were performed in tissue samples and cancer cell lines to determine the impact of epigenetic mechanisms on EFEMP1 transcriptional regulation. Phenotypic assays, using transfected cell lines, permitted the evaluation of EFEMP1’s role in PCa development. EFEMP1 methylation assay discriminated PCa from normal prostate tissue (NPT; P < 0.001, Kruskall–Wallis test) and renal and bladder cancers (96% sensitivity and 98% specificity). EFEMP1 transcription levels inversely correlated with promoter methylation and histone deacetylation, suggesting that both epigenetic mechanisms are involved in gene regulation. Phenotypic assays showed that EFEMP1 de novo expression reduces malignant phenotype of PCa cells. EFEMP1 promoter methylation is prevalent in PCa and accurately discriminates PCa from non-cancerous prostate tissues and other urological neoplasms. This epigenetic alteration occurs early in prostate carcinogenesis and, in association with histone deacetylation, progressively leads to gene down-regulation, fostering cell proliferation, invasion and evasion of apoptosis. PMID:25211630
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Wang, Pu; Zhang, Hao; Hou, Haoli; Wang, Qing; Li, Yingnan; Huang, Yan; Xie, Liangfu; Gao, Fei; He, Shibin; Li, Lijia
2016-07-01
Epigenetic modifications play crucial roles in the regulation of chromatin architecture and are involved in cell cycle progression, including mitosis and meiosis. To explore the relationship between epigenetic modifications and the cell cycle, we treated maize (Zea mays) seedlings with six different epigenetic modification-related inhibitors and identified the postsynthetic phase (G2 ) arrest via flow cytometry analysis. Total H4K5ac levels were significantly increased and the distribution of H3S10ph signalling was obviously changed in mitosis under various treatments. Further statistics of the cells in different periods of mitosis confirmed that the cell cycle was arrested at preprophase. Concentrations of hydrogen peroxide were relatively higher in the treated plants and the antioxidant thiourea could negate the influence of the inhibitors. Moreover, all of the treated plants displayed negative results in the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labelling (TUNEL) and γ-H2AX immunostaining assays after exposure for 3 d. Additionally, the expression level of topoisomerase genes in the treated plants was relatively lower than that in the untreated plants. These results suggest that these inhibitors of epigenetic modifications could cause preprophase arrest via reactive oxygen species formation inhibiting the expression of DNA topoisomerase genes, accompanied by changes in the H4K5ac and H3S10ph histone modifications. © 2016 The Authors. New Phytologist © 2016 New Phytologist Trust.
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Inflammation and epigenetic regulation in osteoarthritis
Shen, Jie; Abu-Amer, Yousef; O'Keefe, Regis J.; McAlinden, Audrey
2017-01-01
Osteoarthritis (OA) was once defined as a non-inflammatory arthropathy, but it is now well-recognized that there is a major inflammatory component to this disease. In addition to synovial cells, articular chondrocytes and other cells of diarthrodial joints are also known to express inflammatory mediators. It has been proposed that targeting inflammation pathways could be a promising strategy to treat OA. There have been many reports of cross-talk between inflammation and epigenetic factors in cartilage. Specifically, inflammatory mediators have been shown to regulate levels of enzymes that catalyze changes in DNA methylation and histone structure, as well as alter levels of non-coding RNAs. In addition, expression levels of a number of these epigenetic factors have been shown to be altered in OA, thereby suggesting potential interplay between inflammation and epigenetics in this disease. This review provides information on inflammatory pathways in arthritis and summarizes published research on how epigenetic regulators are affected by inflammation in chondrocytes. Furthermore, we discuss data showing how altered expression of some of these epigenetic factors can induce either catabolic or anti-catabolic effects in response to inflammatory signals. A better understanding of how inflammation affects epigenetic factors in OA may provide us with novel therapeutic strategies to treat this condition. PMID:27389927
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Pisanic, Thomas R.; Athamanolap, Pornpat; Poh, Weijie; Chen, Chen; Hulbert, Alicia; Brock, Malcolm V.; Herman, James G.; Wang, Tza-Huei
2015-01-01
Many cancers comprise heterogeneous populations of cells at primary and metastatic sites throughout the body. The presence or emergence of distinct subclones with drug-resistant genetic and epigenetic phenotypes within these populations can greatly complicate therapeutic intervention. Liquid biopsies of peripheral blood from cancer patients have been suggested as an ideal means of sampling intratumor genetic and epigenetic heterogeneity for diagnostics, monitoring and therapeutic guidance. However, current molecular diagnostic and sequencing methods are not well suited to the routine assessment of epigenetic heterogeneity in difficult samples such as liquid biopsies that contain intrinsically low fractional concentrations of circulating tumor DNA (ctDNA) and rare epigenetic subclonal populations. Here we report an alternative approach, deemed DREAMing (Discrimination of Rare EpiAlleles by Melt), which uses semi-limiting dilution and precise melt curve analysis to distinguish and enumerate individual copies of epiallelic species at single-CpG-site resolution in fractions as low as 0.005%, providing facile and inexpensive ultrasensitive assessment of locus-specific epigenetic heterogeneity directly from liquid biopsies. The technique is demonstrated here for the evaluation of epigenetic heterogeneity at p14ARF and BRCA1 gene-promoter loci in liquid biopsies obtained from patients in association with non-small cell lung cancer (NSCLC) and myelodysplastic/myeloproliferative neoplasms (MDS/MPN), respectively. PMID:26304549
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The Regulation of Transcription in Memory Consolidation
Alberini, Cristina M.; Kandel, Eric R.
2015-01-01
De novo transcription of DNA is a fundamental requirement for the formation of long-term memory. It is required during both consolidation and reconsolidation, the posttraining and postreactivation phases that change the state of the memory from a fragile into a stable and long-lasting form. Transcription generates both mRNAs that are translated into proteins, which are necessary for the growth of new synaptic connections, as well as noncoding RNA transcripts that have regulatory or effector roles in gene expression. The result is a cascade of events that ultimately leads to structural changes in the neurons that mediate long-term memory storage. The de novo transcription, critical for synaptic plasticity and memory formation, is orchestrated by chromatin and epigenetic modifications. The complexity of transcription regulation, its temporal progression, and the effectors produced all contribute to the flexibility and persistence of long-term memory formation. In this article, we provide an overview of the mechanisms contributing to this transcriptional regulation underlying long-term memory formation. PMID:25475090
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Modulation of learning and memory by cytokines: signaling mechanisms and long term consequences.
Donzis, Elissa J; Tronson, Natalie C
2014-11-01
This review describes the role of cytokines and their downstream signaling cascades on the modulation of learning and memory. Immune proteins are required for many key neural processes and dysregulation of these functions by systemic inflammation can result in impairments of memory that persist long after the resolution of inflammation. Recent research has demonstrated that manipulations of individual cytokines can modulate learning, memory, and synaptic plasticity. The many conflicting findings, however, have prevented a clear understanding of the precise role of cytokines in memory. Given the complexity of inflammatory signaling, understanding its modulatory role requires a shift in focus from single cytokines to a network of cytokine interactions and elucidation of the cytokine-dependent intracellular signaling cascades. Finally, we propose that whereas signal transduction and transcription may mediate short-term modulation of memory, long-lasting cellular and molecular mechanisms such as epigenetic modifications and altered neurogenesis may be required for the long lasting impact of inflammation on memory and cognition. Copyright © 2014 Elsevier Inc. All rights reserved.
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Primer in Genetics and Genomics, Article 6: Basics of Epigenetic Control.
Fessele, Kristen L; Wright, Fay
2018-01-01
The epigenome is a collection of chemical compounds that attach to and overlay the DNA sequence to direct gene expression. Epigenetic marks do not alter DNA sequence but instead allow or silence gene activity and the subsequent production of proteins that guide the growth and development of an organism, direct and maintain cell identity, and allow for the production of primordial germ cells (PGCs; ova and spermatozoa). The three main epigenetic marks are (1) histone modification, (2) DNA methylation, and (3) noncoding RNA, and each works in a different way to regulate gene expression. This article reviews these concepts and discusses their role in normal functions such as X-chromosome inactivation, epigenetic reprogramming during embryonic development and PGC production, and the clinical example of the imprinting disorders Angelman and Prader-Willi syndromes.
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Employing epigenetics to augment the expression of therapeutic proteins in mammalian cells.
Kwaks, Ted H J; Otte, Arie P
2006-03-01
Recombinant proteins form an increasingly large part of the portfolio of biopharmaceutical companies. Production of these often complex transgenic proteins is achieved predominantly in mammalian cell lines but the process is hampered by low yields and unstable expression. Some of these problems are caused by gene silencing at the level of chromatin - so-called epigenetic gene silencing. Here, we describe approaches, which have emerged during the past few years, designed to interfere with epigenetic gene silencing with the aim of enhancing and stabilizing transgene expression. These include targeting histones, the inclusion of specific DNA elements and targeting sites of high gene-expression. We conclude that employing epigenetic gene regulation tools, in combination with further process optimization, might represent the next step forward in the production of therapeutic proteins.
