Epigenetic regulation of persistent pain

PubMed Central

Bai, Guang; Ren, Ke; Dubner, Ronald

2014-01-01

Persistent or chronic pain is tightly associated with various environmental changes and linked to abnormal gene expression within cells processing nociceptive signaling. Epigenetic regulation governs gene expression in response to environmental cues. Recent animal model and clinical studies indicate that epigenetic regulation plays an important role in the development/maintenance of persistent pain and, possibly the transition of acute pain to chronic pain, thus shedding light in a direction for development of new therapeutics for persistent pain. PMID:24948399

Epigenetics and colorectal cancer pathogenesis.

PubMed

Bardhan, Kankana; Liu, Kebin

2013-06-05

Colorectal cancer (CRC) develops through a multistage process that results from the progressive accumulation of genetic mutations, and frequently as a result of mutations in the Wnt signaling pathway. However, it has become evident over the past two decades that epigenetic alterations of the chromatin, particularly the chromatin components in the promoter regions of tumor suppressors and oncogenes, play key roles in CRC pathogenesis. Epigenetic regulation is organized at multiple levels, involving primarily DNA methylation and selective histone modifications in cancer cells. Assessment of the CRC epigenome has revealed that virtually all CRCs have aberrantly methylated genes and that the average CRC methylome has thousands of abnormally methylated genes. Although relatively less is known about the patterns of specific histone modifications in CRC, selective histone modifications and resultant chromatin conformation have been shown to act, in concert with DNA methylation, to regulate gene expression to mediate CRC pathogenesis. Moreover, it is now clear that not only DNA methylation but also histone modifications are reversible processes. The increased understanding of epigenetic regulation of gene expression in the context of CRC pathogenesis has led to development of epigenetic biomarkers for CRC diagnosis and epigenetic drugs for CRC therapy.

Epigenetics and Colorectal Cancer Pathogenesis

PubMed Central

Bardhan, Kankana; Liu, Kebin

2013-01-01

Colorectal cancer (CRC) develops through a multistage process that results from the progressive accumulation of genetic mutations, and frequently as a result of mutations in the Wnt signaling pathway. However, it has become evident over the past two decades that epigenetic alterations of the chromatin, particularly the chromatin components in the promoter regions of tumor suppressors and oncogenes, play key roles in CRC pathogenesis. Epigenetic regulation is organized at multiple levels, involving primarily DNA methylation and selective histone modifications in cancer cells. Assessment of the CRC epigenome has revealed that virtually all CRCs have aberrantly methylated genes and that the average CRC methylome has thousands of abnormally methylated genes. Although relatively less is known about the patterns of specific histone modifications in CRC, selective histone modifications and resultant chromatin conformation have been shown to act, in concert with DNA methylation, to regulate gene expression to mediate CRC pathogenesis. Moreover, it is now clear that not only DNA methylation but also histone modifications are reversible processes. The increased understanding of epigenetic regulation of gene expression in the context of CRC pathogenesis has led to development of epigenetic biomarkers for CRC diagnosis and epigenetic drugs for CRC therapy. PMID:24216997

Epigenetic regulation in obesity.

PubMed

Drummond, Elaine M; Gibney, Eileen R

2013-07-01

Research suggests that 65% of variation in obesity is genetic. However, much of the known genetic associations have little known function and their effect size small, thus the gene-environment interaction, including epigenetic influences on gene expression, is suggested to be an important factor in the susceptibilty to obesity. This review will explore the potential of epigenetic markers to influence expression of genes associated with obesity. Epigenetic changes in utero are known to have direct implications on the phenotype of the offspring. More recently work has focused on how such epigenetic changes continue to regulate risk of obesity from infancy through to adulthood. Work has shown that, for example, hypomethylation of the MC4 gene causes an increase in expression, and has a direct impact on appetite and intake, and thus influences risk of obesity. Similar influences are also seen in other aspects of obesity including inflammation and adiposity. Maternal diet during foetal development has many epigenetic implications, which affect the offspring's risk factors for obesity during childhood and adulthood, and even in subsequent generations. Genes associated with risk of obesity, are susceptible to epigenetic mutations, which have subsequent effects on disease mechanisms, such as appetite and impaired glucose and insulin tolerance.

Epigenetics of prostate cancer.

PubMed

Li, Long-Cheng

2007-05-01

Prostate cancer is the most common type of cancer other than skin cancer and the second leading cause of cancer death in men in the United States. Its exact causes are unknown. Several risk factors have been associated with prostate cancer including age, race, family history and diet. Epigenetic mechanisms including DNA methylation and histone modifications are important means of gene regulation and play essential roles in diverse biological and disease processes. Recently, frequent epigenetic aberrations such as DNA hypo- and hypermethylation and altered histone acetylation and methylation have been observed in prostate cancer affecting the expression and function of a large array of genes, leading to tumorigenesis, tumor progression and metastasis. In this chapter, we examined the current literature regarding epigenetic changes in prostate cancer and discuss the clinical potential of cancer epigenetics for the diagnosis and treatment of this disease.

Epigenetic regulation in dental pulp inflammation

PubMed Central

Hui, T; Wang, C; Chen, D; Zheng, L; Huang, D; Ye, L

2016-01-01

Dental caries, trauma, and other possible factors could lead to injury of the dental pulp. Dental infection could result in immune and inflammatory responses mediated by molecular and cellular events and tissue breakdown. The inflammatory response of dental pulp could be regulated by genetic and epigenetic events. Epigenetic modifications play a fundamental role in gene expression. The epigenetic events might play critical roles in the inflammatory process of dental pulp injury. Major epigenetic events include methylation and acetylation of histones and regulatory factors, DNA methylation, and small non-coding RNAs. Infections and other environmental factors have profound effects on epigenetic modifications and trigger diseases. Despite growing evidences of literatures addressing the role of epigenetics in the field of medicine and biology, very little is known about the epigenetic pathways involved in dental pulp inflammation. This review summarized the current knowledge about epigenetic mechanisms during dental pulp inflammation. Progress in studies of epigenetic alterations during inflammatory response would provide opportunities for the development of efficient medications of epigenetic therapy for pulpitis. PMID:26901577

Epigenetic Regulation in Plant Responses to the Environment

PubMed Central

Baulcombe, David C.; Dean, Caroline

2014-01-01

In this article, we review environmentally mediated epigenetic regulation in plants using two case histories. One of these, vernalization, mediates adaptation of plants to different environments and it exemplifies processes that are reset in each generation. The other, virus-induced silencing, involves transgenerationally inherited epigenetic modifications. Heritable epigenetic marks may result in heritable phenotypic variation, influencing fitness, and so be subject to natural selection. However, unlike genetic inheritance, the epigenetic modifications show instability and are influenced by the environment. These two case histories are then compared with other phenomena in plant biology that are likely to represent epigenetic regulation in response to the environment. PMID:25183832

Epigenetic regulation in allergic diseases and related studies

PubMed Central

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

Abnormal Epigenetic Regulation of Immune System during Aging.

PubMed

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.

Inflammation and epigenetic regulation in osteoarthritis

PubMed Central

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

Epigenetics of reproductive infertility.

PubMed

Das, Laxmidhar; Parbin, Sabnam; Pradhan, Nibedita; Kausar, Chahat; Patra, Samir K

2017-06-01

Infertility is a complex pathophysiological condition. It may caused by specific or multiple physical and physiological factors, including abnormalities in homeostasis, hormonal imbalances and genetic alterations. In recent times various studies implicated that, aberrant epigenetic mechanisms are associated with reproductive infertility. There might be transgenerational effects associated with epigenetic modifications of gametes and studies suggest the importance of alterations in epigenetic modification at early and late stages of gametogenesis. To determine the causes of infertility it is necessary to understand the altered epigenetic modifications of associated gene and mechanisms involved therein. This review is devoted to elucidate the recent mechanistic advances in regulation of genes by epigenetic modification and emphasizes their possible role related to reproductive infertility. It includes environmental, nutritional, hormonal and physiological factors and influence of internal structural architecture of chromatin nucleosomes affecting DNA and histone modifications in both male and female gametes, early embryogenesis and offspring. Finally, we would like to emphasize that research on human infertility by gene knock out of epigenetic modifiers genes must be relied upon animal models.

Targeting of epigenetic regulators in neuroblastoma.

PubMed

Jubierre, Luz; Jiménez, Carlos; Rovira, Eric; Soriano, Aroa; Sábado, Constantino; Gros, Luis; Llort, Anna; Hladun, Raquel; Roma, Josep; Toledo, Josep Sánchez de; Gallego, Soledad; Segura, Miguel F

2018-04-27

Approximately 15,000 new cases of pediatric cancer are diagnosed yearly in Europe, with 8-10% corresponding to neuroblastoma, a rare disease with an incidence of 8-9 cases per million children <15 years of age. Although the survival rate for low-risk and intermediate-risk patients is excellent, half of children with high-risk, refractory, or relapsed tumors will be cured, and two-thirds of the other half will suffer major side effects and life-long disabilities. Epigenetic therapies aimed at reversing the oncogenic alterations in chromatin structure and function are an emerging alternative against aggressive tumors that are or will become resistant to conventional treatments. This approach proposes targeting epigenetic regulators, which are proteins that are involved in the creation, detection, and interpretation of epigenetic signals, such as methylation or histone post-translational modifications. In this review, we focused on the most promising epigenetic regulators for targeting and current drugs that have already reached clinical trials.

Epigenetic regulation of inflammation in stroke

PubMed Central

Ng, Gavin Yong-Quan; Yun-An, Lim; Sobey, Christopher G.; Dheen, Thameem; Fann, David Yang-Wei; Arumugam, Thiruma V.

2018-01-01

Despite extensive research, treatments for clinical stroke are still limited only to the administration of tissue plasminogen activator and the recent introduction of mechanical thrombectomy, which can be used in only a limited proportion of patients due to time constraints. A plethora of inflammatory events occur during stroke, arising in part due to the body’s immune response to brain injury. Neuroinflammation contributes significantly to neuronal cell death and the development of functional impairment and death in stroke patients. Therefore, elucidating the molecular and cellular mechanisms underlying inflammatory damage following stroke injury will be essential for the development of useful therapies. Research findings increasingly point to the likelihood that epigenetic mechanisms play a role in the pathophysiology of stroke. Epigenetics involves the differential regulation of gene expression, including those involved in brain inflammation and remodelling after stroke. Hence, it is conceivable that epigenetic mechanisms may contribute to differential interindividual vulnerability and injury responses to cerebral ischaemia. In this review, we summarize recent findings on the emerging role of epigenetics in the regulation of neuroinflammation in stroke. We also discuss potential epigenetic targets that may be assessed for the development of stroke therapies. PMID:29774056

Epigenetics: Beyond Chromatin Modifications and Complex Genetic Regulation1

PubMed Central

Eichten, Steven R.; Schmitz, Robert J.; Springer, Nathan M.

2014-01-01

Chromatin modifications and epigenetics may play important roles in many plant processes, including developmental regulation, responses to environmental stimuli, and local adaptation. Chromatin modifications describe biochemical changes to chromatin state, such as alterations in the specific type or placement of histones, modifications of DNA or histones, or changes in the specific proteins or RNAs that associate with a genomic region. The term epigenetic is often used to describe a variety of unexpected patterns of gene regulation or inheritance. Here, we specifically define epigenetics to include the key aspects of heritability (stable transmission of gene expression states through mitotic or meiotic cell divisions) and independence from DNA sequence changes. We argue against generically equating chromatin and epigenetics; although many examples of epigenetics involve chromatin changes, those chromatin changes are not always heritable or may be influenced by genetic changes. Careful use of the terms chromatin modifications and epigenetics can help separate the biochemical mechanisms of regulation from the inheritance patterns of altered chromatin states. Here, we also highlight examples in which chromatin modifications and epigenetics affect important plant processes. PMID:24872382

The Role of Epigenetics in the Fibrotic Processes Associated with Glaucoma

PubMed Central

O'Brien, Colm

2014-01-01

Glaucoma is an optic neuropathy that affects 60 million people worldwide. The main risk factor for glaucoma is increased intraocular pressure (IOP), this is currently the only target for treatment of glaucoma. However, some patients show disease progression despite well-controlled IOP. Another possible therapeutic target is the extracellular matrix (ECM) changes in glaucoma. There is an accumulation of ECM in the lamina cribrosa (LC) and trabecular meshwork (TM) and upregulation of profibrotic factors such as transforming growth factor β (TGFβ), collagen1α1 (COL1A1), and α-smooth muscle actin (αSMA). One method of regulating fibrosis is through epigenetics; the study of heritable changes in gene function caused by mechanisms other than changes in the underlying DNA sequence. Epigenetic mechanisms have been shown to drive renal and pulmonary fibrosis by upregulating profibrotic factors. Hypoxia alters epigenetic mechanisms through regulating the cell's response and there is a hypoxic environment in the LC and TM in glaucoma. This review looks at the role that hypoxia plays in inducing aberrant epigenetic mechanisms and the role these mechanisms play in inducing fibrosis. Evidence suggests that a hypoxic environment in glaucoma may induce aberrant epigenetic mechanisms that contribute to disease fibrosis. These may prove to be relevant therapeutic targets in glaucoma. PMID:24800062

Epigenetic events underlie the pathogenesis of sinonasal papillomas.

PubMed

Stephen, Josena K; Vaught, Lori E; Chen, Kang M; Sethi, Seema; Shah, Veena; Benninger, Michael S; Gardner, Glendon M; Schweitzer, Vanessa G; Khan, Mumtaz; Worsham, Maria J

2007-10-01

Benign inverted papillomas have been reported as monoclonal but lacking common genetic alterations identified in squamous cell carcinoma of the head and neck. Epigenetic changes alter the heritable state of gene expression and chromatin organization without change in DNA sequence. We investigated whether epigenetic events of aberrant promoter hypermethylation in genes known to be involved in squamous head and neck cancer underlie the pathogenesis of sinonasal papillomas. Ten formalin-fixed paraffin DNA samples from three inverted papilloma cases, two exophytic (everted) papilloma cases, and two cases with inverted and exophytic components were studied. DNA was obtained from microdissected areas of normal and papilloma areas and examined using a panel of 41 gene probes, designed to interrogate 35 unique genes for aberrant methylation status (22 genes) using the methylation-specific multiplex-ligation-specific polymerase assay. Methylation-specific PCR was employed to confirm aberrant methylation detected by the methylation-specific multiplex-ligation-specific polymerase assay. All seven cases indicated at least one epigenetic event of aberrant promoter hypermethylation. The CDKN2B gene was a consistent target of aberrant methylation in six of seven cases. Methylation-specific PCR confirmed hypermethylation of CDKN2B. Recurrent biopsies from two inverted papilloma cases had common epigenetic events. Promoter hypermethylation of CDKN2B was a consistent epigenetic event. Common epigenetic alterations in recurrent biopsies underscore a monoclonal origin for these lesions. Epigenetic events contribute to the underlying pathogenesis of benign inverted and exophytic papillomas. As a consistent target of aberrant promoter hypermethylation, CDKN2B may serve as an important epigenetic biomarker for gene reactivation studies.

Dietary Epigenetics in Cancer and Aging

PubMed Central

Tollefsbol, Trygve O.

2013-01-01

Although epigenetic aberrations frequently occur in aging and cancer and form a core component of these conditions, perhaps the most useful aspect of epigenetic processes is that they are readily reversible. Unlike genetic effects that also play a role in cancer and aging, epigenetic aberrations can be relatively easily corrected. One of the most widespread approaches to the epigenetic alterations in cancer and aging is dietary control. This can be achieved not only through the quality of the diet, but also through the quantity of calories that are consumed. Many phytochemicals such as sulforaphane from cruciferous vegetables and green tea have anticancer epigenetic effects and are also efficacious for preventing or treating the epigenetic aberrations of other age-associated diseases besides cancer. Likewise, the quantity of calories that are consumed have proven to be advantageous in preventing cancer and extending the lifespan through control of epigenetic mediators. The purpose of this chapter is to review some of the most recent advances in the epigenetics of cancer and aging and to provide insights into advances being made with respect to dietary intervention into these biological processes that have vast health implications and high translational potential. PMID:24114485

Genome-Wide Methylome Analyses Reveal Novel Epigenetic Regulation Patterns in Schizophrenia and Bipolar Disorder

PubMed Central

Li, Yongsheng; Camarillo, Cynthia; Xu, Juan; Arana, Tania Bedard; Xiao, Yun; Zhao, Zheng; Chen, Hong; Ramirez, Mercedes; Zavala, Juan; Escamilla, Michael A.; Armas, Regina; Mendoza, Ricardo; Ontiveros, Alfonso; Nicolini, Humberto; Jerez Magaña, Alvaro Antonio; Rubin, Lewis P.; Li, Xia; Xu, Chun

2015-01-01

Schizophrenia (SZ) and bipolar disorder (BP) are complex genetic disorders. Their appearance is also likely informed by as yet only partially described epigenetic contributions. Using a sequencing-based method for genome-wide analysis, we quantitatively compared the blood DNA methylation landscapes in SZ and BP subjects to control, both in an understudied population, Hispanics along the US-Mexico border. Remarkably, we identified thousands of differentially methylated regions for SZ and BP preferentially located in promoters 3′-UTRs and 5′-UTRs of genes. Distinct patterns of aberrant methylation of promoter sequences were located surrounding transcription start sites. In these instances, aberrant methylation occurred in CpG islands (CGIs) as well as in flanking regions as well as in CGI sparse promoters. Pathway analysis of genes displaying these distinct aberrant promoter methylation patterns showed enhancement of epigenetic changes in numerous genes previously related to psychiatric disorders and neurodevelopment. Integration of gene expression data further suggests that in SZ aberrant promoter methylation is significantly associated with altered gene transcription. In particular, we found significant associations between (1) promoter CGIs hypermethylation with gene repression and (2) CGI 3′-shore hypomethylation with increased gene expression. Finally, we constructed a specific methylation analysis platform that facilitates viewing and comparing aberrant genome methylation in human neuropsychiatric disorders. PMID:25734057

Allosteric regulation of epigenetic modifying enzymes.

PubMed

Zucconi, Beth E; Cole, Philip A

2017-08-01

Epigenetic enzymes including histone modifying enzymes are key regulators of gene expression in normal and disease processes. Many drug development strategies to target histone modifying enzymes have focused on ligands that bind to enzyme active sites, but allosteric pockets offer potentially attractive opportunities for therapeutic development. Recent biochemical studies have revealed roles for small molecule and peptide ligands binding outside of the active sites in modulating the catalytic activities of histone modifying enzymes. Here we highlight several examples of allosteric regulation of epigenetic enzymes and discuss the biological significance of these findings. Copyright © 2017 Elsevier Ltd. All rights reserved.

Epigenetic regulation of multiple tumor-related genes leads to suppression of breast tumorigenesis by dietary genistein.

PubMed

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.

Epigenetic regulation of immune checkpoints: another target for cancer immunotherapy?

PubMed

Ali, Mahmoud A; Matboli, Marwa; Tarek, Marwa; Reda, Maged; Kamal, Kamal M; Nouh, Mahmoud; Ashry, Ahmed M; El-Bab, Ahmed Fath; Mesalam, Hend A; Shafei, Ayman El-Sayed; Abdel-Rahman, Omar

2017-01-01

Epigenetic changes in oncogenes and tumor-suppressor genes contribute to carcinogenesis. Understanding the epigenetic and genetic components of tumor immune evasion is crucial. Few cancer genetic mutations have been linked to direct correlations with immune evasion. Studies on the epigenetic modulation of the immune checkpoints have revealed a critical interaction between epigenetic and immune modulation. Epigenetic modifiers can activate many silenced genes. Some of them are immune checkpoints regulators that turn on immune responses and others turn them off resulting in immune evasion. Many forms of epigenetic inheritance mechanisms may play a role in regulation of immune checkpoints including: covalent modifications, noncoding RNA and histone modifications. In this review, we will show how the potential interaction between epigenetic and immune modulation may lead to new approaches for specific epigenome/immunome-targeted therapies for cancer.

Epigenetics in breast and prostate cancer.

PubMed

Wu, Yanyuan; Sarkissyan, Marianna; Vadgama, Jaydutt V

2015-01-01

Most recent investigations into cancer etiology have identified a key role played by epigenetics. Specifically, aberrant DNA and histone modifications which silence tumor suppressor genes or promote oncogenes have been demonstrated in multiple cancer models. While the role of epigenetics in several solid tumor cancers such as colorectal cancer are well established, there is emerging evidence that epigenetics also plays a critical role in breast and prostate cancer. In breast cancer, DNA methylation profiles have been linked to hormone receptor status and tumor progression. Similarly in prostate cancer, epigenetic patterns have been associated with androgen receptor status and response to therapy. The regulation of key receptor pathways and activities which affect clinical therapy treatment options by epigenetics renders this field high priority for elucidating mechanisms and potential targets. A new set of methylation arrays are now available to screen epigenetic changes and provide the cutting-edge tools needed to perform such investigations. The role of nutritional interventions affecting epigenetic changes particularly holds promise. Ultimately, determining the causes and outcomes from epigenetic changes will inform translational applications for utilization as biomarkers for risk and prognosis as well as candidates for therapy.

Epigenetics in Breast and Prostate Cancer

PubMed Central

Wu, Yanyuan; Sarkissyan, Marianna; Vadgama, Jaydutt V.

2015-01-01

SUMMARY Most recent investigations into cancer etiology have identified a key role played by epigenetics. Specifically, aberrant DNA and histone modifications which silence tumor suppressor genes or promote oncogenes have been demonstrated in multiple cancer models. While the role of epigenetics in several solid tumor cancers such as colorectal cancer are well established, there is emerging evidence that epigenetics also plays a critical role in breast and prostate cancer. In breast cancer, DNA methylation profiles have been linked to hormone receptor status and tumor progression. Similarly in prostate cancer, epigenetic patterns have been associated with androgen receptor status and response to therapy. The regulation of key receptor pathways and activities which affect clinical therapy treatment options by epigenetics renders this field high priority for elucidating mechanisms and potential targets. A new set of methylation arrays are now available to screen epigenetic changes and provide the cuttingedge tools needed to perform such investigations. The role of nutritional interventions affecting epigenetic changes particularly holds promise. Ultimately, determining the causes and outcomes from epigenetic changes will inform translational applications for utilization as biomarkers for risk and prognosis as well as candidates for therapy. PMID:25421674

Hypoxia-Mediated Epigenetic Regulation of Stemness in Brain Tumor Cells.

PubMed

Prasad, Pankaj; Mittal, Shivani Arora; Chongtham, Jonita; Mohanty, Sujata; Srivastava, Tapasya

2017-06-01

Activation of pluripotency regulatory circuit is an important event in solid tumor progression and the hypoxic microenvironment is known to enhance the stemness feature of some cells. The distinct population of cancer stem cells (CSCs)/tumor initiating cells exist in a niche and augment invasion, metastasis, and drug resistance. Previously, studies have reported global hypomethylation and site-specific aberrant methylation in gliomas along with other epigenetic modifications as important contributors to genomic instability during glioma progression. Here, we have demonstrated the role of hypoxia-mediated epigenetic modifications in regulating expression of core pluripotency factors, OCT4 and NANOG, in glioma cells. We observe hypoxia-mediated induction of demethylases, ten-eleven-translocation (TET) 1 and 3, but not TET2 in our cell-line model. Immunoprecipitation studies reveal active demethylation and direct binding of TET1 and 3 at the Oct4 and Nanog regulatory regions. Tet1 and 3 silencing assays further confirmed induction of the pluripotency pathway involving Oct4, Nanog, and Stat3, by these paralogues, although with varying degrees. Knockdown of Tet1 and Tet3 inhibited the formation of neurospheres in hypoxic conditions. We observed independent roles of TET1 and TET3 in differentially regulating pluripotency and differentiation associated genes in hypoxia. Overall, this study demonstrates an active demethylation in hypoxia by TET1 and 3 as a mechanism of Oct4 and Nanog overexpression thus contributing to the formation of CSCs in gliomas. Stem Cells 2017;35:1468-1478. © 2017 AlphaMed Press.

Transcriptional profiling of epigenetic regulators in somatic embryos during temperature induced formation of an epigenetic memory in Norway spruce.

PubMed

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.

Targeting the Epigenome in Lung Cancer: Expanding Approaches to Epigenetic Therapy

PubMed Central

Jakopovic, Marko; Thomas, Anish; Balasubramaniam, Sanjeeve; Schrump, David; Giaccone, Giuseppe; Bates, Susan E.

2013-01-01

Epigenetic aberrations offer dynamic and reversible targets for cancer therapy; increasingly, alteration via overexpression, mutation, or rearrangement is found in genes that control the epigenome. Such alterations suggest a fundamental role in carcinogenesis. Here, we consider three epigenetic mechanisms: DNA methylation, histone tail modification and non-coding, microRNA regulation. Evidence for each of these in lung cancer origin or progression has been gathered, along with evidence that epigenetic alterations might be useful in early detection. DNA hypermethylation of tumor suppressor promoters has been observed, along with global hypomethylation and hypoacetylation, suggesting an important role for tumor suppressor gene silencing. These features have been linked as prognostic markers with poor outcome in lung cancer. Several lines of evidence have also suggested a role for miRNA in carcinogenesis and in outcome. Cigarette smoke downregulates miR-487b, which targets both RAS and MYC; RAS is also a target of miR-let-7, again downregulated in lung cancer. Together the evidence implicates epigenetic aberration in lung cancer and suggests that targeting these aberrations should be carefully explored. To date, DNA methyltransferase and histone deacetylase inhibitors have had minimal clinical activity. Explanations include the possibility that the agents are not sufficiently potent to invoke epigenetic reversion to a more normal state; that insufficient time elapses in most clinical trials to observe true epigenetic reversion; and that doses often used may provoke off-target effects such as DNA damage that prevent epigenetic reversion. Combinations of epigenetic therapies may address those problems. When epigenetic agents are used in combination with chemotherapy or targeted therapy it is hoped that downstream biological effects will provoke synergistic cytotoxicity. This review evaluates the challenges of exploiting the epigenome in the treatment of lung cancer

Epigenetic Deregulation of MicroRNAs in Rhabdomyosarcoma and Neuroblastoma and Translational Perspectives

PubMed Central

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

Clinical implications of epigenetic regulation in oral cancer.

PubMed

D'Souza, Wendy; Saranath, Dhananjaya

2015-12-01

Oral cancer is a high incidence cancer which is of major public health concern in India being the most common cancer in males and fifth most common cancer in females in India, contributing to 26% of the global oral cancer burden. The major risk factors of oral cancer are tobacco, alcohol and high risk Human Papilloma Virus type 16/18. However, only 3-12% of the high risk individuals with dysplasia develop oral cancer. Thus, individual genomic variants representing the genomic constitution and epigenetic alterations play a critical role in the development of oral cancer. Extensive epigenetic studies on the molecular lesions including oncogenes, tumor suppressor genes, genes associated with apoptosis, DNA damage repair have been reported. The current review highlights epigenetic regulation with a focus on molecular biomarkers and epidrug therapy in oral cancer. Epigenetic regulation by hypermethylation, histone modifications and specific microRNAs are often associated with early events and advanced stages in oral cancer, and thus indicate epidrug therapy for intervention. The presence of epigenetic marks in oral lesions, cancers and tumor associated mucosa emphasizes indications as biomarkers and epidrugs with therapeutic potential for better patient management. Copyright © 2015 Elsevier Ltd. All rights reserved.

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

Nutritional regulation of epigenetic changes

USDA-ARS?s Scientific Manuscript database

The "Nutritional Regulation of Epigenetic Changes" Symposium was held in San Diego on April 25 in conjunction with the 2012 Annual Meetings of the American Society of Nutrition. The symposium was co-chaired by Drs. Romagnoo and Ziegler. In his opening remarks, Dr. Zeigler highlighted salient aspec...

Regulation of Stem Cell Aging by Metabolism and Epigenetics.

PubMed

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.

Epigenetic mechanisms in experience-driven memory formation and behavior.

PubMed

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.

Genetic Determinants of Epigenetic Patterns: Providing Insight into Disease.

PubMed

Cazaly, Emma; Charlesworth, Jac; Dickinson, Joanne L; Holloway, Adele F

2015-03-26

The field of epigenetics and our understanding of the mechanisms that regulate the establishment, maintenance and heritability of epigenetic patterns continue to grow at a remarkable rate. This information is providing increased understanding of the role of epigenetic changes in disease, insight into the underlying causes of these epigenetic changes and revealing new avenues for therapeutic intervention. Epigenetic modifiers are increasingly being pursued as therapeutic targets in a range of diseases, with a number of agents targeting epigenetic modifications already proving effective in diseases such as cancer. Although it is well established that DNA mutations and aberrant expression of epigenetic modifiers play a key role in disease, attention is now turning to the interplay between genetic and epigenetic factors in complex disease etiology. The role of genetic variability in determining epigenetic profiles, which can then be modified by environmental and stochastic factors, is becoming more apparent. Understanding the interplay between genetic and epigenetic factors is likely to aid in identifying individuals most likely to benefit from epigenetic therapies. This goal is coming closer to realization because of continual advances in laboratory and statistical tools enabling improvements in the integration of genomic, epigenomic and phenotypic data.

Epigenetic deregulation in chronic lymphocytic leukemia: Clinical and biological impact.

PubMed

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.

Epigenetic regulation by selected dietary phytochemicals in cancer chemoprevention

PubMed Central

Shukla, Samriddhi; Meeran, Syed M.; Katiyar, Santosh K.

2014-01-01

The growing interest in cancer epigenetics is largely due to the reversible nature of epigenetic changes which tend to alter during the course of carcinogenesis. Major epigenetic changes including DNA methylation, chromatin modifications and miRNA regulation play important roles in tumorigenic process. There are several epigenetically active synthetic molecules such as DNA methyltransferase (DNMTs) and histone deacetylases (HDACs) inhibitors, which are either approved or, are under clinical trials for the treatment of various cancers. However, most of the synthetic inhibitors have shown adverse side effects, narrow in their specificity and also expensive. Hence, bioactive phytochemicals, which are widely available with lesser toxic effects, have been tested for their role in epigenetic modulatory activities in gene regulation for cancer prevention and therapy. Encouragingly, many bioactive phytochemicals potentially altered the expression of key tumor suppressor genes, tumor promoter genes and oncogenes through modulation of DNA methylation and chromatin modification in cancer. These bioactive phytochemicals either alone or in combination with other phytochemicals showed promising results against various cancers. Here, we summarize and discuss the role of some commonly investigated phytochemicals and their epigenetic targets that are of particular interest in cancer prevention and cancer therapy. PMID:25236912

Epigenetics and Colorectal Cancer

PubMed Central

Lao, Victoria Valinluck; Grady, William M.

2012-01-01

Colorectal cancer is a leading cause of cancer deaths in the world. It results from an accumulation of genetic and epigenetic changes in colon epithelial cells that transforms them into adenocarcinomas. There have been major advances in our understanding of cancer epigenetics over the last decade, particularly regarding aberrant DNA methylation. Assessment of the colon cancer epigenome has revealed that virtually all colorectal cancers have aberrantly methylated genes and the average colorectal cancer methylome has hundreds to thousands of abnormally methylated genes. As with gene mutations in the cancer genome, a subset of these methylated genes, called driver genes, is presumed to play a functional role in colorectal cancer. The assessment of methylated genes in colorectal cancers has also revealed a unique molecular subgroup of colorectal cancers called CpG Island Methylator Phenotype (CIMP) cancers; these tumors have a particularly high frequency of methylated genes. The advances in our understanding of aberrant methylation in colorectal cancer has led to epigenetic alterations being developed as clinical biomarkers for diagnostic, prognostic, and therapeutic applications. Progress in the assessment of epigenetic alterations in colorectal cancer and their clinical applications has shown that these alterations will be commonly used in the near future as molecular markers to direct the prevention and treatment of colorectal cancer. PMID:22009203

Genome-Wide Epigenetic Studies in Human Disease: A Primer on -Omic Technologies

PubMed Central

Yan, Huihuang; Tian, Shulan; Slager, Susan L.; Sun, Zhifu; Ordog, Tamas

2016-01-01

Epigenetic information encoded in covalent modifications of DNA and histone proteins regulates fundamental biological processes through the action of chromatin regulators, transcription factors, and noncoding RNA species. Epigenetic plasticity enables an organism to respond to developmental and environmental signals without genetic changes. However, aberrant epigenetic control plays a key role in pathogenesis of disease. Normal epigenetic states could be disrupted by detrimental mutations and expression alteration of chromatin regulators or by environmental factors. In this primer, we briefly review the epigenetic basis of human disease and discuss how recent discoveries in this field could be translated into clinical diagnosis, prevention, and treatment. We introduce platforms for mapping genome-wide chromatin accessibility, nucleosome occupancy, DNA-binding proteins, and DNA methylation, primarily focusing on the integration of DNA methylation and chromatin immunoprecipitation–sequencing technologies into disease association studies. We highlight practical considerations in applying high-throughput epigenetic assays and formulating analytical strategies. Finally, we summarize current challenges in sample acquisition, experimental procedures, data analysis, and interpretation and make recommendations on further refinement in these areas. Incorporating epigenomic testing into the clinical research arsenal will greatly facilitate our understanding of the epigenetic basis of disease and help identify novel therapeutic targets. PMID:26721890

Protein Arginine Methylation and Citrullination in Epigenetic Regulation

PubMed Central

2015-01-01

The post-translational modification of arginine residues represents a key mechanism for the epigenetic control of gene expression. Aberrant levels of histone arginine modifications have been linked to the development of several diseases including cancer. In recent years, great progress has been made in understanding the physiological role of individual arginine modifications and their effects on chromatin function. The present review aims to summarize the structural and functional aspects of histone arginine modifying enzymes and their impact on gene transcription. We will discuss the potential for targeting these proteins with small molecules in a variety of disease states. PMID:26686581

Epigenetic regulation and chromatin remodeling in learning and memory.