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Epigenetic regulation in allergic diseases and related studies
Kuo, Chang-Hung; Hsieh, Chong-Chao; Lee, Min-Sheng; Chang, Kai-Ting; Kuo, Hsuan-Fu
2014-01-01
Asthma, a chronic inflammatory disorder of the airway, has features of both heritability as well as environmental influences which can be introduced in utero exposures and modified through aging, and the features may attribute to epigenetic regulation. Epigenetic regulation explains the association between early prenatal maternal smoking and later asthma-related outcomes. Epigenetic marks (DNA methylation, modifications of histone tails or noncoding RNAs) work with other components of the cellular regulatory machinery to control the levels of expressed genes, and several allergy- and asthma-related genes have been found to be susceptible to epigenetic regulation, including genes important to T-effector pathways (IFN-γ, interleukin [IL] 4, IL-13, IL-17) and T-regulatory pathways (FoxP3). Therefore, the mechanism by which epigenetic regulation contributes to allergic diseases is a critical issue. In the past most published experimental work, with few exceptions, has only comprised small observational studies and models in cell systems and animals. However, very recently exciting and elegant experimental studies and novel translational research works were published with new and advanced technologies investigating epigenetic mark on a genomic scale and comprehensive approaches to data analysis. Interestingly, a potential link between exposure to environmental pollutants and the occurrence of allergic diseases is revealed recently, particular in developed and industrialized countries, and endocrine disrupting chemicals (EDCs) as environmental hormone may play a key role. This review addresses the important question of how EDCs (nonylphenol, 4 octylphenol, and phthalates) influences on asthma-related gene expression via epigenetic regulation in immune cells, and how anti-asthmatic agents prohibit expression of inflammatory genes via epigenetic modification. The discovery and validation of epigenetic biomarkers linking exposure to allergic diseases might lead to better epigenotyping of risk, prognosis, treatment prediction, and development of novel therapies. PMID:24527405
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Guo, Yue; Shu, Limin; Zhang, Chengyue; Su, Zheng-Yuan; Kong, Ah-Ng Tony
2015-03-15
Colorectal cancer remains the most prevalent malignancy in humans. The impact of epigenetic alterations on the development of this complex disease is now being recognized. The dynamic and reversible nature of epigenetic modifications makes them a promising target in colorectal cancer chemoprevention and treatment. Curcumin (CUR), the major component in Curcuma longa, has been shown as a potent chemopreventive phytochemical that modulates various signaling pathways. Deleted in lung and esophageal cancer 1 (DLEC1) is a tumor suppressor gene with reduced transcriptional activity and promoter hypermethylation in various cancers, including colorectal cancer. In the present study, we aimed to investigate the inhibitory role of DLEC1 in anchorage-independent growth of the human colorectal adenocarcinoma HT29 cells and epigenetic regulation by CUR. Specifically, we found that CUR treatment inhibited colony formation of HT29 cells, whereas stable knockdown of DLEC1 using lentiviral short hairpin RNA vector increased cell proliferation and colony formation. Knockdown of DLEC1 in HT29 cells attenuated the ability of CUR to inhibit anchorage-independent growth. Methylation-specific polymerase chain reaction (MSP), bisulfite genomic sequencing, and methylated DNA immunoprecipitation revealed that CUR decreased CpG methylation of the DLEC1 promoter in HT29 cells after 5 days of treatment, corresponding to increased mRNA expression of DLEC1. Furthermore, CUR decreased the protein expression of DNA methyltransferases and subtypes of histone deacetylases (HDAC4, 5, 6, and 8). Taken together, our results suggest that the inhibitory effect of CUR on anchorage-independent growth of HT29 cells could, at least in part, involve the epigenetic demethylation and up-regulation of DLEC1. Copyright © 2015 Elsevier Inc. All rights reserved.
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Stem Cell Technology for (Epi)genetic Brain Disorders.
Riemens, Renzo J M; Soares, Edilene S; Esteller, Manel; Delgado-Morales, Raul
2017-01-01
Despite the enormous efforts of the scientific community over the years, effective therapeutics for many (epi)genetic brain disorders remain unidentified. The common and persistent failures to translate preclinical findings into clinical success are partially attributed to the limited efficiency of current disease models. Although animal and cellular models have substantially improved our knowledge of the pathological processes involved in these disorders, human brain research has generally been hampered by a lack of satisfactory humanized model systems. This, together with our incomplete knowledge of the multifactorial causes in the majority of these disorders, as well as a thorough understanding of associated (epi)genetic alterations, has been impeding progress in gaining more mechanistic insights from translational studies. Over the last years, however, stem cell technology has been offering an alternative approach to study and treat human brain disorders. Owing to this technology, we are now able to obtain a theoretically inexhaustible source of human neural cells and precursors in vitro that offer a platform for disease modeling and the establishment of therapeutic interventions. In addition to the potential to increase our general understanding of how (epi)genetic alterations contribute to the pathology of brain disorders, stem cells and derivatives allow for high-throughput drugs and toxicity testing, and provide a cell source for transplant therapies in regenerative medicine. In the current chapter, we will demonstrate the validity of human stem cell-based models and address the utility of other stem cell-based applications for several human brain disorders with multifactorial and (epi)genetic bases, including Parkinson's disease (PD), Alzheimer's disease (AD), fragile X syndrome (FXS), Angelman syndrome (AS), Prader-Willi syndrome (PWS), and Rett syndrome (RTT).
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Shifting behaviour: epigenetic reprogramming in eusocial insects.
Patalano, Solenn; Hore, Timothy A; Reik, Wolf; Sumner, Seirian
2012-06-01
Epigenetic modifications are ancient and widely utilised mechanisms that have been recruited across fungi, plants and animals for diverse but fundamental biological functions, such as cell differentiation. Recently, a functional DNA methylation system was identified in the honeybee, where it appears to underlie queen and worker caste differentiation. This discovery, along with other insights into the epigenetics of social insects, allows provocative analogies to be drawn between insect caste differentiation and cellular differentiation, particularly in mammals. Developing larvae in social insect colonies are totipotent: they retain the ability to specialise as queens or workers, in a similar way to the totipotent cells of early embryos before they differentiate into specific cell lineages. Further, both differentiating cells and insect castes lose phenotypic plasticity by committing to their lineage, losing the ability to be readily reprogrammed. Hence, a comparison of the epigenetic mechanisms underlying lineage differentiation (and reprogramming) between cells and social insects is worthwhile. Here we develop a conceptual model of how loss and regain of phenotypic plasticity might be conserved for individual specialisation in both cells and societies. This framework forges a novel link between two fields of biological research, providing predictions for a unified approach to understanding the molecular mechanisms underlying biological complexity. Copyright © 2012 Elsevier Ltd. All rights reserved.
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Nuclear organization mediates cancer-compromised genetic and epigenetic control.
Zaidi, Sayyed K; Fritz, Andrew; Tracy, Kirsten; Gordon, Jonathan; Tye, Coralee; Boyd, Joseph; Van Wijnen, Andre; Nickerson, Jeffrey; Imbalzano, Anthony; Lian, Jane; Stein, Janet; Stein, Gary
2018-05-09
Nuclear organization is functionally linked to genetic and epigenetic regulation of gene expression for biological control and is modified in cancer. Nuclear organization supports cell growth and phenotypic properties of normal and cancer cells by facilitating physiologically responsive interactions of chromosomes, genes and regulatory complexes at dynamic three-dimensional microenvironments. We will review nuclear structure/function relationships that include: 1. Epigenetic bookmarking of genes by phenotypic transcription factors to control fidelity and plasticity of gene expression as cells enter and exit mitosis; 2. Contributions of chromatin remodeling to breast cancer nuclear morphology, metabolism and effectiveness of chemotherapy; 3. Relationships between fidelity of nuclear organization and metastasis of breast cancer to bone; 4. Dynamic modifications of higher-order inter- and intra-chromosomal interactions in breast cancer cells; 5. Coordinate control of cell growth and phenotype by tissue-specific transcription factors; 6. Oncofetal epigenetic control by bivalent histone modifications that are functionally related to sustaining the stem cell phenotype; and 7. Noncoding RNA-mediated regulation in the onset and progression of breast cancer. The discovery of components to nuclear organization that are functionally related to cancer and compromise gene expression have the potential for translation to innovative cancer diagnosis and targeted therapy. Copyright © 2018 Elsevier Ltd. All rights reserved.
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Metabolic and Epigenetic Coordination of T Cell and Macrophage Immunity.
Phan, Anthony T; Goldrath, Ananda W; Glass, Christopher K
2017-05-16
Recognition of pathogens by innate and adaptive immune cells instructs rapid alterations of cellular processes to promote effective resolution of infection. To accommodate increased bioenergetic and biosynthetic demands, metabolic pathways are harnessed to maximize proliferation and effector molecule production. In parallel, activation initiates context-specific gene-expression programs that drive effector functions and cell fates that correlate with changes in epigenetic landscapes. Many chromatin- and DNA-modifying enzymes make use of substrates and cofactors that are intermediates of metabolic pathways, providing potential cross talk between metabolism and epigenetic regulation of gene expression. In this review, we discuss recent studies of T cells and macrophages supporting a role for metabolic activity in integrating environmental signals with activation-induced gene-expression programs through modulation of the epigenome and speculate as to how this may influence context-specific macrophage and T cell responses to infection. Copyright © 2017 Elsevier Inc. All rights reserved.
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Metabolic and epigenetic coordination of T cell and Macrophage immunity
Phan, Anthony T.; Goldrath, Ananda W.; Glass, Christopher K.
2017-01-01
Recognition of pathogens by innate and adaptive immune cells instructs rapid alterations of cellular processes to promote effective resolution of infection. To accommodate increased bioenergetic and biosynthetic demands, metabolic pathways are harnessed to maximize proliferation and effector molecule production. In parallel, activation initiates context-specific gene-expression programs that drive effector functions and cell fates that correlate with changes in epigenetic landscapes. Many chromatin- and DNA-modifying enzymes make use of substrates and cofactors that are intermediates of metabolic pathways, providing potential cross talk between metabolism and epigenetic regulation of gene expression. In this review, we discuss recent studies of T cells and macrophages supporting a role for metabolic activity in integrating environmental signals with activation-induced gene-expression programs through modulation of the epigenome and speculate as to how this may influence context-specific macrophage and T cell responses to infection. PMID:28514673
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NFIB-mediated repression of the epigenetic factor Ezh2 regulates cortical development.