PubMed

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.

Epigenetic regulation of development and pathogenesis in fungal plant pathogens.

PubMed

Dubey, Akanksha; Jeon, Junhyun

2017-08-01

Evidently, epigenetics is at forefront in explaining the mechanisms underlying the success of human pathogens and in the identification of pathogen-induced modifications within host plants. However, there is a lack of studies highlighting the role of epigenetics in the modulation of the growth and pathogenicity of fungal plant pathogens. In this review, we attempt to highlight and discuss the role of epigenetics in the regulation of the growth and pathogenicity of fungal phytopathogens using Magnaporthe oryzae, a devastating fungal plant pathogen, as a model system. With the perspective of wide application in the understanding of the development, pathogenesis and control of other fungal pathogens, we attempt to provide a synthesized view of the epigenetic studies conducted on M. oryzae to date. First, we discuss the mechanisms of epigenetic modifications in M. oryzae and their impact on fungal development and pathogenicity. Second, we highlight the unexplored epigenetic mechanisms and areas of research that should be considered in the near future to construct a holistic view of epigenetic functioning in M. oryzae and other fungal plant pathogens. Importantly, the development of a complete understanding of the modulation of epigenetic regulation in fungal pathogens can help in the identification of target points to combat fungal pathogenesis. © 2016 BSPP AND JOHN WILEY & SONS LTD.

Epigenetic regulation by selected dietary phytochemicals in cancer chemoprevention.

PubMed

Shukla, Samriddhi; Meeran, Syed M; Katiyar, Santosh K

2014-12-01

The growing interest in cancer epigenetics is largely due to the reversible nature of epigenetic changes which tend to alter during the course of carcinogenesis. Major epigenetic changes including DNA methylation, chromatin modifications and miRNA regulation play important roles in tumorigenic process. There are several epigenetically active synthetic molecules such as DNA methyltransferase (DNMTs) and histone deacetylases (HDACs) inhibitors, which are either approved or, are under clinical trials for the treatment of various cancers. However, most of the synthetic inhibitors have shown adverse side effects, narrow in their specificity and also expensive. Hence, bioactive phytochemicals, which are widely available with lesser toxic effects, have been tested for their role in epigenetic modulatory activities in gene regulation for cancer prevention and therapy. Encouragingly, many bioactive phytochemicals potentially altered the expression of key tumor suppressor genes, tumor promoter genes and oncogenes through modulation of DNA methylation and chromatin modification in cancer. These bioactive phytochemicals either alone or in combination with other phytochemicals showed promising results against various cancers. Here, we summarize and discuss the role of some commonly investigated phytochemicals and their epigenetic targets that are of particular interest in cancer prevention and cancer therapy. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Epigenetic silencing of the NR4A3 tumor suppressor, by aberrant JAK/STAT signaling, predicts prognosis in gastric cancer

NASA Astrophysics Data System (ADS)

Yeh, Chung-Min; Chang, Liang-Yu; Lin, Shu-Hui; Chou, Jian-Liang; Hsieh, Hsiao-Yen; Zeng, Li-Han; Chuang, Sheng-Yu; Wang, Hsiao-Wen; Dittner, Claudia; Lin, Cheng-Yu; Lin, Jora M. J.; Huang, Yao-Ting; Ng, Enders K. W.; Cheng, Alfred S. L.; Wu, Shu-Fen; Lin, Jiayuh; Yeh, Kun-Tu; Chan, Michael W. Y.

2016-08-01

While aberrant JAK/STAT signaling is crucial to the development of gastric cancer (GC), its effects on epigenetic alterations of its transcriptional targets remains unclear. In this study, by expression microarrays coupled with bioinformatic analyses, we identified a putative STAT3 target gene, NR4A3 that was downregulated in MKN28 GC daughter cells overexpressing a constitutively activated STAT3 mutant (S16), as compared to an empty vector control (C9). Bisulphite pyrosequencing and demethylation treatment showed that NR4A3 was epigenetically silenced by promoter DNA methylation in S16 and other GC cell lines including AGS cells, showing constitutive activation of STAT3. Subsequent experiments revealed that NR4A3 promoter binding by STAT3 might repress its transcription. Long-term depletion of STAT3 derepressed NR4A3 expression, by promoter demethylation, in AGS GC cells. NR4A3 re-expression in GC cell lines sensitized the cells to cisplatin, and inhibited tumor growth in vitro and in vivo, in an animal model. Clinically, GC patients with high NR4A3 methylation, or lower NR4A3 protein expression, had significantly shorter overall survival. Intriguingly, STAT3 activation significantly associated only with NR4A3 methylation in low-stage patient samples. Taken together, aberrant JAK/STAT3 signaling epigenetically silences a potential tumor suppressor, NR4A3, in gastric cancer, plausibly representing a reliable biomarker for gastric cancer prognosis.

Epigenetic Regulation of Transcription in Trypanosomatid Protozoa.

PubMed

Martínez-Calvillo, Santiago; Romero-Meza, Gabriela; Vizuet-de-Rueda, Juan C; Florencio-Martínez, Luis E; Manning-Cela, Rebeca; Nepomuceno-Mejía, Tomás

2018-02-01

The Trypanosomatid family includes flagellated parasites that cause fatal human diseases. Remarkably, protein-coding genes in these organisms are positioned in long tandem arrays that are transcribed polycistronically. However, the knowledge about regulation of transcription initiation and termination in trypanosomatids is scarce. The importance of epigenetic regulation in these processes has become evident in the last years, as distinctive histone modifications and histone variants have been found in transcription initiation and termination regions. Moreover, multiple chromatin-related proteins have been identified and characterized in trypanosomatids, including histone-modifying enzymes, effector complexes, chromatin-remodelling enzymes and histone chaperones. Notably, base J, a modified thymine residue present in the nuclear DNA of trypanosomatids, has been implicated in transcriptional regulation. Here we review the current knowledge on epigenetic control of transcription by all three RNA polymerases in this group of early-diverged eukaryotes.

Epigenetic regulation of bud dormancy events in perennial plants

PubMed Central

Ríos, Gabino; Leida, Carmen; Conejero, Ana; Badenes, María Luisa

2014-01-01

Release of bud dormancy in perennial plants resembles vernalization in Arabidopsis thaliana and cereals. In both cases, a certain period of chilling is required for accomplishing the reproductive phase, and several transcription factors with the MADS-box domain perform a central regulatory role in these processes. The expression of DORMANCY-ASSOCIATED MADS-box (DAM)-related genes has been found to be up-regulated in dormant buds of numerous plant species, such as poplar, raspberry, leafy spurge, blackcurrant, Japanese apricot, and peach. Moreover, functional evidence suggests the involvement of DAM genes in the regulation of seasonal dormancy in peach. Recent findings highlight the presence of genome-wide epigenetic modifications related to dormancy events, and more specifically the epigenetic regulation of DAM-related genes in a similar way to FLOWERING LOCUS C, a key integrator of vernalization effectors on flowering initiation in Arabidopsis. We revise the most relevant molecular and genomic contributions in the field of bud dormancy, and discuss the increasing evidence for chromatin modification involvement in the epigenetic regulation of seasonal dormancy cycles in perennial plants. PMID:24917873

Epigenetic regulation in human melanoma: past and future.

PubMed

Sarkar, Debina; Leung, Euphemia Y; Baguley, Bruce C; Finlay, Graeme J; Askarian-Amiri, Marjan E

2015-01-01

The development and progression of melanoma have been attributed to independent or combined genetic and epigenetic events. There has been remarkable progress in understanding melanoma pathogenesis in terms of genetic alterations. However, recent studies have revealed a complex involvement of epigenetic mechanisms in the regulation of gene expression, including methylation, chromatin modification and remodeling, and the diverse activities of non-coding RNAs. The roles of gene methylation and miRNAs have been relatively well studied in melanoma, but other studies have shown that changes in chromatin status and in the differential expression of long non-coding RNAs can lead to altered regulation of key genes. Taken together, they affect the functioning of signaling pathways that influence each other, intersect, and form networks in which local perturbations disturb the activity of the whole system. Here, we focus on how epigenetic events intertwine with these pathways and contribute to the molecular pathogenesis of melanoma.

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

Epigenetic Regulation of Autism-Associated Genes by Environmental Insults: Novel Associations

DTIC Science & Technology

2009-08-01

TITLE: Epigenetic Regulation of Autism -Associated Genes by Environmental Insults: Novel Associations PRINCIPAL INVESTIGATOR: Daryl Spinner Ph.D...SUBTITL Epigenetic regulation of Autism -associated genes by environmental insults: Novel associations 5a. CONTRACT NUMBER 5b. GRANT NUMBER...environmental-induced cases of autism . Accordingly, we established mouse embryonic cortical cultures of neurons and astrocytes, and exposed them to commonly

Epigenetics of the antibody response

PubMed Central

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

Epigenetic regulation of serotype expression antagonizes transcriptome dynamics in Paramecium tetraurelia

PubMed Central

Cheaib, Miriam; Dehghani Amirabad, Azim; Nordström, Karl J. V.; Schulz, Marcel H.; Simon, Martin

2015-01-01

Phenotypic variation of a single genotype is achieved by alterations in gene expression patterns. Regulation of such alterations depends on their time scale, where short-time adaptations differ from permanently established gene expression patterns maintained by epigenetic mechanisms. In the ciliate Paramecium, serotypes were described for an epigenetically controlled gene expression pattern of an individual multigene family. Paradoxically, individual serotypes can be triggered in Paramecium by alternating environments but are then stabilized by epigenetic mechanisms, thus raising the question to which extend their expression follows environmental stimuli. To characterize environmental adaptation in the context of epigenetically controlled serotype expression, we used RNA-seq to characterize transcriptomes of serotype pure cultures. The resulting vegetative transcriptome resource is first analysed for genes involved in the adaptive response to the altered environment. Secondly, we identified groups of genes that do not follow the adaptive response but show co-regulation with the epigenetically controlled serotype system, suggesting that their gene expression pattern becomes manifested by similar mechanisms. In our experimental set-up, serotype expression and the entire group of co-regulated genes were stable among environmental changes and only heat-shock genes altered expression of these gene groups. The data suggest that the maintenance of these gene expression patterns in a lineage represents epigenetically controlled robustness counteracting short-time adaptation processes. PMID:26231545

Epigenetic regulation of cardiac fibrosis

PubMed Central

Stratton, Matthew S.; McKinsey, Timothy A.

2016-01-01

Fibrosis is defined as excess deposition of extracellular matrix (ECM), resulting in tissue scarring and organ dysfunction. In the heart, fibrosis may be reparative, replacing areas of myocyte loss with a structural scar following infarction, or reactive, which is triggered in the absence of cell death and involves interstitial ECM deposition in response to long-lasting stress. Interstitial fibrosis can increase the passive stiffness of the myocardium, resulting in impaired relaxation and diastolic dysfunction. Additionally, fibrosis can lead to disruption of electrical conduction in the heart, causing arrhythmias, and can limit myocyte oxygen availability and thus exacerbate myocardial ischemia. Here, we review recent studies that have illustrated key roles for epigenetic events in the control of pro-fibrotic gene expression, and highlight the potential of small molecules that target epigenetic regulators as a means of treating fibrotic cardiac diseases. PMID:26876451

DNA replication components as regulators of epigenetic inheritance--lesson from fission yeast centromere.

PubMed

He, Haijin; Gonzalez, Marlyn; Zhang, Fan; Li, Fei

2014-06-01

Genetic information stored in DNA is accurately copied and transferred to subsequent generations through DNA replication. This process is accomplished through the concerted actions of highly conserved DNA replication components. Epigenetic information stored in the form of histone modifications and DNA methylation, constitutes a second layer of regulatory information important for many cellular processes, such as gene expression regulation, chromatin organization, and genome stability. During DNA replication, epigenetic information must also be faithfully transmitted to subsequent generations. How this monumental task is achieved remains poorly understood. In this review, we will discuss recent advances on the role of DNA replication components in the inheritance of epigenetic marks, with a particular focus on epigenetic regulation in fission yeast. Based on these findings, we propose that specific DNA replication components function as key regulators in the replication of epigenetic information across the genome.

Comparison and evaluation of gene therapy and epigenetic approaches for wound healing.

PubMed

Cutroneo, K R; Chiu, J F

2000-01-01

During the past decade considerable evidence has mounted concerning the importance of growth factors in the wound healing process both for cell replication and for stimulating reparative cells to synthesize and secrete extracellular matrix components. During normal wound healing the growth factor concentration has to be maintained at a certain level. If the growth factor concentration is too low, normal healing fails to occur. Whereas if the growth factor concentration is too high due to either over-expression of the growth factor or too much growth factor being applied to the wound, aberrant wound healing will occur. One approach for controlling the amount of growth factor at the wound site during normal healing is through gene therapy and the titration of gene dosage. However if a narrow window exists between the beneficial therapeutic effect and toxic effects with increasing gene dosage, an agent may be necessary to give in combination with gene therapy to regulate the over-expression of growth factor. In addition to genetic approaches to regulate wound healing, epigenetic approaches also exist. Antisense oligodeoxynucleotides have been shown to regulate wound repair in certain model systems and to determine the protein(s) necessary for normal wound healing. A novel approach to regulate the activity of collagen genes, thereby affecting fibrosis, is to use a sense oligodeoxynucleotide having the same sequence of the cis element which regulates the promoter activity of a particular collagen gene. This exogenous oligodeoxynucleotide will compete with the cis element in the collagen gene for the trans-acting factor which regulates promoter activity. These epigenetic approaches afford the opportunity to regulate over-expression of growth factor and therefore preclude the potential toxic effects of gene therapy. Both genetic and epigenetic approaches for regulating the wound healing process, either normal or aberrant wound healing, have certain advantages and

Stress, Epigenetics, and Alcoholism

PubMed Central

Moonat, Sachin; Pandey, Subhash C.

2012-01-01

Acute and chronic stressors have been associated with alterations in mood and increased anxiety that may eventually result in the development of stress-related psychiatric disorders. Stress and associated disorders, including anxiety, are key factors in the development of alcoholism because alcohol consumption can temporarily reduce the drinker’s dysphoria. One molecule that may help mediate the relationship between stress and alcohol consumption is brain-derived neurotrophic factor (BDNF), a protein that regulates the structure and function of the sites where two nerve cells interact and exchange nerve signals (i.e., synapses) and which is involved in numerous physiological processes. Aberrant regulation of BDNF signaling and alterations in synapse activity (i.e., synaptic plasticity) have been associated with the pathophysiology of stress-related disorders and alcoholism. Mechanisms that contribute to the regulation of genetic information without modification of the DNA sequence (i.e., epigenetic mechanisms) may play a role in the complex control of BDNF signaling and synaptic plasticity—for example, by modifying the structure of the DNA–protein complexes (i.e., chromatin) that make up the chromosomes and thereby modulating the expression of certain genes. Studies regarding the epigenetic control of BDNF signaling and synaptic plasticity provide a promising direction to understand the mechanisms mediating the interaction between stress and alcoholism. PMID:23584115

Stress, epigenetics, and alcoholism.

PubMed

Moonat, Sachin; Pandey, Subhash C

2012-01-01

Acute and chronic stressors have been associated with alterations in mood and increased anxiety that may eventually result in the development of stress-related psychiatric disorders. Stress and associated disorders, including anxiety, are key factors in the development of alcoholism because alcohol consumption can temporarily reduce the drinker's dysphoria. One molecule that may help mediate the relationship between stress and alcohol consumption is brain-derived neurotrophic factor (BDNF), a protein that regulates the structure and function of the sites where two nerve cells interact and exchange nerve signals (i.e., synapses) and which is involved in numerous physiological processes. Aberrant regulation of BDNF signaling and alterations in synapse activity (i.e., synaptic plasticity) have been associated with the pathophysiology of stress-related disorders and alcoholism. Mechanisms that contribute to the regulation of genetic information without modification of the DNA sequence (i.e., epigenetic mechanisms) may play a role in the complex control of BDNF signaling and synaptic plasticity-for example, by modifying the structure of the DNA-protein complexes (i.e., chromatin) that make up the chromosomes and thereby modulating the expression of certain genes. Studies regarding the epigenetic control of BDNF signaling and synaptic plasticity provide a promising direction to understand the mechanisms mediating the interaction between stress and alcoholism.

Emerging Trends in Epigenetic Regulation of Nutrient Deficiency Response in Plants.

PubMed

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.

[Epigenetics of prostate cancer].

PubMed

Yi, Xiao-Ming; Zhou, Wen-Quan

2010-07-01

Prostate cancer is one of the most common malignant tumors in males, and its etiology and pathogenesis remain unclear. Epigenesis is involved in prostate cancer at all stages of the process, and closely related with its growth and metastasis. DNA methylation and histone modification are the most important manifestations of epigenetics in prostate cancer. The mechanisms of carcinogenesis of DNA methylation include whole-genome hypomethylation, aberrant local hypermethylation of promoters and genomic instability. DNA methylation is closely related to the process of prostate cancer, as in DNA damage repair, hormone response, tumor cell invasion/metastasis, cell cycle regulation, and so on. Histone modification causes corresponding changes in chromosome structure and the level of gene transcription, and it may affect the cycle, differentiation and apoptosis of cells, resulting in prostate cancer. Some therapies have been developed targeting the epigenetic changes in prostate cancer, including DNA methyltransferases and histone deacetylase inhibitors, and have achieved certain desirable results.

Epigenetic regulation of serotype expression antagonizes transcriptome dynamics in Paramecium tetraurelia.

PubMed

Cheaib, Miriam; Dehghani Amirabad, Azim; Nordström, Karl J V; Schulz, Marcel H; Simon, Martin

2015-08-01

Phenotypic variation of a single genotype is achieved by alterations in gene expression patterns. Regulation of such alterations depends on their time scale, where short-time adaptations differ from permanently established gene expression patterns maintained by epigenetic mechanisms. In the ciliate Paramecium, serotypes were described for an epigenetically controlled gene expression pattern of an individual multigene family. Paradoxically, individual serotypes can be triggered in Paramecium by alternating environments but are then stabilized by epigenetic mechanisms, thus raising the question to which extend their expression follows environmental stimuli. To characterize environmental adaptation in the context of epigenetically controlled serotype expression, we used RNA-seq to characterize transcriptomes of serotype pure cultures. The resulting vegetative transcriptome resource is first analysed for genes involved in the adaptive response to the altered environment. Secondly, we identified groups of genes that do not follow the adaptive response but show co-regulation with the epigenetically controlled serotype system, suggesting that their gene expression pattern becomes manifested by similar mechanisms. In our experimental set-up, serotype expression and the entire group of co-regulated genes were stable among environmental changes and only heat-shock genes altered expression of these gene groups. The data suggest that the maintenance of these gene expression patterns in a lineage represents epigenetically controlled robustness counteracting short-time adaptation processes. © The Author 2015. Published by Oxford University Press on behalf of Kazusa DNA Research Institute.

Epigenetic regulation of intragenic transposable elements impacts gene transcription in Arabidopsis thaliana

PubMed Central

Le, Tu N.; Miyazaki, Yuji; Takuno, Shohei; Saze, Hidetoshi

2015-01-01

Genomes of higher eukaryotes, including plants, contain numerous transposable elements (TEs), that are often silenced by epigenetic mechanisms, such as histone modifications and DNA methylation. Although TE silencing adversely affects expression of nearby genes, recent studies reveal the presence of intragenic TEs marked by repressive heterochromatic epigenetic marks within transcribed genes. However, even for the well-studied plant model Arabidopsis thaliana, the abundance of intragenic TEs, how they are epigenetically regulated, and their potential impacts on host gene expression, remain unexplored. In this study, we comprehensively analyzed genome-wide distribution and epigenetic regulation of intragenic TEs in A. thaliana. Our analysis revealed that about 3% of TEs are located within gene bodies, dominantly at intronic regions. Most of them are shorter and less methylated than intergenic TEs, but they are still targeted by RNA-directed DNA methylation-dependent and independent pathways. Surprisingly, the heterochromatic epigenetic marks at TEs are maintained within actively transcribed genes. Moreover, the heterochromatic state of intronic TEs is critical for proper transcription of associated genes. Our study provides the first insight into how intragenic TEs affect the transcriptional landscape of the A. thaliana genome, and suggests the importance of epigenetic mechanisms for regulation of TEs within transcriptional gene units. PMID:25813042

Epigenetic regulation of cell fate reprogramming in aging and disease: A predictive computational model.

PubMed

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.

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

Epigenetic regulation of the expression of genes involved in steroid hormone biosynthesis and action

PubMed Central

Martinez-Arguelles, Daniel B.; Papadopoulos, Vassilios

2010-01-01

Steroid hormones participate in organ development, reproduction, body homeostasis, and stress responses. The steroid machinery is expressed in a development- and tissue-specific manner, with the expression of these factors being tightly regulated by an array of transcription factors (TFs). Epigenetics provides an additional layer of gene regulation through DNA methylation and histone tail modifications. Evidence of epigenetic regulation of key steroidogenic enzymes is increasing, though this does not seem to be a predominant regulatory pathway. Steroid hormones exert their action in target tissues through steroid nuclear receptors belonging to the NR3A and NR3C families. Nuclear receptor expression levels and post-translational modifications regulate their function and dictate their sensitivity to steroid ligands. Nuclear receptors and TFs are more likely to be epigenetically regulated than proteins involved in steroidogenesis and have secondary impact on the expression of these steroidogenic enzymes. Here we review evidence for epigenetic regulation of enzymes, transcription factors, and nuclear receptors related to steroid biogenesis and action. PMID:20156469

Epigenetic regulation of female puberty.

PubMed

Lomniczi, Alejandro; Wright, Hollis; Ojeda, Sergio R

2015-01-01

Substantial progress has been made in recent years toward deciphering the molecular and genetic underpinnings of the pubertal process. The availability of powerful new methods to interrogate the human genome has led to the identification of genes that are essential for puberty to occur. Evidence has also emerged suggesting that the initiation of puberty requires the coordinated activity of gene sets organized into functional networks. At a cellular level, it is currently thought that loss of transsynaptic inhibition, accompanied by an increase in excitatory inputs, results in the pubertal activation of GnRH release. This concept notwithstanding, a mechanism of epigenetic repression targeting genes required for the pubertal activation of GnRH neurons was recently identified as a core component of the molecular machinery underlying the central restraint of puberty. In this chapter we will discuss the potential contribution of various mechanisms of epigenetic regulation to the hypothalamic control of female puberty. Copyright © 2014 Elsevier Inc. All rights reserved.

IL-20 is epigenetically regulated in NSCLC and down regulates the expression of VEGF.

PubMed

Baird, Anne-Marie; Gray, Steven G; O'Byrne, Kenneth J

2011-08-01

IL-20 is a pleiotrophic member of the IL-10 family and plays a role in skin biology and the development of haematopoietic cells. Recently, IL-20 has been demonstrated to have potential anti-angiogenic effects in non-small cell lung cancer (NSCLC) by down regulating COX-2. The expression of IL-20 and its cognate receptors (IL-20RA/B and IL-22R1) was examined in a series of resected fresh frozen NSCLC tumours. Additionally, the expression and epigenetic regulation of this family was examined in normal bronchial epithelial and NSCLC cell lines. Furthermore, the effect of IL-20 on VEGF family members was examined. The expression of IL-20 and its receptors are frequently dysregulated in NSCLC. IL-20RB mRNA was significantly elevated in NSCLC tumours (p<0.01). Protein levels of the receptors, IL-20RB and IL-22R1, were significantly increased (p<0.01) in the tumours of NSCLC patients. IL-20 and its receptors were found to be epigenetically regulated through histone post-translational modifications and DNA CpG residue methylation. In addition, treatment with recombinant IL-20 resulted in decreased expression of the VEGF family members at the mRNA level. This family of genes are dysregulated in NSCLC and are subject to epigenetic regulation. Whilst the anti-angiogenic properties of IL-20 require further clarification, targeting this family via epigenetic means may be a viable therapeutic option in lung cancer treatment. Copyright © 2011 Elsevier Ltd. All rights reserved.

Peptides (Epigenetic Regulators) in the Structure of Rodents with a Long and Short Lifespan.

PubMed

Khavinson, V Kh; Kormilets, D Yu; Mar'yanovich, A T

2017-09-01

We have discovered motives of short-chain epigenetically active peptides in some proteins of long-lived African mole rat Heterocephalus glaber. These epigenetic regulators are located in the protein structure between lysine and arginine residues, thus facilitating their release in limited proteolysis. Some of these epigenetic regulators are not found in the proteins of short-lived species - Norway rat Rattus norvegicus and house mouse Mus musculus.

Molecular targets of epigenetic regulation and effectors of environmental influences

DOE Office of Scientific and Technical Information (OSTI.GOV)

Choudhuri, Supratim, E-mail: Supratim.Choudhuri@fda.hhs.go; Cui Yue; Klaassen, Curtis D., E-mail: cklaasse@kumc.ed

The true understanding of what we currently define as epigenetics evolved over time as our knowledge on DNA methylation and chromatin modifications and their effects on gene expression increased. The current explosion of research on epigenetics and the increasing documentation of the effects of various environmental factors on DNA methylation, chromatin modification, as well as on the expression of small non-coding RNAs (ncRNAs) have expanded the scope of research on the etiology of various diseases including cancer. The current review briefly discusses the molecular mechanisms of epigenetic regulation and expands the discussion with examples on the role of environment, suchmore » as the immediate environment during development, in inducing epigenetic changes and modulating gene expression.« less

Epigenetic regulation of vascular smooth muscle cell function in atherosclerosis.

PubMed

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.

Epigenetic regulation of vascular smooth muscle cell function in atherosclerosis.

PubMed

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.

Aberrant cognitive phenotypes and altered hippocampal BDNF expression related to epigenetic modifications in mice lacking the post-synaptic scaffolding protein SHANK1: Implications for autism spectrum disorder.

PubMed

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.

Aberrant TGFβ/SMAD4 signaling contributes to epigenetic silencing of a putative tumor suppressor, RunX1T1, in ovarian cancer

PubMed Central

Yang, Hui-Wen; Chou, Jian-Liang; Chen, Lin-Yu; Yeh, Chia-Ming; Chen, Yu-Hsin; Lin, Ru-Inn; Su, Her-Young; Chen, Gary CW; Deatherage, Daniel E; Huang, Yi-Wen; Yan, Pearlly S; Lin, Huey-Jen; Nephew, Kenneth P; Huang, Tim H-M; Lai, Hung-Cheng

2011-01-01

Aberrant TGFβ signaling pathway may alter the expression of down-stream targets and promotes ovarian carcinogenesis. However, the mechanism of this impairment is not fully understood. Our previous study identified RunX1T1 as a putative SMAD4 target in an immortalized ovarian surface epithelial cell line, IOSE. In this study, we report that transcription of RunX1T1 was confirmed to be positively regulated by SMAD4 in IOSE cells and epigenetically silenced in a panel of ovarian cancer cell lines by promoter hypermethylation and histone methylation at H3 lysine 9. SMAD4 depletion increased repressive histone modifications of RunX1T1 promoter without affecting promoter methylation in IOSE cells. Epigenetic treatment can restore RunX1T1 expression by reversing its epigenetic status in MCP 3 ovarian cancer cells. When transiently treated with a demethylating agent, the expression of RunX1T1 was partially restored in MCP 3 cells, but gradual re-silencing through promoter re-methylation was observed after the treatment. Interestingly, SMAD4 knockdown accelerated this re-silencing process, suggesting that normal TGFβ signaling is essential for the maintenance of RunX1T1 expression. In vivo analysis confirmed that hypermethylation of RunX1T1 was detected in 35.7% (34/95) of ovarian tumors with high clinical stages (p = 0.035) and in 83% (5/6) of primary ovarian cancer-initiating cells. Additionally, concurrent methylation of RunX1T1 and another SMAD4 target, FBXO32 which was previously found to be hypermethylated in ovarian cancer was observed in this same sample cohort (p < 0.05). Restoration of RunX1T1 inhibited cancer cell growth. Taken together, dysregulated TGFβ/SMAD4 signaling may lead to epigenetic silencing of a putative tumor suppressor, RunX1T1, during ovarian carcinogenesis. PMID:21540640

Next stop for the CRISPR revolution: RNA-guided epigenetic regulators.

PubMed

Vora, Suhani; Tuttle, Marcelle; Cheng, Jenny; Church, George

2016-09-01

Clustered regularly interspaced short palindromic repeats (CRISPRs) and CRISPR-associated (Cas) proteins offer a breakthrough platform for cheap, programmable, and effective sequence-specific DNA targeting. The CRISPR-Cas system is naturally equipped for targeted DNA cutting through its native nuclease activity. As such, groups researching a broad spectrum of biological organisms have quickly adopted the technology with groundbreaking applications to genomic sequence editing in over 20 different species. However, the biological code of life is not only encoded in genetics but also in epigenetics as well. While genetic sequence editing is a powerful ability, we must also be able to edit and regulate transcriptional and epigenetic code. Taking inspiration from work on earlier sequence-specific targeting technologies such as zinc fingers (ZFs) and transcription activator-like effectors (TALEs), researchers quickly expanded the CRISPR-Cas toolbox to include transcriptional activation, repression, and epigenetic modification. In this review, we highlight advances that extend the CRISPR-Cas toolkit for transcriptional and epigenetic regulation, as well as best practice guidelines for these tools, and a perspective on future applications. © 2016 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.

Epigenetic regulation of open chromatin in pluripotent stem cells

PubMed Central

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

Epigenetic Alterations in Colorectal Cancer: Emerging Biomarkers

PubMed Central

Okugawa, Yoshinaga; Grady, William M.; Goel, Ajay

2015-01-01

Colorectal cancer (CRC) is a leading cause of cancer deaths worldwide. One of the fundamental processes driving the initiation and progression of CRC is the accumulation of a variety of genetic and epigenetic changes in colon epithelial cells. Over the past decade, major advances have been made in our understanding of cancer epigenetics, particularly regarding aberrant DNA methylation, microRNA (miRNA) and noncoding RNA deregulation, and alterations in histone modification states. Assessment of the colon cancer “epigenome” has revealed that virtually all CRCs have aberrantly methylated genes and altered miRNA expression. The average CRC methylome has hundreds to thousands of abnormally methylated genes and dozens of altered miRNAs. As with gene mutations in the cancer genome, a subset of these epigenetic alterations, called driver events, is presumed to have a functional role in CRC. In addition, the advances in our understanding of epigenetic alterations in CRC have led to these alterations being developed as clinical biomarkers for diagnostic, prognostic and therapeutic applications. Progress in this field suggests that these epigenetic alterations will be commonly used in the near future to direct the prevention and treatment of CRC. PMID:26216839

Mutations in epigenetic regulators including SETD2 are gained during relapse in paediatric acute lymphoblastic leukaemia.