Piper, Michael; Barry, Guy; Harvey, Tracey J; McLeay, Robert; Smith, Aaron G; Harris, Lachlan; Mason, Sharon; Stringer, Brett W; Day, Bryan W; Wray, Naomi R; Gronostajski, Richard M; Bailey, Timothy L; Boyd, Andrew W; Richards, Linda J
2014-02-19
Epigenetic mechanisms are essential in regulating neural progenitor cell self-renewal, with the chromatin-modifying protein Enhancer of zeste homolog 2 (EZH2) emerging as a central player in promoting progenitor cell self-renewal during cortical development. Despite this, how Ezh2 is itself regulated remains unclear. Here, we demonstrate that the transcription factor nuclear factor IB (NFIB) plays a key role in this process. Nfib(-/-) mice exhibit an increased number of proliferative ventricular zone cells that express progenitor cell markers and upregulation of EZH2 expression within the neocortex and hippocampus. NFIB binds to the Ezh2 promoter and overexpression of NFIB represses Ezh2 transcription. Finally, key downstream targets of EZH2-mediated epigenetic repression are misregulated in Nfib(-/-) mice. Collectively, these results suggest that the downregulation of Ezh2 transcription by NFIB is an important component of the process of neural progenitor cell differentiation during cortical development.
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Cocaine Directly Impairs Memory Extinction and Alters Brain DNA Methylation Dynamics in Honey Bees.
Søvik, Eirik; Berthier, Pauline; Klare, William P; Helliwell, Paul; Buckle, Edwina L S; Plath, Jenny A; Barron, Andrew B; Maleszka, Ryszard
2018-01-01
Drug addiction is a chronic relapsing behavioral disorder. The high relapse rate has often been attributed to the perseverance of drug-associated memories due to high incentive salience of stimuli learnt under the influence of drugs. Drug addiction has also been interpreted as a memory disorder since drug associated memories are unusually enduring and some drugs, such as cocaine, interfere with neuroepigenetic machinery known to be involved in memory processing. Here we used the honey bee (an established invertebrate model for epigenomics and behavioral studies) to examine whether or not cocaine affects memory processing independently of its effect on incentive salience. Using the proboscis extension reflex training paradigm we found that cocaine strongly impairs consolidation of extinction memory. Based on correlation between the observed effect of cocaine on learning and expression of epigenetic processes, we propose that cocaine interferes with memory processing independently of incentive salience by directly altering DNA methylation dynamics. Our findings emphasize the impact of cocaine on memory systems, with relevance for understanding how cocaine can have such an enduring impact on behavior.
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Cocaine Directly Impairs Memory Extinction and Alters Brain DNA Methylation Dynamics in Honey Bees
Søvik, Eirik; Berthier, Pauline; Klare, William P.; Helliwell, Paul; Buckle, Edwina L. S.; Plath, Jenny A.; Barron, Andrew B.; Maleszka, Ryszard
2018-01-01
Drug addiction is a chronic relapsing behavioral disorder. The high relapse rate has often been attributed to the perseverance of drug-associated memories due to high incentive salience of stimuli learnt under the influence of drugs. Drug addiction has also been interpreted as a memory disorder since drug associated memories are unusually enduring and some drugs, such as cocaine, interfere with neuroepigenetic machinery known to be involved in memory processing. Here we used the honey bee (an established invertebrate model for epigenomics and behavioral studies) to examine whether or not cocaine affects memory processing independently of its effect on incentive salience. Using the proboscis extension reflex training paradigm we found that cocaine strongly impairs consolidation of extinction memory. Based on correlation between the observed effect of cocaine on learning and expression of epigenetic processes, we propose that cocaine interferes with memory processing independently of incentive salience by directly altering DNA methylation dynamics. Our findings emphasize the impact of cocaine on memory systems, with relevance for understanding how cocaine can have such an enduring impact on behavior. PMID:29487536
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Nanotechnology Approaches to Studying Epigenetic Changes in Cancer
NASA Astrophysics Data System (ADS)
Riehn, Robert
2011-03-01
Placing polyelectrolytes into confined geometries has a profound effect on their molecular configuration. For instance, placing long DNA molecules into channels with a cross-section of about 100 nm 2 stretches them out to about 70% of their contour length. We are using this effect to map epigenetic changes on single DNA and chromatin strands. This mapping on single molecules becomes central in the study of the heterogeneity of cell population in cancer, since rapid change of epigenetic makeup, propagated through rare cancer stem cells, is a hallmark of its progression. We demonstrate the basic building blocks for the single-molecule epigenetic analysis of genomic sized DNA. In particular, we have achieved the mapping of methylated regions in DNA with heterogeneous 5-methyl cytosine modification using a specific fluorescent marker. We further show that chromatin with an intact histone structure can be stretched similar to DNA, and that the epigenetic state of histone tails can be detected using fluorescent antibodies.
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Local epigenetic reprograming induced by G-quadruplex ligands
Recolin, Bénédicte; Campbell, Beth C.; Maiter, Ahmed; Sale, Julian E.; Balasubramanian, Shankar
2017-01-01
DNA and histone modifications regulate transcriptional activity and thus represent valuable targets to reprogram the activity of genes. Current epigenetic therapies target the machinery that regulates these modifications, leading to global transcriptional reprogramming with the potential for extensive undesired effects. Epigenetic information can also be modified as a consequence of disrupting processive DNA replication. Here we demonstrate that impeding replication by small molecule-mediated stabilisation of G-quadruplex nucleic acid secondary structures triggers local epigenetic plasticity. We report the use of the BU-1 locus of chicken DT40 cells to screen for small molecules able to induce G-quadruplex-dependent transcriptional reprogramming. Further characterisation of the top hit compound revealed its ability to induce a dose-dependent inactivation of BU-1 expression in two steps, first loss of H3K4me3 and subsequently DNA cytosine methylation, changes that were heritable across cell divisions even after the compound was removed. Targeting DNA secondary structures thus represents a potentially new approach for locus-specific epigenetic reprogramming. PMID:29064488
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Local epigenetic reprogramming induced by G-quadruplex ligands
NASA Astrophysics Data System (ADS)
Guilbaud, Guillaume; Murat, Pierre; Recolin, Bénédicte; Campbell, Beth C.; Maiter, Ahmed; Sale, Julian E.; Balasubramanian, Shankar
2017-11-01
DNA and histone modifications regulate transcriptional activity and thus represent valuable targets to reprogram the activity of genes. Current epigenetic therapies target the machinery that regulates these modifications, leading to global transcriptional reprogramming with the potential for extensive undesired effects. Epigenetic information can also be modified as a consequence of disrupting processive DNA replication. Here, we demonstrate that impeding replication by small-molecule-mediated stabilization of G-quadruplex nucleic acid secondary structures triggers local epigenetic plasticity. We report the use of the BU-1 locus of chicken DT40 cells to screen for small molecules able to induce G-quadruplex-dependent transcriptional reprogramming. Further characterization of the top hit compound revealed its ability to induce a dose-dependent inactivation of BU-1 expression in two steps: the loss of H3K4me3 and then subsequent DNA cytosine methylation, changes that were heritable across cell divisions even after the compound was removed. Targeting DNA secondary structures thus represents a potentially new approach for locus-specific epigenetic reprogramming.
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Interplay between diet, gut microbiota, epigenetic events, and colorectal cancer
Bultman, Scott J.
2016-01-01
Despite the success of colonoscopy screening, colorectal cancer (CRC) remains one of the most common and deadly cancers, and CRC incidence is rising in some countries where screening is not routine and populations have recently switched from traditional diets to western diets. Diet and energy balance influence CRC by multiple mechanisms. They modulate the composition and function of gut microbiota, which have a prodigious metabolic capacity and can produce oncometabolites or tumor-suppressive metabolites depending, in part, on which dietary factors and digestive components are present in the GI tract. Gut microbiota also have a profound effect on immune cells in the lamina propria, which influences inflammation and subsequently CRC. Nutrient availability, which is an outcome of diet and energy balance, determines the abundance of certain energy metabolites that are essential co-factors for epigenetic enzymes and therefore impinges upon epigenetic regulation of gene expression. Aberrant epigenetic marks accumulate during CRC, and epimutations that are selected for drive tumorigenesis by causing transcriptome profiles to diverge from the cell of origin. In some instances, the above mechanisms are intertwined as exemplified by dietary fiber being metabolized by colonic bacteria into butyrate, which is both a short-chain fatty acid (SCFA) and a histone deacetylase (HDAC) inhibitor that epigenetically upregulates tumor-suppressor genes in CRC cells and anti-inflammatory genes in immune cells. PMID:27138454
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Vogt, Gunter
2018-03-01
In the last 15 years, considerable attempts have been undertaken to develop the obligately parthenogenetic marbled crayfish Procambarus virginalis as a new model in biology. Its main advantage is the production of large numbers of offspring that are genetically identical to the mother, making this crustacean particularly suitable for research in epigenetics. Now, a draft genome, transcriptome and genome-wide methylome are available opening new windows for research. In this article, I summarize the biological advantages and genomic and epigenetic features of marbled crayfish and, based on first promising data, discuss what this new model could contribute to answering of ''big'' biological questions. Genome mining is expected to reveal new insights into the genetic specificities of decapod crustaceans, the genetic basis of arthropod reproduction, moulting and immunity, and more general topics such as the genetic underpinning of adaptation to fresh water, omnivory, biomineralization, sexual system change, behavioural variation, clonal genome evolution, and resistance to cancer. Epigenetic investigations with the marbled crayfish can help clarifying the role of epigenetic mechanisms in gene regulation, tissue specification, adult stem cell regulation, cell ageing, organ regeneration and disease susceptibility. Marbled crayfish is further suitable to elucidate the relationship between genetic and epigenetic variation, the transgenerational inheritance of epigenetic signatures and the contribution of epigenetic phenotype variation to the establishment of social hierarchies, environmental adaptation and speciation. These issues can be tackled by experiments with highly standardized laboratory lineages, comparison of differently adapted wild populations and the generation of genetically and epigenetically edited strains.
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Epigenetic dysregulation in cognitive disorders.
Gräff, Johannes; Mansuy, Isabelle M
2009-07-01
Epigenetic mechanisms are not only essential for biological functions requiring stable molecular changes such as the establishment of cell identity and tissue formation, they also constitute dynamic intracellular processes for translating environmental stimuli into modifications in gene expression. Over the past decade it has become increasingly clear that both aspects of epigenetic mechanisms play a pivotal role in complex brain functions. Evidence from patients with neurodegenerative and neurodevelopmental disorders such as Alzheimer's disease and Rett syndrome indicated that epigenetic mechanisms and chromatin remodeling need to be tightly controlled for proper cognitive functions, and their dysregulation can have devastating consequences. However, because they are dynamic, epigenetic mechanisms are also potentially reversible and may provide powerful means for pharmacological intervention. This review outlines major cognitive disorders known to be associated with epigenetic dysregulation, and discusses the potential of 'epigenetic medicine' as a promising cure.
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Epigenetics and therapeutic targets mediating neuroprotection.
Qureshi, Irfan A; Mehler, Mark F
2015-12-02
The rapidly evolving science of epigenetics is transforming our understanding of the nervous system in health and disease and holds great promise for the development of novel diagnostic and therapeutic approaches targeting neurological diseases. Increasing evidence suggests that epigenetic factors and mechanisms serve as important mediators of the pathogenic processes that lead to irrevocable neural injury and of countervailing homeostatic and regenerative responses. Epigenetics is, therefore, of considerable translational significance to the field of neuroprotection. In this brief review, we provide an overview of epigenetic mechanisms and highlight the emerging roles played by epigenetic processes in neural cell dysfunction and death and in resultant neuroprotective responses. This article is part of a Special Issue entitled SI: Neuroprotection. Copyright © 2015 Elsevier B.V. All rights reserved.
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Qin, Mingde; Chen, Ruihua; Li, Hong; Liang, Hansi; Xue, Qun; Li, Fang; Chen, Ying; Zhang, Xueguang
2016-01-01
Amniotic fluid stem cells (AFSCs) are a type of fetal stem cell whose stemness encompasses both embryonic and adult stem cells, suggesting that they may be easily and efficiently reprogrammed into induced pluripotent stem cells (iPSCs). To further simplify the reprogramming process, the creation of AFSC-derived iPSCs using a single factor is desirable. Here we report the generation of one-factor human AFSC-iPSCs (AiPSCs) from human AFSCs by ectopic expression of the transcription factor OCT4. Just like human embryonic stem cells, AiPSCs exhibited similar epigenetic status, global gene expression profiles, teratoma formation and in vitro & in vivo pluripotency. Our results indicate that the OCT4 is necessary and sufficient to directly reprogram human AFSCs into pluripotent AiPSCs. Moreover, reflecting the similar memory characteristics of AFSCs and neural stem cells, we show that AiPSC membrane-derived vesicles (MVs) repair cerebral ischemia damage. We anticipate that the successful generation of one-factor AiPSCs will facilitate the creation of patient-specific pluripotent stem cells without the need for transgenic expression of oncogenes. Moreover, MVs from tissue-specific AiPSCs have potential in tissue repair, representing a novel application of iPSCs. PMID:27019637
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Mechanism and stem-cell activity of 5-carboxycytosine decarboxylation determined by isotope tracing.
Schiesser, Stefan; Hackner, Benjamin; Pfaffeneder, Toni; Müller, Markus; Hagemeier, Christian; Truss, Matthias; Carell, Thomas
2012-06-25
Eraserhead: Stem cells seem to erase epigenetic information by decarboxylation of the newly discovered epigenetic base 5-carboxycytosine (caC; see picture). This reaction is likely to involve a nucleophilic attack of the C5-C6 double bond. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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New insights into the epigenetics of inflammatory rheumatic diseases.
Ballestar, Esteban; Li, Tianlu
2017-10-01
Over the past decade, awareness of the importance of epigenetic alterations in the pathogenesis of rheumatic diseases has grown in parallel with a general recognition of the fundamental role of epigenetics in the regulation of gene expression. Large-scale efforts to generate genome-wide maps of epigenetic modifications in different cell types, as well as in physiological and pathological contexts, illustrate the increasing recognition of the relevance of epigenetics. To date, although several reports have demonstrated the occurrence of epigenetic alterations in a wide range of inflammatory rheumatic conditions, epigenomic information is rarely used in a clinical setting. By contrast, several epigenetic biomarkers and treatments are currently in use for personalized therapies in patients with cancer. This Review highlights advances from the past 5 years in the field of epigenetics and their application to inflammatory rheumatic diseases, delineating the future lines of development for a rational use of epigenetic information in clinical settings and in personalized medicine. These advances include the identification of epipolymorphisms associated with clinical outcomes, DNA methylation as a contributor to disease susceptibility in rheumatic conditions, the discovery of novel epigenetic mechanisms that modulate disease susceptibility and the development of new epigenetic therapies.
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Shen, Ding-Wu; Pouliot, Lynn M.; Hall, Matthew D.
2012-01-01
Cisplatin is one of the most effective broad-spectrum anticancer drugs. Its effectiveness seems to be due to the unique properties of cisplatin, which enters cells via multiple pathways and forms multiple different DNA-platinum adducts while initiating a cellular self-defense system by activating or silencing a variety of different genes, resulting in dramatic epigenetic and/or genetic alternations. As a result, the development of cisplatin resistance in human cancer cells in vivo and in vitro by necessity stems from bewilderingly complex genetic and epigenetic changes in gene expression and alterations in protein localization. Extensive published evidence has demonstrated that pleiotropic alterations are frequently detected during development of resistance to this toxic metal compound. Changes occur in almost every mechanism supporting cell survival, including cell growth-promoting pathways, apoptosis, developmental pathways, DNA damage repair, and endocytosis. In general, dozens of genes are affected in cisplatin-resistant cells, including pathways involved in copper metabolism as well as transcription pathways that alter the cytoskeleton, change cell surface presentation of proteins, and regulate epithelial-to-mesenchymal transition. Decreased accumulation is one of the most common features resulting in cisplatin resistance. This seems to be a consequence of numerous epigenetic and genetic changes leading to the loss of cell-surface binding sites and/or transporters for cisplatin, and decreased fluid phase endocytosis. PMID:22659329
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Shen, Ding-Wu; Pouliot, Lynn M; Hall, Matthew D; Gottesman, Michael M
2012-07-01
Cisplatin is one of the most effective broad-spectrum anticancer drugs. Its effectiveness seems to be due to the unique properties of cisplatin, which enters cells via multiple pathways and forms multiple different DNA-platinum adducts while initiating a cellular self-defense system by activating or silencing a variety of different genes, resulting in dramatic epigenetic and/or genetic alternations. As a result, the development of cisplatin resistance in human cancer cells in vivo and in vitro by necessity stems from bewilderingly complex genetic and epigenetic changes in gene expression and alterations in protein localization. Extensive published evidence has demonstrated that pleiotropic alterations are frequently detected during development of resistance to this toxic metal compound. Changes occur in almost every mechanism supporting cell survival, including cell growth-promoting pathways, apoptosis, developmental pathways, DNA damage repair, and endocytosis. In general, dozens of genes are affected in cisplatin-resistant cells, including pathways involved in copper metabolism as well as transcription pathways that alter the cytoskeleton, change cell surface presentation of proteins, and regulate epithelial-to-mesenchymal transition. Decreased accumulation is one of the most common features resulting in cisplatin resistance. This seems to be a consequence of numerous epigenetic and genetic changes leading to the loss of cell-surface binding sites and/or transporters for cisplatin, and decreased fluid phase endocytosis.
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Noise and Epigenetic Inheritance of Single-Cell Division Times Influence Population Fitness.
Cerulus, Bram; New, Aaron M; Pougach, Ksenia; Verstrepen, Kevin J
2016-05-09
The fitness effect of biological noise remains unclear. For example, even within clonal microbial populations, individual cells grow at different speeds. Although it is known that the individuals' mean growth speed can affect population-level fitness, it is unclear how or whether growth speed heterogeneity itself is subject to natural selection. Here, we show that noisy single-cell division times can significantly affect population-level growth rate. Using time-lapse microscopy to measure the division times of thousands of individual S. cerevisiae cells across different genetic and environmental backgrounds, we find that the length of individual cells' division times can vary substantially between clonal individuals and that sublineages often show epigenetic inheritance of division times. By combining these experimental measurements with mathematical modeling, we find that, for a given mean division time, increasing heterogeneity and epigenetic inheritance of division times increases the population growth rate. Furthermore, we demonstrate that the heterogeneity and epigenetic inheritance of single-cell division times can be linked with variation in the expression of catabolic genes. Taken together, our results reveal how a change in noisy single-cell behaviors can directly influence fitness through dynamics that operate independently of effects caused by changes to the mean. These results not only allow a better understanding of microbial fitness but also help to more accurately predict fitness in other clonal populations, such as tumors. Copyright © 2016 Elsevier Ltd. All rights reserved.