PubMed

Mar, Brenton G; Bullinger, Lars B; McLean, Kathleen M; Grauman, Peter V; Harris, Marian H; Stevenson, Kristen; Neuberg, Donna S; Sinha, Amit U; Sallan, Stephen E; Silverman, Lewis B; Kung, Andrew L; Lo Nigro, Luca; Ebert, Benjamin L; Armstrong, Scott A

2014-03-24

Relapsed paediatric acute lymphoblastic leukaemia (ALL) has high rates of treatment failure. Epigenetic regulators have been proposed as modulators of chemoresistance, here, we sequence genes encoding epigenetic regulators in matched diagnosis-remission-relapse ALL samples. We find significant enrichment of mutations in epigenetic regulators at relapse with recurrent somatic mutations in SETD2, CREBBP, MSH6, KDM6A and MLL2, mutations in signalling factors are not enriched. Somatic alterations in SETD2, including frameshift and nonsense mutations, are present at 12% in a large de novo ALL patient cohort. We conclude that the enrichment of mutations in epigenetic regulators at relapse is consistent with a role in mediating therapy resistance.

Impact of nutrition on pollutant toxicity: an update with new insights into epigenetic regulation

PubMed Central

Hoffman, Jessie B; Petriello, Michael C; Hennig, Bernhard

2017-01-01

Exposure to environmental pollutants is a global health problem and is associated with the development of many chronic diseases including cardiovascular disease, diabetes, and metabolic syndrome. There is a growing body of evidence that nutrition can both positively and negatively modulate the toxic effects of pollutant exposure. Diets high in pro-inflammatory fats, such as linoleic acid, can exacerbate pollutant toxicity while diets rich in bioactive and anti-inflammatory food components, including omega-3 fatty acids and polyphenols, can attenuate toxicant-associated inflammation. Previously, researchers have elucidated direct mechanisms of nutritional modulation including alteration of NF-κB signaling, but recently increased focus has been given to the ways in which nutrition and pollutants affect epigenetics. Nutrition has been demonstrated to modulate epigenetic markers that have been linked either to increased disease risks or to protection against diseases. Overnutrition (i.e. obesity) and undernutrition (i.e. famine) have been observed to alter prenatal epigenetic tags that may increase the risk of offspring developing disease later in life. Conversely, bioactive food components, including curcumin, have been shown to alter epigenetic markers that suppress activation of NF-κB, thus reducing inflammatory responses. Exposure to pollutants also alters epigenetic markers and may contribute to inflammation and disease. It has been demonstrated that pollutants, via epigenetic modulations, can increase activation of NF-κB and upregulate miRNAs associated with inflammation, cardiac injury, and oxidative damage. Importantly, recent evidence suggests that nutritional components, including EGCG, can protect against pollutant-induced inflammation through epigenetic regulation of pro-inflammatory target genes of NF-κB. Further research is needed to better understand how nutrition can modulate pollutant toxicity through epigenetic regulation. Further research is

Epigenetic Regulation of Bovine Spermatogenic Cell-Specific Gene Boule

PubMed Central

Luo, Hua; Xu, Hongtao; Pan, Zengxiang; Xie, Zhuang; Li, Qifa

2015-01-01

Non-primate mammals have two deleted azoospermia (DAZ) family genes, DAZL and Boule; genes in this family encode RNA-binding proteins essential for male fertility in diverse animals. Testicular DAZL transcription is regulated by epigenetic factors such as DNA methylation. However, nothing is known about the epigenetic regulation of Boule. Here, we explored the role of DNA methylation in the regulation of the bovine Boule (bBoule) gene. We found that a long CpG island (CGI) in the bBoule promoter was hypermethylated in the testes of cattle-yak hybrids with low bBoule expression, whereas cattle had relatively low methylation levels (P < 0.01), and there was no difference in the methylation level in the short CGI of the gene body between cattle and cattle-yak hybrids (P > 0.05). We identified a 107 bp proximal core promoter region of bBoule. Intriguingly, the differences in the methylation level between cattle and cattle-yak hybrids were larger in the core promoter than outside the core promoter. An in vitro methylation assay showed that the core promoter activity of bBoule decreased significantly after M.SssI methylase treatment (P < 0.01). We also observed dramatically increased bBoule transcription in bovine mammary epithelial cells (BMECs) after treatment with the methyltransferase inhibitor 5-Aza-dC. Taken together, our results establish that methylation status of the core promoter might be involved in testicular bBoule transcription, and may provide new insight into the epigenetic regulation of DAZ family genes and clinical insights regarding male infertility. PMID:26030766

Promising landscape for regulating macrophage polarization: epigenetic viewpoint

PubMed Central

Chen, Lu; Zhang, Wen; Xu, Zhenyu; Zuo, Jian; Jiang, Hui; Luan, Jiajie

2017-01-01

Macrophages are critical myeloid cells with the hallmark of phenotypic heterogeneity and functional plasticity. Macrophages phenotypes are commonly described as classically-activated M1 and alternatively-activated M2 macrophages which play an essential role in the tissues homeostasis and diseases pathogenesis. Alternations of macrophage polarization and function states require precise regulation of target-gene expression. Emerging data demonstrate that epigenetic mechanisms and transcriptional factors are becoming increasingly appreciated in the orchestration of macrophage polarization in response to local environmental signals. This review is to focus on the advanced concepts of epigenetics changes involved with the macrophage polarization, including microRNAs, DNA methylation and histone modification, which are responsible for the altered cellular signaling and signature genes expression during M1 or M2 polarization. Eventually, the persistent investigation and understanding of epigenetic mechanisms in tissue macrophage polarization and function will enhance the potential to develop novel therapeutic targets for various diseases. PMID:28915705

Epigenetic changes in solid and hematopoietic tumors.

PubMed

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.

LncRNA Structural Characteristics in Epigenetic Regulation

PubMed Central

Wang, Chenguang; Wang, Lianzong; Ding, Yu; Lu, Xiaoyan; Zhang, Guosi; Yang, Jiaxin; Zheng, Hewei; Wang, Hong; Jiang, Yongshuai; Xu, Liangde

2017-01-01

The rapid development of new generation sequencing technology has deepened the understanding of genomes and functional products. RNA-sequencing studies in mammals show that approximately 85% of the DNA sequences have RNA products, for which the length greater than 200 nucleotides (nt) is called long non-coding RNAs (lncRNA). LncRNAs now have been shown to play important epigenetic regulatory roles in key molecular processes, such as gene expression, genetic imprinting, histone modification, chromatin dynamics, and other activities by forming specific structures and interacting with all kinds of molecules. This paper mainly discusses the correlation between the structure and function of lncRNAs with the recent progress in epigenetic regulation, which is important to the understanding of the mechanism of lncRNAs in physiological and pathological processes. PMID:29292750

Material Cues as Potent Regulators of Epigenetics and Stem Cell Function.

PubMed

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.

Epigenetic regulation of memory formation and maintenance

PubMed Central

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

Epigenetic dysregulation of key developmental genes in radiation-induced rat mammary carcinomas.

PubMed

Daino, Kazuhiro; Nishimura, Mayumi; Imaoka, Tatsuhiko; Takabatake, Masaru; Morioka, Takamitsu; Nishimura, Yukiko; Shimada, Yoshiya; Kakinuma, Shizuko

2018-02-13

With the increase in the number of long-term cancer survivors worldwide, there is a growing concern about the risk of secondary cancers induced by radiotherapy. Epigenetic modifications of genes associated with carcinogenesis are attractive targets for the prevention of cancer owing to their reversible nature. To identify genes with possible changes in functionally relevant DNA methylation patterns in mammary carcinomas induced by radiation exposure, we performed microarray-based global DNA methylation and expression profiling in γ-ray-induced rat mammary carcinomas and normal mammary glands. The gene expression profiling identified dysregulation of developmentally related genes, including the downstream targets of polycomb repressive complex 2 (PRC2) and overexpression of enhancer of zeste homolog 2, a component of PRC2, in the carcinomas. By integrating expression and DNA methylation profiles, we identified ten hypermethylated and three hypomethylated genes that possibly act as tumor-suppressor genes and oncogenes dysregulated by aberrant DNA methylation; half of these genes encode developmental transcription factors. Bisulfite sequencing and quantitative PCR confirmed the dysregulation of the polycomb-regulated developmentally related transcription-factor genes Dmrt2, Hoxa7, Foxb1, Sox17, Lhx8, Gata3 and Runx1. Silencing of Hoxa7 was further verified by immunohistochemistry. These results suggest that, in radiation-induced mammary gland carcinomas, PRC2-mediated aberrant DNA methylation leads to dysregulation of developmentally related transcription-factor genes. Our findings provide clues to molecular mechanisms linking epigenetic regulation and radiation-induced breast carcinogenesis and underscore the potential of such epigenetic mechanisms as targets for cancer prevention. © 2018 UICC.

Concise Review: Epigenetic Regulation of Myogenesis in Health and Disease

PubMed Central

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

Epigenetic regulation of miRNA-cancer stem cells nexus by nutraceuticals.

PubMed

Ahmad, Aamir; Li, Yiwei; Bao, Bin; Kong, Dejuan; Sarkar, Fazlul H

2014-01-01

Nutraceuticals, the bioactive food components represented by many naturally occurring dietary compounds, have been investigated for a few decades for their numerous beneficial effects, including their anticancer properties. The initial interest in the cancer-preventing/therapeutic ability of these agents was based on their ability to affect multiple signaling pathways that are deregulated in cancer cells. With a shift in the focus of cancer research to the emerging areas such as epigenetic regulation, microRNAs (miRNAs) and the cancer stem cells (CSCs), nutraceuticals initially appeared out of place. However, research investigations over the last several years have slowly but firmly presented evidence that supports a relevance of these agents in modern day research. While nutraceuticals are increasingly being realized to alter miRNA/CSCs expression and function, the molecular mechanism(s) are not very clearly understood. Epigenetic regulation is one mechanism by which these agents exert their anticancer effects. In this focused mini review, we summarize our current understanding of epigenetic regulation of miRNAs and CSCs by nutraceuticals. We discuss both direct and indirect evidences that support such an activity of these compounds. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Epigenetic regulation of miRNA-Cancer Stem Cells nexus by Nutraceuticals

PubMed Central

Ahmad, Aamir; Li, Yiwei; Bao, Bin; Kong, Dejuan; Sarkar, Fazlul H.

2014-01-01

Nutraceuticals, the bioactive food components represented by many naturally occurring dietary compounds, have been investigated for a few decades for their numerous beneficial effects, including their anticancer properties. The initial interest in the cancer-preventing/therapeutic ability of these agents was based on their ability to affect multiple signaling pathways that are deregulated in cancer cells. With a shift in the focus of cancer research to the emerging areas such as epigenetic regulation, microRNAs (miRNAs) and the cancer stem cells (CSCs), nutraceuticals initially appeared out of place. However, research investigations over the last several years have slowly but firmly presented evidence that supports a relevance of these agents in modern day research. While nutraceuticals are increasingly being realized to alter miRNA/CSCs expression and function, the molecular mechanism(s) are not very clearly understood. Epigenetic regulation is one mechanism by which these agents exert their anticancer effects. In this focused mini review, we summarize our current understanding of epigenetic regulation of miRNAs and CSCs by nutraceuticals. We discuss both direct and indirect evidences that support such an activity of these compounds. PMID:24272883

Epigenetics in prostate cancer: biologic and clinical relevance.

PubMed

Jerónimo, Carmen; Bastian, Patrick J; Bjartell, Anders; Carbone, Giuseppina M; Catto, James W F; Clark, Susan J; Henrique, Rui; Nelson, William G; Shariat, Shahrokh F

2011-10-01

Prostate cancer (PCa) is one of the most common human malignancies and arises through genetic and epigenetic alterations. Epigenetic modifications include DNA methylation, histone modifications, and microRNAs (miRNA) and produce heritable changes in gene expression without altering the DNA coding sequence. To review progress in the understanding of PCa epigenetics and to focus upon translational applications of this knowledge. PubMed was searched for publications regarding PCa and DNA methylation, histone modifications, and miRNAs. Reports were selected based on the detail of analysis, mechanistic support of data, novelty, and potential clinical applications. Aberrant DNA methylation (hypo- and hypermethylation) is the best-characterized alteration in PCa and leads to genomic instability and inappropriate gene expression. Global and locus-specific changes in chromatin remodeling are implicated in PCa, with evidence suggesting a causative dysfunction of histone-modifying enzymes. MicroRNA deregulation also contributes to prostate carcinogenesis, including interference with androgen receptor signaling and apoptosis. There are important connections between common genetic alterations (eg, E twenty-six fusion genes) and the altered epigenetic landscape. Owing to the ubiquitous nature of epigenetic alterations, they provide potential biomarkers for PCa detection, diagnosis, assessment of prognosis, and post-treatment surveillance. Altered epigenetic gene regulation is involved in the genesis and progression of PCa. Epigenetic alterations may provide valuable tools for the management of PCa patients and be targeted by pharmacologic compounds that reverse their nature. The potential for epigenetic changes in PCa requires further exploration and validation to enable translation to the clinic. Copyright © 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Epigenetics of Peripheral B-Cell Differentiation and the Antibody Response

PubMed Central

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

Genetics and epigenetics of liver cancer.

PubMed

Ozen, Cigdem; Yildiz, Gokhan; Dagcan, Alper Tunga; Cevik, Dilek; Ors, Aysegul; Keles, Umur; Topel, Hande; Ozturk, Mehmet

2013-05-25

Hepatocellular carcinoma (HCC) represents a major form of primary liver cancer in adults. Chronic infections with hepatitis B (HBV) and C (HCV) viruses and alcohol abuse are the major factors leading to HCC. This deadly cancer affects more than 500,000 people worldwide and it is quite resistant to conventional chemo- and radiotherapy. Genetic and epigenetic studies on HCC may help to understand better its mechanisms and provide new tools for early diagnosis and therapy. Recent literature on whole genome analysis of HCC indicated a high number of mutated genes in addition to well-known genes such as TP53, CTNNB1, AXIN1 and CDKN2A, but their frequencies are much lower. Apart from CTNNB1 mutations, most of the other mutations appear to result in loss-of-function. Thus, HCC-associated mutations cannot be easily targeted for therapy. Epigenetic aberrations that appear to occur quite frequently may serve as new targets. Global DNA hypomethylation, promoter methylation, aberrant expression of non-coding RNAs and dysregulated expression of other epigenetic regulatory genes such as EZH2 are the best-known epigenetic abnormalities. Future research in this direction may help to identify novel biomarkers and therapeutic targets for HCC. Copyright © 2013 Elsevier B.V. All rights reserved.

Overview to symposium "Nutrients and epigenetic regulation of gene expression".

PubMed

Ho, Emily; Zempleni, Janos

2009-12-01

The American Society for Nutrition hosted a symposium entitled Nutrients and Epigenetic Regulation of Gene Expression at the Experimental Biology meeting on April 20, 2009, in New Orleans, LA. The symposium was cochaired by Emily Ho from Oregon State University and the Linus Pauling Institute, and Janos Zempleni from the University of Nebraska at Lincoln. The goal of this symposium was to highlight the interactions among nutrients, epigenetics, and disease susceptibility. The symposium featured 4 speakers, each presenting novel insights into mechanisms by which nutrients participate in gene regulation. Janos Zempleni elucidated mechanisms by which the covalent binding of biotin to histones represses transposable elements, thereby enhancing genome stability. Emily Ho shared valuable insights into bioactive food compounds that inhibit histone deacetylases. James Kirkland from the University of Guelph in Canada talked about a niacin-dependent poly(ADP-ribosylation) of histones, an epigenetic mark that is not currently being given full consideration in nutrition. Patrick Stover from Cornell University described the interrelationships among 1-carbon metabolism, DNA methylation, gene silencing, and their influence in the etiology of folate-related pathologies. All 4 presentations were videotaped and can be viewed online (www.nutrition.org).

Milk’s Role as an Epigenetic Regulator in Health and Disease

PubMed Central

Melnik, Bodo C.; Schmitz, Gerd

2017-01-01

It is the intention of this review to characterize milk’s role as an epigenetic regulator in health and disease. Based on translational research, we identify milk as a major epigenetic modulator of gene expression of the milk recipient. Milk is presented as an epigenetic “doping system” of mammalian development. Milk exosome-derived micro-ribonucleic acids (miRNAs) that target DNA methyltransferases are implicated to play the key role in the upregulation of developmental genes such as FTO, INS, and IGF1. In contrast to miRNA-deficient infant formula, breastfeeding via physiological miRNA transfer provides the appropriate signals for adequate epigenetic programming of the newborn infant. Whereas breastfeeding is restricted to the lactation period, continued consumption of cow’s milk results in persistent epigenetic upregulation of genes critically involved in the development of diseases of civilization such as diabesity, neurodegeneration, and cancer. We hypothesize that the same miRNAs that epigenetically increase lactation, upregulate gene expression of the milk recipient via milk-derived miRNAs. It is of critical concern that persistent consumption of pasteurized cow’s milk contaminates the human food chain with bovine miRNAs, that are identical to their human analogs. Commercial interest to enhance dairy lactation performance may further increase the epigenetic miRNA burden for the milk consumer. PMID:28933365

Krebs cycle intermediates regulate DNA and histone methylation: epigenetic impact on the aging process.