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Li, Yuanyuan; Chen, Huaping; Hardy, Tabitha M; Tollefsbol, Trygve O
2013-01-01
Breast cancer is one of the most lethal diseases in women; however, the precise etiological factors are still not clear. Genistein (GE), a natural isoflavone found in soybean products, is believed to be a potent chemopreventive agent for breast cancer. One of the most important mechanisms for GE inhibition of breast cancer may involve its potential in impacting epigenetic processes allowing reversal of aberrant epigenetic events during breast tumorigenesis. To investigate epigenetic regulation for GE impedance of breast tumorigenesis, we monitored epigenetic alterations of several key tumor-related genes in an established breast cancer transformation system. Our results show that GE significantly inhibited cell growth in a dose-dependent manner in precancerous breast cells and breast cancer cells, whereas it exhibited little effect on normal human mammary epithelial cells. Furthermore, GE treatment increased expression of two crucial tumor suppressor genes, p21(WAF1) (p21) and p16(INK4a) (p16), although it decreased expression of two tumor promoting genes, BMI1 and c-MYC. GE treatment led to alterations of histone modifications in the promoters of p21 and p16 as well as the binding ability of the c-MYC-BMI1 complex to the p16 promoter contributing to GE-induced epigenetic activation of these tumor suppressor genes. In addition, an orally-fed GE diet prevented breast tumorigenesis and inhibited breast cancer development in breast cancer mice xenografts. Our results suggest that genistein may repress early breast tumorigenesis by epigenetic regulation of p21 and p16 by impacting histone modifications as well as the BMI1-c-MYC complex recruitment to the regulatory region in the promoters of these genes. These studies will facilitate more effective use of soybean product in breast cancer prevention and also help elucidate the mechanisms during the process of early breast tumorigenesis.
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Epigenetic Heterogeneity of B-Cell Lymphoma: Chromatin Modifiers
Hopp, Lydia; Nersisyan, Lilit; Löffler-Wirth, Henry; Arakelyan, Arsen; Binder, Hans
2015-01-01
We systematically studied the expression of more than fifty histone and DNA (de)methylating enzymes in lymphoma and healthy controls. As a main result, we found that the expression levels of nearly all enzymes become markedly disturbed in lymphoma, suggesting deregulation of large parts of the epigenetic machinery. We discuss the effect of DNA promoter methylation and of transcriptional activity in the context of mutated epigenetic modifiers such as EZH2 and MLL2. As another mechanism, we studied the coupling between the energy metabolism and epigenetics via metabolites that act as cofactors of JmjC-type demethylases. Our study results suggest that Burkitt’s lymphoma and diffuse large B-cell Lymphoma differ by an imbalance of repressive and poised promoters, which is governed predominantly by the activity of methyltransferases and the underrepresentation of demethylases in this regulation. The data further suggest that coupling of epigenetics with the energy metabolism can also be an important factor in lymphomagenesis in the absence of direct mutations of genes in metabolic pathways. Understanding of epigenetic deregulation in lymphoma and possibly in cancers in general must go beyond simple schemes using only a few modes of regulation. PMID:26506391
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Zebrafish Discoveries in Cancer Epigenetics.
Chernyavskaya, Yelena; Kent, Brandon; Sadler, Kirsten C
2016-01-01
The cancer epigenome is fundamentally different than that of normal cells. How these differences arise in and contribute to carcinogenesis is not known, and studies using model organisms such as zebrafish provide an opportunity to address these important questions. Modifications of histones and DNA comprise the complex epigenome, and these influence chromatin structure, genome stability and gene expression, all of which are fundamental to the cellular changes that cause cancer. The cancer genome atlas covers the wide spectrum of genetic changes associated with nearly every cancer type, however, this catalog is currently uni-dimensional. As the pattern of epigenetic marks and chromatin structure in cancer cells is described and overlaid on the mutational landscape, the map of the cancer genome becomes multi-dimensional and highly complex. Two major questions remain in the field: (1) how the epigenome becomes repatterned in cancer and (2) which of these changes are cancer-causing. Zebrafish provide a tractable in vivo system to monitor the epigenome during transformation and to identify epigenetic drivers of cancer. In this chapter, we review principles of cancer epigenetics and discuss recent work using zebrafish whereby epigenetic modifiers were established as cancer driver genes, thus providing novel insights into the mechanisms of epigenetic reprogramming in cancer.
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Potential Role of Epigenetic Mechanism in Manganese Induced Neurotoxicity
Tarale, Prashant; Chakrabarti, Tapan; Sivanesan, Saravanadevi; Naoghare, Pravin; Bafana, Amit; Krishnamurthi, Kannan
2016-01-01
Manganese is a vital nutrient and is maintained at an optimal level (2.5–5 mg/day) in human body. Chronic exposure to manganese is associated with neurotoxicity and correlated with the development of various neurological disorders such as Parkinson's disease. Oxidative stress mediated apoptotic cell death has been well established mechanism in manganese induced toxicity. Oxidative stress has a potential to alter the epigenetic mechanism of gene regulation. Epigenetic insight of manganese neurotoxicity in context of its correlation with the development of parkinsonism is poorly understood. Parkinson's disease is characterized by the α-synuclein aggregation in the form of Lewy bodies in neuronal cells. Recent findings illustrate that manganese can cause overexpression of α-synuclein. α-Synuclein acts epigenetically via interaction with histone proteins in regulating apoptosis. α-Synuclein also causes global DNA hypomethylation through sequestration of DNA methyltransferase in cytoplasm. An individual genetic difference may also have an influence on epigenetic susceptibility to manganese neurotoxicity and the development of Parkinson's disease. This review presents the current state of findings in relation to role of epigenetic mechanism in manganese induced neurotoxicity, with a special emphasis on the development of Parkinson's disease. PMID:27314012
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Ogasawara, Takashi; Hatano, Masahiko; Satake, Hisae; Ikari, Jun; Taniguchi, Toshibumi; Tsuruoka, Nobuhide; Watanabe-Takano, Haruko; Fujimura, Lisa; Sakamoto, Akemi; Hirata, Hirokuni; Sugiyama, Kumiya; Fukushima, Yasutsugu; Nakae, Susumu; Matsumoto, Kenji; Saito, Hirohisa; Fukuda, Takeshi; Kurasawa, Kazuhiro; Tatsumi, Koichiro; Tokuhisa, Takeshi
2017-01-01
Mice deficient in the transcriptional repressor B-cell CLL/lymphoma 6 (Bcl6) exhibit similar T helper 2 (TH2) immune responses as patients with allergic diseases. However, the molecular mechanisms underlying Bcl6-directed regulation of TH2 cytokine genes remain unclear. We identified multiple Bcl6/STAT binding sites (BSs) in TH2 cytokine gene loci. We found that Bcl6 is modestly associated with the BSs, and it had no significant effect on cytokine production in newly differentiated TH2 cells. Contrarily, in memory TH2 (mTH2) cells derived from adaptively transferred TH2 effectors, Bcl6 outcompeted STAT5 for binding to TH2 cytokine gene loci, particularly Interleukin4 (Il4) loci, and attenuated GATA binding protein 3 (GATA3) binding to highly conserved intron enhancer regions in mTH2 cells. Bcl6 suppressed cytokine production epigenetically in mTH2 cells to negatively tune histone acetylation at TH2 cytokine gene loci, including Il4 loci. In addition, IL-33, a pro-TH2 cytokine, diminished Bcl6’s association with loci to which GATA3 recruitment was inversely augmented, resulting in altered IL-4, but not IL-5 and IL-13, production in mTH2 cells but no altered production in newly differentiated TH2 cells. Use of a murine asthma model that generates high levels of pro-TH2 cytokines, such as IL-33, suggested that the suppressive function of Bcl6 in mTH2 cells is abolished in severe asthma. These findings indicate a role of the interaction between TH2-promoting factors and Bcl6 in promoting appropriate IL-4 production in mTH2 cells and suggest that chronic allergic diseases involve the TH2-promoting factor-mediated functional breakdown of Bcl6, resulting in allergy exacerbation. PMID:28096407
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Chacon, Jessica Ann; Schutsky, Keith; Powell, Daniel J.
2016-01-01
Genomic destabilizers, such as radiation and chemotherapy, and epigenetic modifiers are used for the treatment of cancer due to their apoptotic effects on the aberrant cells. However, these therapies may also induce widespread changes within the immune system and cancer cells, which may enable tumors to avoid immune surveillance and escape from host anti-tumor immunity. Genomic destabilizers can induce immunogenic death of tumor cells, but also induce upregulation of immune inhibitory ligands on drug-resistant cells, resulting in tumor progression. While administration of immunomodulatory antibodies that block the interactions between inhibitory receptors on immune cells and their ligands on tumor cells can mediate cancer regression in a subset of treated patients, it is crucial to understand how genomic destabilizers alter the immune system and malignant cells, including which inhibitory molecules, receptors and/or ligands are upregulated in response to genotoxic stress. Knowledge gained in this area will aid in the rational design of trials that combine genomic destabilizers, epigenetic modifiers and immunotherapeutic agents that may be synergized to improve clinical responses and prevent tumor escape from the immune system. Our review article describes the impact genomic destabilizers, such as radiation and chemotherapy, and epigenetic modifiers have on anti-tumor immunity and the tumor microenvironment. Although genomic destabilizers cause DNA damage on cancer cells, these therapies can also have diverse effects on the immune system, promote immunogenic cell death or survival and alter the cancer cell expression of immune inhibitor molecules. PMID:27854240
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Epigenetic Risk Factors in PTSD and Depression
Raabe, Florian Joachim; Spengler, Dietmar
2013-01-01
Epidemiological and clinical studies have shown that children exposed to adverse experiences are at increased risk for the development of depression, anxiety disorders, and posttraumatic stress disorder (PTSD). A history of child abuse and maltreatment increases the likelihood of being subsequently exposed to traumatic events or of developing PTSD as an adult. The brain is highly plastic during early life and encodes acquired information into lasting memories that normally subserve adaptation. Translational studies in rodents showed that enduring sensitization of neuronal and neuroendocrine circuits in response to early life adversity are likely risk factors of life time vulnerability to stress. Hereby, the hypothalamic-pituitary-adrenal (HPA) axis integrates cognitive, behavioral, and emotional responses to early-life stress and can be epigenetically programed during sensitive windows of development. Epigenetic mechanisms, comprising reciprocal regulation of chromatin structure and DNA methylation, are important to establish and maintain sustained, yet potentially reversible, changes in gene transcription. The relevance of these findings for the development of PTSD requires further studies in humans where experience-dependent epigenetic programing can additionally depend on genetic variation in the underlying substrates which may protect from or advance disease development. Overall, identification of early-life stress-associated epigenetic risk markers informing on previous stress history can help to advance early diagnosis, personalized prevention, and timely therapeutic interventions, thus reducing long-term social and health costs. PMID:23966957
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Metabolic Induction of Trained Immunity through the Mevalonate Pathway.
Bekkering, Siroon; Arts, Rob J W; Novakovic, Boris; Kourtzelis, Ioannis; van der Heijden, Charlotte D C C; Li, Yang; Popa, Calin D; Ter Horst, Rob; van Tuijl, Julia; Netea-Maier, Romana T; van de Veerdonk, Frank L; Chavakis, Triantafyllos; Joosten, Leo A B; van der Meer, Jos W M; Stunnenberg, Henk; Riksen, Niels P; Netea, Mihai G
2018-01-11
Innate immune cells can develop long-term memory after stimulation by microbial products during infections or vaccinations. Here, we report that metabolic signals can induce trained immunity. Pharmacological and genetic experiments reveal that activation of the cholesterol synthesis pathway, but not the synthesis of cholesterol itself, is essential for training of myeloid cells. Rather, the metabolite mevalonate is the mediator of training via activation of IGF1-R and mTOR and subsequent histone modifications in inflammatory pathways. Statins, which block mevalonate generation, prevent trained immunity induction. Furthermore, monocytes of patients with hyper immunoglobulin D syndrome (HIDS), who are mevalonate kinase deficient and accumulate mevalonate, have a constitutive trained immunity phenotype at both immunological and epigenetic levels, which could explain the attacks of sterile inflammation that these patients experience. Unraveling the role of mevalonate in trained immunity contributes to our understanding of the pathophysiology of HIDS and identifies novel therapeutic targets for clinical conditions with excessive activation of trained immunity. Copyright © 2017 Elsevier Inc. All rights reserved.
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Epigenetic deregulation in chronic lymphocytic leukemia: Clinical and biological impact.
Mansouri, Larry; Wierzbinska, Justyna Anna; Plass, Christoph; Rosenquist, Richard
2018-02-07
Deregulated transcriptional control caused by aberrant DNA methylation and/or histone modifications is a hallmark of cancer cells. In chronic lymphocytic leukemia (CLL), the most common adult leukemia, the epigenetic 'landscape' has added a new layer of complexity to our understanding of this clinically and biologically heterogeneous disease. Early studies identified aberrant DNA methylation, often based on single gene promoter analysis with both biological and clinical impact. Subsequent genome-wide profiling studies revealed differential DNA methylation between CLLs and controls and in prognostics subgroups of the disease. From these studies, it became apparent that DNA methylation in regions outside of promoters, such as enhancers, is important for the regulation of coding genes as well as for the regulation of non-coding RNAs. Although DNA methylation profiles are reportedly stable over time and in relation to therapy, a higher epigenetic heterogeneity or 'burden' is seen in more aggressive CLL subgroups, albeit as non-recurrent 'passenger' events. More recently, DNA methylation profiles in CLL analyzed in relation to differentiating normal B-cell populations revealed that the majority of the CLL epigenome reflects the epigenomes present in the cell of origin and that only a small fraction of the epigenetic alterations represents truly CLL-specific changes. Furthermore, CLL patients can be grouped into at least three clinically relevant epigenetic subgroups, potentially originating from different cells at various stages of differentiation and associated with distinct outcomes. In this review, we summarize the current understanding of the DNA methylome in CLL, the role of histone modifying enzymes, highlight insights derived from animal models and attempts made to target epigenetic regulators in CLL along with the future directions of this rapidly advancing field. Copyright © 2018 Elsevier Ltd. All rights reserved.
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Histone H3 Lysine Methylation in Cognition and Intellectual Disability Disorders
ERIC Educational Resources Information Center
Parkel, Sven; Lopez-Atalaya, Jose P.; Barco, Angel
2013-01-01
Recent research indicates that epigenetic mechanisms and, in particular, the post-translational modification (PTM) of histones may contribute to memory encoding and storage. Among the dozens of possible histone PTMs, the methylation/demethylation of lysines in the N-terminal tail of histone H3 exhibits particularly strong links with cognitive…
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The ULT1 and ULT2 trxG genes play overlapping roles in Arabidopsis development and gene regulation
USDA-ARS?s Scientific Manuscript database
The epigenetic regulation of gene expression is critical for ensuring the proper deployment and stability of defined genome transcription programs at specific developmental stages. The cellular memory of stable gene expression states during animal and plant development is mediated by the opposing ac...
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Epigenomic Analysis of Multi-lineage Differentiation of Human Embryonic Stem Cells
Xie, Wei; Schultz, Matthew D.; Lister, Ryan; Hou, Zhonggang; Rajagopal, Nisha; Ray, Pradipta; Whitaker, John W.; Tian, Shulan; Hawkins, R. David; Leung, Danny; Yang, Hongbo; Wang, Tao; Lee, Ah Young; Swanson, Scott A.; Zhang, Jiuchun; Zhu, Yun; Kim, Audrey; Nery, Joseph R.; Urich, Mark A.; Kuan, Samantha; Yen, Chia-an; Klugman, Sarit; Yu, Pengzhi; Suknuntha, Kran; Propson, Nicholas E.; Chen, Huaming; Edsall, Lee E.; Wagner, Ulrich; Li, Yan; Ye, Zhen; Kulkarni, Ashwinikumar; Xuan, Zhenyu; Chung, Wen-Yu; Chi, Neil C.; Antosiewicz-Bourget, Jessica E.; Slukvin, Igor; Stewart, Ron; Zhang, Michael Q.; Wang, Wei; Thomson, James A.; Ecker, Joseph R.; Ren, Bing
2013-01-01
SUMMARY Epigenetic mechanisms have been proposed to play crucial roles in mammalian development, but their precise functions are only partially understood. To investigate epigenetic regulation of embryonic development, we differentiated human embryonic stem cells into mesendoderm, neural progenitor cells, trophoblast-like cells, and mesenchymal stem cells, and systematically characterized DNA methylation, chromatin modifications, and the transcriptome in each lineage. We found that promoters that are active in early developmental stages tend to be CG rich and mainly engage H3K27me3 upon silencing in non-expressing lineages. By contrast, promoters for genes expressed preferentially at later stages are often CG poor and primarily employ DNA methylation upon repression. Interestingly, the early developmental regulatory genes are often located in large genomic domains that are generally devoid of DNA methylation in most lineages, which we termed DNA methylation valleys (DMVs). Our results suggest that distinct epigenetic mechanisms regulate early and late stages of ES cell differentiation. PMID:23664764
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Anticancer Natural Compounds as Epigenetic Modulators of Gene Expression
Ratovitski, Edward A.
2017-01-01
Abstract: Accumulating evidence shows that hallmarks of cancer include: “genetic and epigenetic alterations leading to inactivation of cancer suppressors, overexpression of oncogenes, deregulation of intracellular signaling cascades, alterations of cancer cell metabolism, failure to undergo cancer cell death, induction of epithelial to mesenchymal transition, invasiveness, metastasis, deregulation of immune response and changes in cancer microenvironment, which underpin cancer development”. Natural compounds as bioactive ingredients isolated from natural sources (plants, fungi, marine life forms) have revolutionized the field of anticancer therapeutics and rapid developments in preclinical studies are encouraging. Natural compounds could affect the epigenetic molecular mechanisms that modulate gene expression, as well as DNA damage and repair mechanisms. The current review will describe the latest achievements in using naturally produced compounds targeting epigenetic regulators and modulators of gene transcription in vitro and in vivo to generate novel anticancer therapeutics. PMID:28367075
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Zinc Fingers, TALEs, and CRISPR Systems: A Comparison of Tools for Epigenome Editing.