PubMed

Salminen, Antero; Kauppinen, Anu; Hiltunen, Mikko; Kaarniranta, Kai

2014-07-01

Many aging theories have proposed that mitochondria and energy metabolism have a major role in the aging process. There are recent studies indicating that Krebs cycle intermediates can shape the epigenetic landscape of chromatin by regulating DNA and histone methylation. A growing evidence indicates that epigenetics plays an important role in the regulation of healthspan but also is involved in the aging process. 2-Oxoglutarate (α-ketoglutarate) is a key metabolite in the Krebs cycle but it is also an obligatory substrate for 2-oxoglutarate-dependent dioxygenases (2-OGDO). The 2-OGDO enzyme family includes the major enzymes of DNA and histone demethylation, i.e. Ten-Eleven Translocation (TETs) and Jumonji C domain containing (JmjC) demethylases. In addition, 2-OGDO members can regulate collagen synthesis and hypoxic responses in a non-epigenetical manner. Interestingly, succinate and fumarate, also Krebs cycle intermediates, are potent inhibitors of 2-OGDO enzymes, i.e. the balance of Krebs cycle reactions can affect the level of DNA and histone methylation and thus control gene expression. We will review the epigenetic mechanisms through which Krebs cycle intermediates control the DNA and histone methylation. We propose that age-related disturbances in the Krebs cycle function induce stochastic epigenetic changes in chromatin structures which in turn promote the aging process. Copyright © 2014 Elsevier B.V. All rights reserved.

Design of small-molecule epigenetic modulators

PubMed Central

Pachaiyappan, Boobalan

2013-01-01

The field of epigenetics has expanded rapidly to reveal multiple new targets for drug discovery. The functional elements of the epigenomic machinery can be catagorized as writers, erasers and readers, and together these elements control cellular gene expression and homeostasis. It is increasingly clear that aberrations in the epigenome can underly a variety of diseases, and thus discovery of small molecules that modulate the epigenome in a specific manner is a viable approach to the discovery of new therapeutic agents. In this Digest, the components of epigenetic control of gene expression will be briefly summarized, and efforts to identify small molecules that modulate epigenetic processes will be described. PMID:24300735

Epigenetic: A missing paradigm in cellular and molecular pathways of sulfur mustard lung: a prospective and comparative study

PubMed Central

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

Epigenetic events associated with breast cancer and their prevention by dietary components targeting the epigenome

USDA-ARS?s Scientific Manuscript database

Aberrant epigenetic alterations in the genome such as DNA methylation and chromatin remodeling play a significant role in breast cancer development. Since epigenetic alterations are considered to be more easily reversible compared to genetic changes, epigenetic therapy is potentially very useful in ...

Genes, epigenetic regulation and environmental factors: which is the most relevant in developing autoimmune diseases?

PubMed

Costenbader, Karen H; Gay, Steffen; Alarcón-Riquelme, Marta E; Iaccarino, Luca; Doria, Andrea

2012-06-01

Autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis and inflammatory bowel disease, have complex pathogeneses and likely multifactorial etiologies. The current paradigm for understanding their development is that the disease is triggered in genetically-susceptible individuals by exposure to environmental factors. Some of these environmental factors have been specifically identified, while others are hypothesized and not yet proven, and it is likely that most have yet to be identified. One interesting hypothesis is that environmental effects on immune responses could be mediated by changes in epigenetic regulation. Major mechanisms of epigenetic gene regulation include DNA methylation and histone modification. In these cases, gene expression is modified without involving changes in DNA sequence. Epigenetics is a new and interesting research field in autoimmune diseases. We review the roles of genetic factors, epigenetic regulation and the most studied environmental risk factors such as cigarette smoke, crystalline silica, Epstein-Barr virus, and reproductive hormones in the pathogenesis of autoimmune disease. Copyright © 2011 Elsevier B.V. All rights reserved.

Epigenetic mechanisms in anti-cancer actions of bioactive food components – the implications in cancer prevention

PubMed Central

Stefanska, B; Karlic, H; Varga, F; Fabianowska-Majewska, K; Haslberger, AG

2012-01-01

The hallmarks of carcinogenesis are aberrations in gene expression and protein function caused by both genetic and epigenetic modifications. Epigenetics refers to the changes in gene expression programming that alter the phenotype in the absence of a change in DNA sequence. Epigenetic modifications, which include amongst others DNA methylation, covalent modifications of histone tails and regulation by non-coding RNAs, play a significant role in normal development and genome stability. The changes are dynamic and serve as an adaptation mechanism to a wide variety of environmental and social factors including diet. A number of studies have provided evidence that some natural bioactive compounds found in food and herbs can modulate gene expression by targeting different elements of the epigenetic machinery. Nutrients that are components of one-carbon metabolism, such as folate, riboflavin, pyridoxine, cobalamin, choline, betaine and methionine, affect DNA methylation by regulating the levels of S-adenosyl-L-methionine, a methyl group donor, and S-adenosyl-L-homocysteine, which is an inhibitor of enzymes catalyzing the DNA methylation reaction. Other natural compounds target histone modifications and levels of non-coding RNAs such as vitamin D, which recruits histone acetylases, or resveratrol, which activates the deacetylase sirtuin and regulates oncogenic and tumour suppressor micro-RNAs. As epigenetic abnormalities have been shown to be both causative and contributing factors in different health conditions including cancer, natural compounds that are direct or indirect regulators of the epigenome constitute an excellent approach in cancer prevention and potentially in anti-cancer therapy. PMID:22536923

Maternal choline intake alters the epigenetic state of fetal cortisol-regulating genes in humans.

PubMed

Jiang, Xinyin; Yan, Jian; West, Allyson A; Perry, Cydne A; Malysheva, Olga V; Devapatla, Srisatish; Pressman, Eva; Vermeylen, Francoise; Caudill, Marie A

2012-08-01

The in utero availability of methyl donors, such as choline, may modify fetal epigenetic marks and lead to sustainable functional alterations throughout the life course. The hypothalamic-pituitary-adrenal (HPA) axis regulates cortisol production and is sensitive to perinatal epigenetic programming. As an extension of a 12-wk dose-response choline feeding study conducted in third-trimester pregnant women, we investigated the effect of maternal choline intake (930 vs. 480 mg/d) on the epigenetic state of cortisol-regulating genes, and their expression, in placenta and cord venous blood. The higher maternal choline intake yielded higher placental promoter methylation of the cortisol-regulating genes, corticotropin releasing hormone (CRH; P=0.05) and glucocorticoid receptor (NR3C1; P=0.002); lower placental CRH transcript abundance (P=0.04); lower cord blood leukocyte promoter methylation of CRH (P=0.05) and NR3C1 (P=0.04); and 33% lower (P=0.07) cord plasma cortisol. In addition, placental global DNA methylation and dimethylated histone H3 at lysine 9 (H3K9me2) were higher (P=0.02) in the 930 mg choline/d group, as was the expression of select placental methyltransferases. These data collectively suggest that maternal choline intake in humans modulates the epigenetic state of genes that regulate fetal HPA axis reactivity as well as the epigenomic status of fetal derived tissues.

Sensory Cortical Plasticity Participates in the Epigenetic Regulation of Robust Memory Formation

PubMed Central

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

Aberrant regulation of DNA methylation in amyotrophic lateral sclerosis: a new target of disease mechanisms.

PubMed

Martin, Lee J; Wong, Margaret

2013-10-01

Amyotrophic lateral sclerosis (ALS) is the third most common adult-onset neurodegenerative disease. A diagnosis is fatal owing to degeneration of motor neurons in brain and spinal cord that control swallowing, breathing, and movement. ALS can be inherited, but most cases are not associated with a family history of the disease. The mechanisms causing motor neuron death in ALS are still unknown. Given the suspected complex interplay between multiple genes, the environment, metabolism, and lifestyle in the pathogenesis of ALS, we have hypothesized that the mechanisms of disease in ALS involve epigenetic contributions that can drive motor neuron degeneration. DNA methylation is an epigenetic mechanism for gene regulation engaged by DNA methyltransferase (Dnmt)-catalyzed methyl group transfer to carbon-5 in cytosine residues in gene regulatory promoter and nonpromoter regions. Recent genome-wide analyses have found differential gene methylation in human ALS. Neuropathologic assessments have revealed that motor neurons in human ALS show significant abnormalities in Dnmt1, Dnmt3a, and 5-methylcytosine. Similar changes are seen in mice with motor neuron degeneration, and Dnmt3a was found abundantly at synapses and in mitochondria. During apoptosis of cultured motor neuron-like cells, Dnmt1 and Dnmt3a protein levels increase, and 5-methylcytosine accumulates. Enforced expression of Dnmt3a, but not Dnmt1, induces degeneration of cultured neurons. Truncation mutation of the Dnmt3a catalytic domain and Dnmt3a RNAi blocks apoptosis of cultured neurons. Inhibition of Dnmt catalytic activity with small molecules RG108 and procainamide protects motor neurons from excessive DNA methylation and apoptosis in cell culture and in a mouse model of ALS. Thus, motor neurons can engage epigenetic mechanisms to cause their degeneration, involving Dnmts and increased DNA methylation. Aberrant DNA methylation in vulnerable cells is a new direction for discovering mechanisms of ALS

Chromatin modifiers and the promise of epigenetic therapy in acute leukemia

PubMed Central

Greenblatt, Sarah M.; Nimer, Stephen D.

2017-01-01

Hematopoiesis is a tightly regulated process involving the control of gene expression that directs the transition from hematopoietic stem and progenitor cells to terminally differentiated blood cells. In leukemia, the processes directing self-renewal, differentiation, and progenitor cell expansion are disrupted, leading to the accumulation of immature, non-functioning malignant cells. Insights into these processes have come in stages, based upon technological advances in genetic analyses, bioinformatics, and biological sciences. The first cytogenetic studies of leukemic cells identified chromosomal translocations that generate oncogenic fusion proteins, and most commonly affect regulators of transcription. This was followed by the discovery of recurrent somatic mutations in genes encoding regulators of the signal transduction pathways that control cell proliferation and survival. Recently, studies of global changes in methylation and gene expression have led to the understanding that the output of transcriptional regulators and the proliferative signaling pathways, are ultimately influenced by chromatin structure. Candidate gene, whole genome, and whole exome sequencing studies have identified recurrent somatic mutations in genes encoding epigenetic modifiers in both acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL). In contrast to the two hit model of leukemogenesis, emerging evidence suggests that these epigenetic modifiers represent a class of mutations that are critical to the development of leukemia and affect the regulation of various other oncogenic pathways. In this review, we discuss the range of recurrent, somatic mutations in epigenetic modifiers found in leukemia and how these modifiers relate to the classical leukemogenic pathways that lead to impaired cell differentiation and aberrant self-renewal and proliferation. PMID:24609046

Repressive but not activating epigenetic modifications are aberrant on the inactive X chromosome in live cloned cattle.

PubMed

Geng-Sheng, Cao; Yu, Gao; Kun, Wang; Fang-Rong, Ding; Ning, Li

2009-08-01

X inactivation is the process of a chromosome-wide silencing of the majority of genes on the X chromosome during early mammalian development. This process may be aberrant in cloned animals. Here we show that repressive modifications, such as methylation of DNA, and the presence of methylated histones, H3K9me2 and H3K27me3, exhibit distinct aberrance on the inactive X chromosome in live clones. In contrast, H3K4me3, an active gene marker, is obviously missing from the inactive X chromosome in all cattle studied. This suggests that the disappearance of active histone modifications (H3K4me3) seems to be more important for X inactivation than deposition of marks associated with heterochromatin (DNA methylation, H3K27me3 and H3K9me2). It also implies that even apparently normal clones may have subtle abnormalities in repressive, but not activating epigenetic modifications on the inactive X when they survive to term. We also found that the histone H3 methylations were enriched and co-localized at q21-31 of the active X chromosome, which may be associated with an abundance of LINE1 repeat elements. © 2009 The Authors. Journal compilation © 2009 Japanese Society of Developmental Biologists.

Paramutation: the tip of an epigenetic iceberg?

PubMed Central

Suter, Catherine M.; Martin, David I.K.

2009-01-01

Paramutation describes the transfer of an acquired epigenetic state to an unlinked homologous locus, resulting in a meiotically heritable alteration in gene expression. Early investigations of paramutation characterized a mode of change and inheritance distinct from mendelian genetics, catalyzing the concept of the epigenome. Numerous examples of paramutation and paramutation-like phenomena have now emerged, with evidence that implicates small RNAs in the transfer and maintenance of epigenetic states. In animals piRNA-mediated retrotransposon suppression seems to drive a vast system of epigenetic inheritance with paramutation-like characteristics. The classic examples of paramutation might be merely informative aberrations of pervasive and broadly conserved mechanisms that use RNA to sense homology and target epigenetic modification. When viewed in this context, paramutation is only one aspect of a common and broadly distributed form of inheritance based on epigenetic states. PMID:19945764

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

Strategies to re-express epigenetically silenced p15(INK4b) and p21(WAF1) genes in acute myeloid leukemia.

PubMed

Geyer, C Ronald

2010-01-01

p15(INK4B) and p21(WAF1) are TGF-β targets that are silenced in leukemia by epigenetic mechanisms involving DNA methylation and/or histone modifications. Mechanisms for establishing and maintaining epigenetic silencing of p15(INK4B) and p21(WAF1) are not well established. The reversible nature of epigenetic modifications has lead to the development of drugs that target DNA methyltransferases, histone deacetylases, and histone methyltransferases, which have been used to re-express aberrantly silenced genes in leukemia. Recently, non-coding RNA, referred to as natural antisense transcripts (NATs), have been implicated in the regulation of epigenetic modifications. Here, we review epigenetic mechanisms for silencing p15(INK4B) and p21(WAF1) and the role of NATs in this process. We also review epigenetic drugs and drug combinations used to re-express p15(INK4B) and p21(WAF1). Lastly, we discuss the potential use of NATs to target the activity of epigenetic drugs to specific genes and to permanently re-express epigenetically silenced genes.

Exploiting Epigenetic Alterations in Prostate Cancer.

PubMed

Baumgart, Simon J; Haendler, Bernard

2017-05-09

Prostate cancer affects an increasing number of men worldwide and is a leading cause of cancer-associated deaths. Beside genetic mutations, many epigenetic alterations including DNA and histone modifications have been identified in clinical prostate tumor samples. They have been linked to aberrant activity of enzymes and reader proteins involved in these epigenetic processes, leading to the search for dedicated inhibitory compounds. In the wake of encouraging anti-tumor efficacy results in preclinical models, epigenetic modulators addressing different targets are now being tested in prostate cancer patients. In addition, the assessment of microRNAs as stratification biomarkers, and early clinical trials evaluating suppressor microRNAs as potential prostate cancer treatment are being discussed.

Epigenetic regulation of HIV, AIDS, and AIDS-related malignancies.

PubMed

Verma, Mukesh

2015-01-01

Although epigenetics is not a new field, its implications for acquired immunodeficiency syndrome (AIDS) research have not been explored fully. To develop therapeutic and preventive approaches against the human immunodeficiency virus (HIV) and AIDS, it is essential to understand the mechanisms of interaction between the virus and the host, involvement of genetic and epigenetic mechanisms, characterization of viral reservoirs, and factors influencing the latency of the virus. Both methylation of viral genes and histone modifications contribute to initiating and maintaining latency and, depending on the context, triggering viral gene repression or expression. This chapter discusses progress made at the National Institutes of Health (NIH), recommendations from the International AIDS Society Scientific Working Group on HIV Cure, and underlying epigenetic regulation. A number of epigenetic inhibitors have shown potential in treating AIDS-related malignancies. Epigenetic drugs approved by the US Food and Drug Administration and their implications for the eradication of HIV/AIDS and AIDS-related malignancies also are discussed.Past and current progress in developing treatments and understanding the molecular mechanisms of AIDS and HIV infection has greatly improved patient survival. However, increased survival has been coupled with the development of cancer at higher rates than those observed among the HIV/AIDS-negative population. During the early days of the AIDS epidemic, the most frequent AIDS-defining malignancies were Kaposi's sarcoma and non-Hodgkin lymphoma (NHL). Now, with increased survival as the result of widespread use in the developed world of highly active antiretroviral therapy (HAART), non-AIDS defining cancers (i.e., anal, skin, and lung cancers, and Hodgkin disease) are on the increase in HIV-infected populations. The current status of AIDS-related malignancies also is discussed.