Waryah, Charlene Babra; Moses, Colette; Arooj, Mahira; Blancafort, Pilar
2018-01-01
The completion of genome, epigenome, and transcriptome mapping in multiple cell types has created a demand for precision biomolecular tools that allow researchers to functionally manipulate DNA, reconfigure chromatin structure, and ultimately reshape gene expression patterns. Epigenetic editing tools provide the ability to interrogate the relationship between epigenetic modifications and gene expression. Importantly, this information can be exploited to reprogram cell fate for both basic research and therapeutic applications. Three different molecular platforms for epigenetic editing have been developed: zinc finger proteins (ZFs), transcription activator-like effectors (TALEs), and the system of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and CRISPR-associated (Cas) proteins. These platforms serve as custom DNA-binding domains (DBDs), which are fused to epigenetic modifying domains to manipulate epigenetic marks at specific sites in the genome. The addition and/or removal of epigenetic modifications reconfigures local chromatin structure, with the potential to provoke long-lasting changes in gene transcription. Here we summarize the molecular structure and mechanism of action of ZF, TALE, and CRISPR platforms and describe their applications for the locus-specific manipulation of the epigenome. The advantages and disadvantages of each platform will be discussed with regard to genomic specificity, potency in regulating gene expression, and reprogramming cell phenotypes, as well as ease of design, construction, and delivery. Finally, we outline potential applications for these tools in molecular biology and biomedicine and identify possible barriers to their future clinical implementation.
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Epigenetic modulators, modifiers and mediators in cancer aetiology and progression
Feinberg, Andrew P.; Koldobskiy, Michael A.; Göndör, Anita
2016-01-01
This year is the tenth anniversary of the publication in this journal of a model suggesting the existence of ‘tumour progenitor genes’. These genes are epigenetically disrupted at the earliest stages of malignancies, even before mutations, and thus cause altered differentiation throughout tumour evolution. The past decade of discovery in cancer epigenetics has revealed a number of similarities between cancer genes and stem cell reprogramming genes, widespread mutations in epigenetic regulators, and the part played by chromatin structure in cellular plasticity in both development and cancer. In the light of these discoveries, we suggest here a framework for cancer epigenetics involving three types of genes: ‘epigenetic mediators’, corresponding to the tumour progenitor genes suggested earlier; ‘epigenetic modifiers’ of the mediators, which are frequently mutated in cancer; and ‘epigenetic modulators’ upstream of the modifiers, which are responsive to changes in the cellular environment and often linked to the nuclear architecture. We suggest that this classification is helpful in framing new diagnostic and therapeutic approaches to cancer. PMID:26972587
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NASA Astrophysics Data System (ADS)
Michieletto, D.; Orlandini, E.; Marenduzzo, D.
2016-10-01
One of the most important problems in development is how epigenetic domains can first be established, and then maintained, within cells. To address this question, we propose a framework that couples three-dimensional chromatin folding dynamics to a "recoloring" process modeling the writing of epigenetic marks. Because many intrachromatin interactions are mediated by bridging proteins, we consider a "two-state" model with self-attractive interactions between two epigenetic marks that are alike (either active or inactive). This model displays a first-order-like transition between a swollen, epigenetically disordered phase and a compact, epigenetically coherent chromatin globule. If the self-attraction strength exceeds a threshold, the chromatin dynamics becomes glassy, and the corresponding interaction network freezes. By modifying the epigenetic read-write process according to more biologically inspired assumptions, our polymer model with recoloring recapitulates the ultrasensitive response of epigenetic switches to perturbations and accounts for long-lived multidomain conformations, strikingly similar to the topologically associating domains observed in eukaryotic chromosomes.
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The human sperm epigenome and its potential role in embryonic development.
Carrell, Douglas T; Hammoud, Saher Sue
2010-01-01
Along with many of the genome-wide transitions in chromatin composition throughout spermatogenesis, epigenetic modifications on histone tails and DNA are continuously modified to ensure stage specific gene expression in the maturing spermatid. Recent findings have suggested that the repertoire of epigenetic modifications in the mature sperm may have a potential role in the developing embryo and alterations in the epigenetic profile have been associated with infertility. These changes include DNA demethylation and the retention of modified histones at important developmental, signaling and micro-RNA genes, which resemble the epigenetic state of an embryonic stem cell. This review assesses the significance of epigenetic changes during spermatogenesis, and provides insight on recent associations made between altered epigenetic profiles in the mature sperm and its relationship to infertility.
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Chun, Sung-Min; Lee, Ji-Young; Choi, Jene; Lee, Je-Hwan; Hwang, Jung Jin; Kim, Chung-Soo; Suh, Young-Ah; Jang, Se Jin
2015-01-01
Histone modification plays a pivotal role on gene regulation, as regarded as global epigenetic markers, especially in tumor related genes. Hence, chemical approaches targeting histone-modifying enzymes have emerged onto the main stage of anticancer drug discovery. Here, we investigated the therapeutic potentials and mechanistic roles of the recently developed histone deacetylase inhibitor, CG200745, in non-small cell lung cancer cells. Treatment with CG200745 increased the global level of histone acetylation, resulting in the inhibition of cell proliferation. ChIP-on-chip analysis with an H4K16ac antibody showed altered H4K16 acetylation on genes critical for cell growth inhibition, although decreased at the transcription start site of a subset of genes. Altered H4K16ac was associated with changes in mRNA expression of the corresponding genes, which were further validated in quantitative RT-PCR and western blotting assays. Our results demonstrated that CG200745 causes NSCLC cell growth inhibition through epigenetic modification of critical genes in cancer cell survival, providing pivotal clues as a promising chemotherapeutics against lung cancer.
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Chun, Sung-Min; Lee, Ji-Young; Choi, Jene; Lee, Je-Hwan; Hwang, Jung Jin; Kim, Chung-Soo; Suh, Young-Ah; Jang, Se Jin
2015-01-01
Histone modification plays a pivotal role on gene regulation, as regarded as global epigenetic markers, especially in tumor related genes. Hence, chemical approaches targeting histone-modifying enzymes have emerged onto the main stage of anticancer drug discovery. Here, we investigated the therapeutic potentials and mechanistic roles of the recently developed histone deacetylase inhibitor, CG200745, in non-small cell lung cancer cells. Treatment with CG200745 increased the global level of histone acetylation, resulting in the inhibition of cell proliferation. ChIP-on-chip analysis with an H4K16ac antibody showed altered H4K16 acetylation on genes critical for cell growth inhibition, although decreased at the transcription start site of a subset of genes. Altered H4K16ac was associated with changes in mRNA expression of the corresponding genes, which were further validated in quantitative RT-PCR and western blotting assays. Our results demonstrated that CG200745 causes NSCLC cell growth inhibition through epigenetic modification of critical genes in cancer cell survival, providing pivotal clues as a promising chemotherapeutics against lung cancer. PMID:25781604
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Epigenetic Events in Liver Cancer Resulting From Alcoholic Liver Disease
French, Samuel W.
2013-01-01
Epigenetic mechanisms play an extensive role in the development of liver cancer (i.e., hepatocellular carcinoma [HCC]) associated with alcoholic liver disease (ALD) as well as in liver disease associated with other conditions. For example, epigenetic mechanisms, such as changes in the methylation and/or acetylation pattern of certain DNA regions or of the histone proteins around which the DNA is wrapped, contribute to the reversion of normal liver cells into progenitor and stem cells that can develop into HCC. Chronic exposure to beverage alcohol (i.e., ethanol) can induce all of these epigenetic changes. Thus, ethanol metabolism results in the formation of compounds that can cause changes in DNA methylation and interfere with other components of the normal processes regulating DNA methylation. Alcohol exposure also can alter histone acetylation/deacetylation and methylation patterns through a variety of mechanisms and signaling pathways. Alcohol also acts indirectly on another molecule called toll-like receptor 4 (TLR4) that is a key component in a crucial regulatory pathway in the cells and whose dysregulation is involved in the development of HCC. Finally, alcohol use regulates an epigenetic mechanism involving small molecules called miRNAs that control transcriptional events and the expression of genes important to ALD. PMID:24313165
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Prenatal Alcohol Exposure and Cellular Differentiation
Veazey, Kylee J.; Muller, Daria; Golding, Michael C.
2013-01-01
Exposure to alcohol significantly alters the developmental trajectory of progenitor cells and fundamentally compromises tissue formation (i.e., histogenesis). Emerging research suggests that ethanol can impair mammalian development by interfering with the execution of molecular programs governing differentiation. For example, ethanol exposure disrupts cellular migration, changes cell–cell interactions, and alters growth factor signaling pathways. Additionally, ethanol can alter epigenetic mechanisms controlling gene expression. Normally, lineage-specific regulatory factors (i.e., transcription factors) establish the transcriptional networks of each new cell type; the cell’s identity then is maintained through epigenetic alterations in the way in which the DNA encoding each gene becomes packaged within the chromatin. Ethanol exposure can induce epigenetic changes that do not induce genetic mutations but nonetheless alter the course of fetal development and result in a large array of patterning defects. Two crucial enzyme complexes—the Polycomb and Trithorax proteins—are central to the epigenetic programs controlling the intricate balance between self-renewal and the execution of cellular differentiation, with diametrically opposed functions. Prenatal ethanol exposure may disrupt the functions of these two enzyme complexes, altering a crucial aspect of mammalian differentiation. Characterizing the involvement of Polycomb and Trithorax group complexes in the etiology of fetal alcohol spectrum disorders will undoubtedly enhance understanding of the role that epigenetic programming plays in this complex disorder. PMID:24313167
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Tan, S.J.; Fang, J.Y.; Wu, Y.; Yang, Z.; Liang, G.; Han, B.
2015-01-01
Efficiency of cell-based tissue engineering and regenerative medicine has been limited by inadequate cellular responses to injury because of aging and poor controllability of cellular interactions. Since cell progression is under a tight epigenetic regulation, epigenetic modulators such as 5-azacytidine (5-Aza-CR) have been utilized to facilitate reprogramming and development of somatic cells in 2-dimensional (2-D) settings. Nonetheless, progression of a specific tissue lineage toward the terminal phenotype is dependent not only on the genomic potential, but also on the microenvironment cues that are beyond the capability of 2-D approaches. In this study, we investigated the combined effects of matrices of variable rigidities and the treatment with the epigenetic modulator 5-Aza-CR on reprogramming adipose-derived stromal cells (ADSCs) into myoblast-like cells by utilizing tunable transglutaminase cross-linked gelatin (Col-Tgel) in vitro and in vivo. Our experiments demonstrated that cellular plasticity and trans-differentiation were significantly enhanced when ADSCs were treated with an effective dose of 5-Aza-CR (1.25 to 12.5 ng) in the optimal myogenic matrix (15 ± 5 kPa Col-Tgel). Our findings suggest that both physical signals and chemical milieu are critical for the regulation of cellular responses. PMID:26548559
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Gilbert, Elizabeth R.; Liu, Dongmin
2012-01-01
Type 2 diabetes (T2D) is a growing health problem worldwide. While peripheral insulin resistance is common during obesity and aging in both animals and people, progression to T2D is largely due to insulin secretory dysfunction and significant apoptosis of functional β-cells, leading to an inability to compensate for insulin resistance. It is recognized that environmental factors and nutrition play an important role in the pathogenesis of diabetes. However, our knowledge surrounding molecular mechanisms by which these factors trigger β-cell dysfunction and diabetes is still limited. Recent discoveries raise the possibility that epigenetic changes in response to environmental stimuli may play an important role in the development of diabetes. In this paper, we review emerging knowledge regarding epigenetic mechanisms that may be involved in β-cell dysfunction and pathogenesis of diabetes, including the role of nutrition, oxidative stress and inflammation. We will mainly focus on the role of DNA methylation and histone modifications but will also briefly review data on miRNA effects on the pancreatic islets. Further studies aimed at better understanding how epigenetic regulation of gene expression controls β-cell function may reveal potential therapeutic targets for prevention and treatment of diabetes. PMID:22810088
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Cui, Yan; Ying, Ying; van Hasselt, Andrew; Ng, Ka Man; Yu, Jun; Zhang, Qian; Jin, Jie; Liu, Dingxie; Rhim, Johng S; Rha, Sun Young; Loyo, Myriam; Chan, Anthony T C; Srivastava, Gopesh; Tsao, George S W; Sellar, Grant C; Sung, Joseph J Y; Sidransky, David; Tao, Qian
2008-08-20
Identification of tumor suppressor genes (TSGs) silenced by CpG methylation uncovers the molecular mechanism of tumorigenesis and potential tumor biomarkers. Loss of heterozygosity at 11q25 is common in multiple tumors including nasopharyngeal carcinoma (NPC). OPCML, located at 11q25, is one of the downregulated genes we identified through digital expression subtraction. Semi-quantitative RT-PCR showed frequent OPCML silencing in NPC and other common tumors, with no homozygous deletion detected by multiplex differential DNA-PCR. Instead, promoter methylation of OPCML was frequently detected in multiple carcinoma cell lines (nasopharyngeal, esophageal, lung, gastric, colon, liver, breast, cervix, prostate), lymphoma cell lines (non-Hodgkin and Hodgkin lymphoma, nasal NK/T-cell lymphoma) and primary tumors, but not in any non-tumor cell line and seldom weakly methylated in normal epithelial tissues. Pharmacological and genetic demethylation restored OPCML expression, indicating a direct epigenetic silencing. We further found that OPCML is stress-responsive, but this response is epigenetically impaired when its promoter becomes methylated. Ecotopic expression of OPCML led to significant inhibition of both anchorage-dependent and -independent growth of carcinoma cells with endogenous silencing. Thus, through functional epigenetics, we identified OPCML as a broad tumor suppressor, which is frequently inactivated by methylation in multiple malignancies.
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Testicular cancer from diagnosis to epigenetic factors
Boccellino, Mariarosaria; Vanacore, Daniela; Zappavigna, Silvia; Cavaliere, Carla; Rossetti, Sabrina; D’Aniello, Carmine; Chieffi, Paolo; Amler, Evzen; Buonerba, Carlo; Di Lorenzo, Giuseppe; Di Franco, Rossella; Izzo, Alessandro; Piscitelli, Raffaele; Iovane, Gelsomina; Muto, Paolo; Botti, Gerardo; Perdonà, Sisto; Caraglia, Michele; Facchini, Gaetano
2017-01-01
Testicular cancer (TC) is one of the most common neoplasms that occurs in male and includes germ cell tumors (GCT), sex cord-gonadal stromal tumors and secondary testicular tumors. Diagnosis of TC involves the evaluation of serum tumor markers alpha-fetoprotein, human chorionic gonadotropin and lactate dehydrogenase, but clinically several types of immunohistochemical markers are more useful and more sensitive in GCT, but not in teratoma. These new biomarkers are genes expressed in primordial germ cells/gonocytes and embryonic pluripotency-related cells but not in normal adult germ cells and they include PLAP, OCT3/4 (POU5F1), NANOG, SOX2, REX1, AP-2γ (TFAP2C) and LIN28. Gene expression in GCT is regulated, at least in part, by DNA and histone modifications, and the epigenetic profile of these tumours is characterised by genome-wide demethylation. There are different epigenetic modifications in TG-subtypes that reflect the normal developmental switch in primordial germ cells from an under- to normally methylated genome. The main purpose of this review is to illustrate the findings of recent investigations in the classification of male genital organs, the discoveries in the use of prognostic and diagnostic markers and the epigenetic aberrations mainly affecting the patterns of DNA methylation/histone modifications of genes (especially tumor suppressors) and microRNAs (miRNAs). PMID:29262668
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2016-01-01
The epigenetic mechanism of DNA methylation is of central importance for cellular differentiation processes. Unrestricted somatic stem cells (USSCs) from human umbilical cord blood, which have a broad differentiation spectrum, reside in an uncommitted epigenetic state with partial methylation of the regulatory region of the gene coding for the pluripotency master regulator OCT4. Thus we hypothesized that further opening of this “poised” epigenetic state could broaden the differentiation potential of USSCs. Here we document that USSCs drastically change their phenotype after treatment by a new elaborated cultivation protocol which utilizes the DNA hypomethylating compound 5′-aza-2-deoxycytidine (5-Aza-CdR) and the histone deacetylase inhibitor trichostatin A (TSA). This treatment leads to a new stable, spheroid-forming cell type which we have named SpheUSSC. These cells can be stably propagated over at least 150 cell divisions, express OCT4, retain the potential to undergo osteogenic differentiation, and have additionally acquired the ability to uniformly differentiate into adipocytes, unlike the source USSC population. Here we describe our treatment protocol and provide evidence that it induces a dedifferentiation step and concomitantly the acquisition of an extended differentiation capability of the new SpheUSSC type. PMID:26788071
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The multifaceted interplay between lipids and epigenetics.
Dekkers, Koen F; Slagboom, P Eline; Jukema, J Wouter; Heijmans, Bastiaan T
2016-06-01
The interplay between lipids and epigenetic mechanisms has recently gained increased interest because of its relevance for common diseases and most notably atherosclerosis. This review discusses recent advances in unravelling this interplay with a particular focus on promising approaches and methods that will be able to establish causal relationships. Complementary approaches uncovered close links between circulating lipids and epigenetic mechanisms at multiple levels. A characterization of lipid-associated genetic variants suggests that these variants exert their influence on lipid levels through epigenetic changes in the liver. Moreover, exposure of monocytes to lipids persistently alters their epigenetic makeup resulting in more proinflammatory cells. Hence, epigenetic changes can both impact on and be induced by lipids. It is the combined application of technological advances to probe epigenetic modifications at a genome-wide scale and methodological advances aimed at causal inference (including Mendelian randomization and integrative genomics) that will elucidate the interplay between circulating lipids and epigenetics. Understanding its role in the development of atherosclerosis holds the promise of identifying a new category of therapeutic targets, since epigenetic changes are amenable to reversal.
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Probing the Role of HDACs and Mechanisms of Chromatin-Mediated Neuroplasticity
Haggarty, Stephen J.; Tsai, Li-Huei
2011-01-01
Advancing our understanding of neuroplasticity and the development of novel therapeutics based upon this knowledge is critical in order to improve the treatment and prevention of a myriad of nervous system disorders. Epigenetic mechanisms of neuroplasticity involve the post-translational modification of chromatin and the recruitment or loss of macromolecular complexes that control neuronal activity-dependent gene expression. While over a century after Ramón y Cajal first described nuclear subcompartments and foci that we now know correspond to sites of active transcription with acetylated histones that are under epigenetic control, the rate and extent to which epigenetic processes act in a dynamic and combinatorial fashion to shape experience-dependent phenotypic and behavioral plasticity in response to various types of neuronal stimuli over a range of time scales is only now coming into focus. With growing recognition that a subset of human diseases involving cognitive dysfunction can be classified as ‘chromatinopathies’, in which aberrant chromatin-mediated neuroplasticity plays a causal role in the underlying disease pathophysiology, understanding the molecular nature of epigenetic mechanisms in the nervous system may provide important new avenues for the development of novel therapeutics. In this review, we discuss the chemistry and neurobiology of the histone deacetylase (HDAC) family of chromatin-modifying enzymes, outline the role of HDACs in the epigenetic control of neuronal function, and discuss the potential relevance of these epigenetic mechanisms to the development of therapeutics aiming to enhance memory and neuroplasticity. Finally, open questions, challenges, and critical needs for the field of ‘neuroepigenetics’ in the years to come will be summarized. PMID:21545841