Epigenetics of bone diseases.

PubMed

Michou, Laetitia

2017-12-12

Histone deacetylation, DNA methylation, and micro-RNAs (miRNAs) are the three main epigenetic mechanisms that regulate gene expression. All the physiological processes involved in bone remodeling are tightly regulated by epigenetic factors. This review discusses the main epigenetic modifications seen in tumoral and non-tumoral bone diseases, with emphasis on miRNAs. The role for epigenetic modifications of gene expression in the most common bone diseases is illustrated by drawing on the latest publications in the field. In multifactorial bone diseases such as osteoporosis, many epigenetic biomarkers, either alone or in combination, have been associated with bone mineral density or suggested to predict osteoporotic fractures. In addition, treatments designed to modulate bone remodeling by selectively targeting the function of specific miRNAs are being evaluated. Advances in the understanding of epigenetic regulation shed new light on the pathophysiology of other non-tumoral bone diseases, including genetic conditions inherited on a Mendelian basis. Finally, in the area of primary and metastatic bone tumors, the last few years have witnessed considerable progress in elucidating the epigenetic regulation of oncogenesis and its local interactions with bone tissue. These new data may allow the development of epigenetic outcome predictors, which are in very high demand, and of innovative therapeutic agents acting via miRNA modulation. Copyright © 2017 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.

Epigenetic suppression of neprilysin regulates breast cancer invasion.

PubMed

Stephen, H M; Khoury, R J; Majmudar, P R; Blaylock, T; Hawkins, K; Salama, M S; Scott, M D; Cosminsky, B; Utreja, N K; Britt, J; Conway, R E

2016-03-07

In women, invasive breast cancer is the second most common cancer and the second cause of cancer-related death. Therefore, identifying novel regulators of breast cancer invasion could lead to additional biomarkers and therapeutic targets. Neprilysin, a cell-surface enzyme that cleaves and inactivates a number of substrates including endothelin-1 (ET1), has been implicated in breast cancer, but whether neprilysin promotes or inhibits breast cancer cell progression and metastasis is unclear. Here, we asked whether neprilysin expression predicts and functionally regulates breast cancer cell invasion. RT-PCR and flow cytometry analysis of MDA-MB-231 and MCF-7 breast cancer cell lines revealed decreased neprilysin expression compared with normal epithelial cells. Expression was also suppressed in invasive ductal carcinoma (IDC) compared with normal tissue. In addition, in vtro invasion assays demonstrated that neprilysin overexpression decreased breast cancer cell invasion, whereas neprilysin suppression augmented invasion. Furthermore, inhibiting neprilysin in MCF-7 breast cancer cells increased ET1 levels significantly, whereas overexpressing neprilysin decreased extracellular-signal related kinase (ERK) activation, indicating that neprilysin negatively regulates ET1-induced activation of mitogen-activated protein kinase (MAPK) signaling. To determine whether neprilysin was epigenetically suppressed in breast cancer, we performed bisulfite conversion analysis of breast cancer cells and clinical tumor samples. We found that the neprilysin promoter was hypermethylated in breast cancer; chemical reversal of methylation in MDA-MB-231 cells reactivated neprilysin expression and inhibited cancer cell invasion. Analysis of cancer databases revealed that neprilysin methylation significantly associates with survival in stage I IDC and estrogen receptor-negative breast cancer subtypes. These results demonstrate that neprilysin negatively regulates the ET axis in breast cancer

Epigenetic suppression of neprilysin regulates breast cancer invasion

PubMed Central

Stephen, H M; Khoury, R J; Majmudar, P R; Blaylock, T; Hawkins, K; Salama, M S; Scott, M D; Cosminsky, B; Utreja, N K; Britt, J; Conway, R E

2016-01-01

In women, invasive breast cancer is the second most common cancer and the second cause of cancer-related death. Therefore, identifying novel regulators of breast cancer invasion could lead to additional biomarkers and therapeutic targets. Neprilysin, a cell-surface enzyme that cleaves and inactivates a number of substrates including endothelin-1 (ET1), has been implicated in breast cancer, but whether neprilysin promotes or inhibits breast cancer cell progression and metastasis is unclear. Here, we asked whether neprilysin expression predicts and functionally regulates breast cancer cell invasion. RT–PCR and flow cytometry analysis of MDA-MB-231 and MCF-7 breast cancer cell lines revealed decreased neprilysin expression compared with normal epithelial cells. Expression was also suppressed in invasive ductal carcinoma (IDC) compared with normal tissue. In addition, in vtro invasion assays demonstrated that neprilysin overexpression decreased breast cancer cell invasion, whereas neprilysin suppression augmented invasion. Furthermore, inhibiting neprilysin in MCF-7 breast cancer cells increased ET1 levels significantly, whereas overexpressing neprilysin decreased extracellular-signal related kinase (ERK) activation, indicating that neprilysin negatively regulates ET1-induced activation of mitogen-activated protein kinase (MAPK) signaling. To determine whether neprilysin was epigenetically suppressed in breast cancer, we performed bisulfite conversion analysis of breast cancer cells and clinical tumor samples. We found that the neprilysin promoter was hypermethylated in breast cancer; chemical reversal of methylation in MDA-MB-231 cells reactivated neprilysin expression and inhibited cancer cell invasion. Analysis of cancer databases revealed that neprilysin methylation significantly associates with survival in stage I IDC and estrogen receptor-negative breast cancer subtypes. These results demonstrate that neprilysin negatively regulates the ET axis in breast cancer

Epigenetic Regulation of Centromere Chromatin Stability by Dietary and Environmental Factors.

PubMed

Hernández-Saavedra, Diego; Strakovsky, Rita S; Ostrosky-Wegman, Patricia; Pan, Yuan-Xiang

2017-11-01

The centromere is a genomic locus required for the segregation of the chromosomes during cell division. This chromosomal region together with pericentromeres has been found to be susceptible to damage, and thus the perturbation of the centromere could lead to the development of aneuploidic events. Metabolic abnormalities that underlie the generation of cancer include inflammation, oxidative stress, cell cycle deregulation, and numerous others. The micronucleus assay, an early clinical marker of cancer, has been shown to provide a reliable measure of genotoxic damage that may signal cancer initiation. In the current review, we will discuss the events that lead to micronucleus formation and centromeric and pericentromeric chromatin instability, as well transcripts emanating from these regions, which were previously thought to be inactive. Studies were selected in PubMed if they reported the effects of nutritional status (macro- and micronutrients) or environmental toxicant exposure on micronucleus frequency or any other chromosomal abnormality in humans, animals, or cell models. Mounting evidence from epidemiologic, environmental, and nutritional studies provides a novel perspective on the origination of aneuploidic events. Although substantial evidence exists describing the role that nutritional status and environmental toxicants have on the generation of micronuclei and other nuclear aberrations, limited information is available to describe the importance of macro- and micronutrients on centromeric and pericentromeric chromatin stability. Moving forward, studies that specifically address the direct link between nutritional status, excess, or deficiency and the epigenetic regulation of the centromere will provide much needed insight into the nutritional and environmental regulation of this chromosomal region and the initiation of aneuploidy. © 2017 American Society for Nutrition.

Role of melatonin in the epigenetic regulation of breast cancer.

PubMed

Korkmaz, Ahmet; Sanchez-Barcelo, Emilio J; Tan, Dun-Xian; Reiter, Russel J

2009-05-01

The oncostatic properties of melatonin as they directly or indirectly involve epigenetic mechanisms of cancer are reviewed with a special focus on breast cancer. Five lines of evidence suggest that melatonin works via epigenetic processes: (1) melatonin influences transcriptional activity of nuclear receptors (ERalpha, GR and RAR) involved in the regulation of breast cancer cell growth; (2) melatonin down-regulates the expression of genes responsible for the local synthesis or activation of estrogens including aromatase, an effect which may be mediated by methylation of the CYP19 gene or deacetylation of CYP19 histones; (3) melatonin inhibits telomerase activity and expression induced by either natural estrogens or xenoestrogens; (4) melatonin modulates the cell cycle through the inhibition of cyclin D1 expression; (5) melatonin influences circadian rhythm disturbances dependent on alterations of the light/dark cycle (i.e., light at night) with the subsequent deregulation of PER2 which acts as a tumor suppressor gene.

Withaferin A and sulforaphane regulate breast cancer cell cycle progression through epigenetic mechanisms.

PubMed

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.

Epigenetic Regulation of Placenta-Specific 8 Contributes to Altered Function of Endothelial Colony-Forming Cells Exposed to Intrauterine Gestational Diabetes Mellitus.

PubMed

Blue, Emily K; Sheehan, BreAnn M; Nuss, Zia V; Boyle, Frances A; Hocutt, Caleb M; Gohn, Cassandra R; Varberg, Kaela M; McClintick, Jeanette N; Haneline, Laura S

2015-07-01

Intrauterine exposure to gestational diabetes mellitus (GDM) is linked to development of hypertension, obesity, and type 2 diabetes in children. Our previous studies determined that endothelial colony-forming cells (ECFCs) from neonates exposed to GDM exhibit impaired function. The current goals were to identify aberrantly expressed genes that contribute to impaired function of GDM-exposed ECFCs and to evaluate for evidence of altered epigenetic regulation of gene expression. Genome-wide mRNA expression analysis was conducted on ECFCs from control and GDM pregnancies. Candidate genes were validated by quantitative RT-PCR and Western blotting. Bisulfite sequencing evaluated DNA methylation of placenta-specific 8 (PLAC8). Proliferation and senescence assays of ECFCs transfected with siRNA to knockdown PLAC8 were performed to determine functional impact. Thirty-eight genes were differentially expressed between control and GDM-exposed ECFCs. PLAC8 was highly expressed in GDM-exposed ECFCs, and PLAC8 expression correlated with maternal hyperglycemia. Methylation status of 17 CpG sites in PLAC8 negatively correlated with mRNA expression. Knockdown of PLAC8 in GDM-exposed ECFCs improved proliferation and senescence defects. This study provides strong evidence in neonatal endothelial progenitor cells that GDM exposure in utero leads to altered gene expression and DNA methylation, suggesting the possibility of altered epigenetic regulation. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Epileptogenesis: can the science of epigenetics give us answers?

PubMed

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.

Epigenetics in Prostate Cancer

PubMed Central

Albany, Costantine; Alva, Ajjai S.; Aparicio, Ana M.; Singal, Rakesh; Yellapragada, Sarvari; Sonpavde, Guru; Hahn, Noah M.

2011-01-01

Prostate cancer (PC) is the most commonly diagnosed nonskin malignancy and the second most common cause of cancer death among men in the United States. Epigenetics is the study of heritable changes in gene expression caused by mechanisms other than changes in the underlying DNA sequences. Two common epigenetic mechanisms, DNA methylation and histone modification, have demonstrated critical roles in prostate cancer growth and metastasis. DNA hypermethylation of cytosine-guanine (CpG) rich sequence islands within gene promoter regions is widespread during neoplastic transformation of prostate cells, suggesting that treatment-induced restoration of a “normal” epigenome could be clinically beneficial. Histone modification leads to altered tumor gene function by changing chromosome structure and the level of gene transcription. The reversibility of epigenetic aberrations and restoration of tumor suppression gene function have made them attractive targets for prostate cancer treatment with modulators that demethylate DNA and inhibit histone deacetylases. PMID:22191037

Epigenetics in prostate cancer.

PubMed

Albany, Costantine; Alva, Ajjai S; Aparicio, Ana M; Singal, Rakesh; Yellapragada, Sarvari; Sonpavde, Guru; Hahn, Noah M

2011-01-01

Prostate cancer (PC) is the most commonly diagnosed nonskin malignancy and the second most common cause of cancer death among men in the United States. Epigenetics is the study of heritable changes in gene expression caused by mechanisms other than changes in the underlying DNA sequences. Two common epigenetic mechanisms, DNA methylation and histone modification, have demonstrated critical roles in prostate cancer growth and metastasis. DNA hypermethylation of cytosine-guanine (CpG) rich sequence islands within gene promoter regions is widespread during neoplastic transformation of prostate cells, suggesting that treatment-induced restoration of a "normal" epigenome could be clinically beneficial. Histone modification leads to altered tumor gene function by changing chromosome structure and the level of gene transcription. The reversibility of epigenetic aberrations and restoration of tumor suppression gene function have made them attractive targets for prostate cancer treatment with modulators that demethylate DNA and inhibit histone deacetylases.

TALE-mediated epigenetic suppression of CDKN2A increases replication in human fibroblasts.

PubMed

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.

TALE-mediated epigenetic suppression of CDKN2A increases replication in human fibroblasts

PubMed Central

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

Design of small molecule epigenetic modulators.

PubMed

Pachaiyappan, Boobalan; Woster, Patrick M

2014-01-01

The field of epigenetics has expanded rapidly to reveal multiple new targets for drug discovery. The functional elements of the epigenomic machinery can be categorized as writers, erasers and readers, and together these elements control cellular gene expression and homeostasis. It is increasingly clear that aberrations in the epigenome can underly a variety of diseases, and thus discovery of small molecules that modulate the epigenome in a specific manner is a viable approach to the discovery of new therapeutic agents. In this Digest, the components of epigenetic control of gene expression will be briefly summarized, and efforts to identify small molecules that modulate epigenetic processes will be described. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

Preserving human potential as freedom: a framework for regulating epigenetic harms.

PubMed

Khan, Fazal

2010-01-01

this type of harm. This article argues that it is imperative to initiate a regulatory framework to address epigenetic risk from specific substances even if conclusive proof of disease causation cannot be established. Shifting the burden of generating epigenetic risk data to producers of suspected harmful substances serves as a start. As information concerning epigenetic risks accrues, the regulatory response should evolve concurrently. As part of a dynamic policy-making approach our goals need to encompass the following: (i) promotion of knowledge in the scientific, legal, and public domains; (ii) assessment and modification of current regulations to address preventable risk; and (iii) an overarching commitment to protect human capabilities in an equitable manner.

Mechanisms involved in epigenetic down-regulation of Gfap under maternal hypothyroidism.

PubMed

Kumar, Praveen; Godbole, Nachiket M; Chaturvedi, Chandra P; Singh, Ravi S; George, Nelson; Upadhyay, Aditya; Anjum, B; Godbole, Madan M; Sinha, Rohit A

2018-07-20

Thyroid hormones (TH) of maternal origin are crucial regulator of mammalian brain development during embryonic period. Although maternal TH deficiency during the critical periods of embryonic neo-cortical development often results in irreversible clinical outcomes, the fundamental basis of these abnormalities at a molecular level is still obscure. One of the key developmental process affected by maternal TH insufficiency is the delay in astrocyte maturation. Glial fibrillary acidic protein (Gfap) is a predominant cell marker of mature astrocyte and is regulated by TH status. Inspite, of being a TH responsive gene during neocortical development the mechanistic basis of Gfap transcriptional regulation by TH has remained elusive. In this study using rat model of maternal hypothyroidism, we provide evidence for an epigenetic silencing of Gfap under TH insufficiency and its recovery upon TH supplementation. Our results demonstrate increased DNA methylation coupled with decreased histone acetylation at the Gfap promoter leading to suppression of Gfap expression under maternal hypothyroidism. In concordance, we also observed a significant increase in histone deacetylase (HDAC) activity in neocortex of TH deficient embryos. Collectively, these results provide novel insight into the role of TH regulated epigenetic mechanisms, including DNA methylation, and histone modifications, which are critically important in mediating precise temporal neural gene regulation. Copyright © 2018 Elsevier Inc. All rights reserved.

Epigenetics of psoriatic disease: A systematic review and critical appraisal.

PubMed

Pollock, Remy A; Abji, Fatima; Gladman, Dafna D

2017-03-01

Psoriasis is an inflammatory disease of the skin that is sometimes accompanied by an auto-inflammatory arthritis called psoriatic arthritis (PsA). Psoriasis and PsA are multifactorial diseases that result from complex interactions of environmental and genetic risk factors. Epigenetic marks, which are labile chemical marks with diverse functions, form a layer of biological information that sits at the interface of genetics and the environment. Aberrant epigenetic regulation has been previously implicated in other rheumatological disorders. The purpose of this review is to summarize and critically evaluate the nascent literature on epigenetics in psoriasis and PsA. A systematic review yielded 52 primary articles after applying inclusion and exclusion criteria. Data were extracted using a standardized template and study quality assessed using a methodological quality checklist. Studies reflect a broad range of epigenetic sub-disciplines, the most common being DNA methylation, followed by the parent of origin effect or genomic imprinting, expression or activity of epigenetic modifying enzymes, and histone modifications. Epidemiological studies demonstrating excessive paternal transmission provided the earliest evidence of epigenetic deregulation in psoriatic disease, however few studies have examined its molecular mechanisms. Methylation studies evolved rapidly from low resolution global to targeted analyses of known psoriatic disease susceptibility loci such as HLA-C*0602. The recent explosion of epigenome-wide association studies has provided us with novel insights into psoriasis pathogenesis, and the mechanism of action of UVB, methotrexate, and anti-TNF therapies, as well as molecular signatures of psoriasis that may have clinical relevance. Finally, recent studies of pharmacological inhibitors of epigenetic modifier enzymes demonstrate their potential applicability as novel treatment modalities for psoriasis. Challenges of epigenetics research in psoriasis and Ps

Methylation and microRNA-mediated epigenetic regulation of SOCS3

PubMed Central

Boosani, Chandra S.; Agrawal, Devendra K.

2017-01-01

Epigenetic gene silencing of several genes causes different pathological conditions in humans, and DNA methylation has been identified as one of the key mechanisms that underlie this evolutionarily conserved phenomenon associated with developmental and pathological gene regulation. Recent advances in the miRNA technology with high throughput analysis of gene regulation further increased our understanding on the role of miRNAs regulating multiple gene expression. There is increasing evidence supporting that the miRNAs not only regulate gene expression but they also are involved in the hypermethylation of promoter sequences, which cumulatively contributes to the epigenetic gene silencing. Here, we critically evaluated the recent progress on the transcriptional regulation of an important suppressor protein that inhibits cytokine-mediated signaling, SOCS3, whose expression is directly regulated both by promoter methylation and also by microRNAs, affecting its vital cell regulating functions. SOCS3 was identified as a potent inhibitor of Jak/STAT signaling pathway which is frequently upregulated in several pathologies, including cardiovascular disease, cancer, diabetes, viral infections, and the expression of SOCS3 was inhibited or greatly reduced due to hypermethylation of the CpG islands in its promoter region or suppression of its expression by different microRNAs. Additionally, we discuss key intracellular signaling pathways regulated by SOCS3 involving cellular events, including cell proliferation, cell growth, cell migration and apoptosis. Identification of the pathway intermediates as specific targets would not only aid in the development of novel therapeutic drugs, but, would also assist in developing new treatment strategies that could successfully be employed in combination therapy to target multiple signaling pathways. PMID:25682267

Epigenetic modifications in multiple myeloma: recent advances on the role of DNA and histone methylation.

PubMed

Amodio, Nicola; D'Aquila, Patrizia; Passarino, Giuseppe; Tassone, Pierfrancesco; Bellizzi, Dina

2017-01-01

Multiple Myeloma (MM) is a clonal late B-cell disorder accounting for about 13% of hematological cancers and 1% of all neoplastic diseases. Recent studies on the molecular pathogenesis and biology of MM have highlighted a complex epigenomic landscape contributing to MM onset, prognosis and high individual variability. Areas covered: We describe here the current knowledge on epigenetic events characterizing MM initiation and progression, focusing on the role of DNA and histone methylation and on the most promising epi-therapeutic approaches targeting the methylation pathway. Expert opinion: Data published so far indicate that alterations of the epigenetic framework, which include aberrant global or gene/non-coding RNA specific methylation profiles, feature prominently in the pathobiology of MM. Indeed, the aberrant expression of components of the epigenetic machinery as well as the reversibility of the epigenetic marks make this pathway druggable, providing the basis for the design of epigenetic therapies against this still fatal malignancy.

Testicular cancer from diagnosis to epigenetic factors

PubMed Central

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

Arsenic exposure disrupts epigenetic regulation of SIRT1 in human keratinocytes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Herbert, Katharine J.; Holloway, Adele; Cook, Anthony L.

2014-11-15

Arsenic is an environmental toxin which increases skin cancer risk for exposed populations worldwide; however the underlying biomolecular mechanism for arsenic-induced carcinogenesis is complex and poorly defined. Recent investigations show that histone deacetylase and DNA methyltransferase activity is impaired, and epigenetic patterns of gene regulation are consistently altered in cancers associated with arsenic exposure. Expression of the histone deacetylase SIRT1 is altered in solid tumours and haematological malignancies; however its role in arsenic-induced pathology is unknown. In this study we investigated the effect of arsenic on epigenetic regulation of SIRT1 and its targeting microRNA, miR-34a in primary human keratinocytes. Acetylationmore » of histone H4 at lysine 16 (H4K16) increased in keratinocytes exposed to 0.5 μM arsenite [As(III)]; and this was associated with chromatin remodelling at the miR-34a promoter. Moreover, although SIRT1 protein initially increased in these As(III)-exposed cells, after 24 days expression was not significantly different from untreated controls. Extended exposure to low-dose As(III) (0.5 μM; > 5 weeks) compromised the pattern of CpG methylation at SIRT1 and miR-34a gene promoters, and this was associated with altered expression for both genes. We have found that arsenic alters epigenetic regulation of SIRT1 expression via structural reorganisation of chromatin at the miR-34a gene promoter in the initial 24 h of exposure; and over time, through shifts in miR-34a and SIRT1 gene methylation. Taken together, this investigation demonstrates that arsenic produces cumulative disruptions to epigenetic regulation of miR-34a expression, and this is associated with impaired coordination of SIRT1 functional activity. - Highlights: • Submicromolar arsenic concentrations disrupt SIRT1 activity and expression in human keratinocytes. • Arsenic-induced chromatin remodelling at the miR-34a gene promoter is associated with

Epigenetic Regulation by Sulforaphane: Opportunities for Breast and Prostate Cancer Chemoprevention.

PubMed

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.

The inactive X chromosome is epigenetically unstable and transcriptionally labile in breast cancer.

PubMed

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.

Landscaping plant epigenetics.

PubMed

McKeown, Peter C; Spillane, Charles

2014-01-01

The understanding of epigenetic mechanisms is necessary for assessing the potential impacts of epigenetics on plant growth, development and reproduction, and ultimately for the response of these factors to evolutionary pressures and crop breeding programs. This volume highlights the latest in laboratory and bioinformatic techniques used for the investigation of epigenetic phenomena in plants. Such techniques now allow genome-wide analyses of epigenetic regulation and help to advance our understanding of how epigenetic regulatory mechanisms affect cellular and genome function. To set the scene, we begin with a short background of how the field of epigenetics has evolved, with a particular focus on plant epigenetics. We consider what has historically been understood by the term "epigenetics" before turning to the advances in biochemistry, molecular biology, and genetics which have led to current-day definitions of the term. Following this, we pay attention to key discoveries in the field of epigenetics that have emerged from the study of unusual and enigmatic phenomena in plants. Many of these phenomena have involved cases of non-Mendelian inheritance and have often been dismissed as mere curiosities prior to the elucidation of their molecular mechanisms. In the penultimate section, consideration is given to how advances in molecular techniques are opening the doors to a more comprehensive understanding of epigenetic phenomena in plants. We conclude by assessing some opportunities, challenges, and techniques for epigenetic research in both model and non-model plants, in particular for advancing understanding of the regulation of genome function by epigenetic mechanisms.

A histone methylation network regulates transgenerational epigenetic memory in C. elegans

PubMed Central

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

Childhood Adversity and Epigenetic Regulation of Glucocorticoid Signaling Genes: Associations in Children and Adults

PubMed Central

Tyrka, Audrey R.; Ridout, Kathryn K.; Parade, Stephanie H.

2017-01-01

Early childhood experiences have lasting effects on development, including the risk for psychiatric disorders. Research examining the biologic underpinnings of these associations has revealed the impact of childhood maltreatment on the physiologic stress response and activity of the hypothalamic pituitary adrenal (HPA) axis. A growing body of literature supports the hypothesis that environmental exposures mediate their biological effects via epigenetic mechanisms. Methylation, which is thought to be the most stable form of epigenetic change, is a likely mechanism by which early life exposures has lasting effects. In this review, we present recent evidence related to epigenetic regulation of genes involved in HPA axis regulation, namely the glucocorticoid receptor gene (NR3C1) and FK506 binding protein 51 (FKBP5), after childhood adversity and associations with risk for psychiatric disorders. Implications for the development of interventions and future research are discussed. PMID:27691985

The Role of Sulforaphane in Epigenetic Mechanisms, Including Interdependence between Histone Modification and DNA Methylation

PubMed Central

Kaufman-Szymczyk, Agnieszka; Majewski, Grzegorz; Lubecka-Pietruszewska, Katarzyna; Fabianowska-Majewska, Krystyna

2015-01-01

Carcinogenesis as well as cancer progression result from genetic and epigenetic changes of the genome that leads to dysregulation of transcriptional activity of genes. Epigenetic mechanisms in cancer cells comprise (i) post-translation histone modification (i.e., deacetylation and methylation); (ii) DNA global hypomethylation; (iii) promoter hypermethylation of tumour suppressor genes and genes important for cell cycle regulation, cell differentiation and apoptosis; and (iv) posttranscriptional regulation of gene expression by noncoding microRNA. These epigenetic aberrations can be readily reversible and responsive to both synthetic agents and natural components of diet. A source of one of such diet components are cruciferous vegetables, which contain high levels of a number of glucosinolates and deliver, after enzymatic hydrolysis, sulforaphane and other bioactive isothiocyanates, that are involved in effective up-regulation of transcriptional activity of certain genes and also in restoration of active chromatin structure. Thus a consumption of cruciferous vegetables, treated as a source of isothiocyanates, seems to be potentially useful as an effective cancer preventive factor or as a source of nutrients improving efficacy of standard chemotherapies. In this review an attempt is made to elucidate the role of sulforaphane in regulation of gene promoter activity through a direct down-regulation of histone deacetylase activity and alteration of gene promoter methylation in indirect ways, but the sulforaphane influence on non-coding micro-RNA will not be a subject of this review. PMID:26703571

Nutritional epigenetics

USDA-ARS?s Scientific Manuscript database

This chapter is intended to provide a timely overview of the current state of research at the intersection of nutrition and epigenetics. I begin by describing epigenetics and molecular mechanisms of eigenetic regulation, then highlight four classes of nutritional exposures currently being investiga...

Interplay between diet, gut microbiota, epigenetic events, and colorectal cancer

PubMed Central

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

Epigenetic modification of miR-141 regulates SKA2 by an endogenous ‘sponge’ HOTAIR in glioma

PubMed Central

Wang, Chao; Zong, Gang; Wang, Hong-Liang; Zhao, Bing

2016-01-01

Aberrant expression of miR-141 has recently implicated in the occurrence and development of various types of malignant tumors. However whether the involvement of miR-141 in the pathogenesis of glioma remains unknown. Here, we showed that miR-141 was markedly downregulated in glioma tissues and cell lines compared with normal brain tissues, and its expression correlated with the pathological grading. Enforced expression of miR-141 in glioma cells significantly inhibited cell proliferation, migration and invasion, whereas knockdown of miR-141 exerted opposite effect. Mechanistic investigations revealed that HOTAIR might act as an endogenous ‘sponge’ of miR-141, thereby regulating the derepression of SKA2. Further, we explored the molecular mechanism by which miR-141 expression was regulated, and found that the miR-141 promoter was hypermethylated and that promoter methylation of miR-141 was mediated by DNMT1 in glioma cells. Finally, both overexpression of miR-141 and knockdown of HOTAIR in a mouse model of human glioma resulted in significant reduction of tumor growth in vivo. Collectively, these results suggest that epigenetic modification of miR-141 and the interaction of ceRNA regulatory network will provide a new approach for therapeutics against glioma. PMID:27121316

Histone Methylation and microRNA-dependent Regulation of Epigenetic Activities in Neural Progenitor Self-Renewal and Differentiation.

PubMed

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.

Cognitive analysis of schizophrenia risk genes that function as epigenetic regulators of gene expression.

PubMed

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.

Modulation of Neuroblastoma Disease Pathogenesis By An Extensive Network of Epigenetically Regulated MicroRNAs

PubMed Central

Das, Sudipto; Bryan, Kenneth; Buckley, Patrick G; Piskareva, Olga; Bray, Isabella M; Foley, Niamh; Ryan, Jacqueline; Lynch, Jennifer; Creevey, Laura; Fay, Joanna; Prenter, Suzanne; Koster, Jan; van Sluis, Peter; Versteeg, Rogier; Eggert, Angelika; Schulte, Johannes H; Schramm, Alexander; Mesdagh, Pieter; Vandesompele, Jo; Speleman, Frank

2012-01-01

MicroRNAs contribute to the pathogenesis of many forms of cancer, including the pediatric cancer neuroblastoma, but the underlying mechanisms leading to altered miRNA expression are often unknown. Here, a novel integrated approach for analyzing DNA methylation coupled with miRNA and mRNA expression data sets identified 67 epigenetically regulated miRNA in neuroblastoma. A large proportion (42%) of these miRNAs were associated with poor patient survival when under-expressed in tumors. Moreover, we demonstrate that this panel of epigenetically silenced miRNAs targets a large set of genes that are over-expressed in tumors from patients with poor survival in a highly redundant manner. The genes targeted by the epigenetically regulated miRNAs are enriched for a number of biological processes, including regulation of cell differentiation. Functional studies involving ectopic over-expression of several of the epigenetically silenced miRNAs had a negative impact on neuroblastoma cell viability, providing further support to the concept that inactivation of these miRNAs is important for neuroblastoma disease pathogenesis. One locus, miR-340, induced either differentiation or apoptosis in a cell context dependent manner, indicating a tumor suppressive function for this miRNA. Intriguingly, it was determined that miR-340 is up-regulated by demethylation of an upstream genomic region that occurs during the process of neuroblastoma cell differentiation induced by all-trans retinoic acid (ATRA). Further biological studies of miR-340 revealed that it directly represses the SOX2 transcription factor by targeting of its 3’ UTR, explaining the mechanism by which SOX2 is down-regulated by ATRA. Although SOX2 contributes to the maintenance of stem cells in an undifferentiated state, we demonstrate that miR-340 mediated down-regulation of SOX2 is not required for ATRA induced differentiation to occur. In summary, our results exemplify the dynamic nature of the miRNA epigenome and

Epigenetic Regulation of Non-Lymphoid Cells by Bisphenol A, a Model Endocrine Disrupter: Potential Implications for Immunoregulation

PubMed Central

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

Epigenetic regulation of miR-200 as the potential strategy for the therapy against triple-negative breast cancer.

PubMed

Mekala, Janaki Ramaiah; Naushad, Shaik Mohammad; Ponnusamy, Lavanya; Arivazhagan, Gayatri; Sakthiprasad, Vaishnave; Pal-Bhadra, Manika

2018-01-30

MicroRNAs (miRNAs) are a class of small, non-coding RNAs that are involved in the regulation of gene expression at the post-transcriptional level. MicroRNAs play an important role in cancer cell proliferation, survival and apoptosis. Epigenetic modifiers regulate the microRNA expression. Among the epigenetic players, histone deacetylases (HDACs) function as the key regulators of microRNA expression. Epigenetic machineries such as DNA and histone modifying enzymes and various microRNAs have been identified as the important contributors in cancer initiation and progression. Recent studies have shown that developing innovative microRNA-targeting therapies might improve the human health, specifically against the disease areas of high unmet medical need. Thus microRNA based therapeutics are gaining importance for anti-cancer therapy. Studies on Triple negative breast cancer (TNBC) have revealed the early relapse and poor overall survival of patients which needs immediate therapeutic attention. In this report, we focus the effect of HDAC inhibitors on TNBC cell proliferation, regulation of microRNA gene expression by a series of HDAC genes, chromatin epigenetics, epigenetic remodelling at miR-200 promoter and its modulation by various HDACs. We also discuss the need for identifying novel HDAC inhibitors for modulation of miR-200 in triple negative breast cancer. Copyright © 2017 Elsevier B.V. All rights reserved.

Epigenetic modifications in prostate cancer.

PubMed

Ngollo, Marjolaine; Dagdemir, Aslihan; Karsli-Ceppioglu, Seher; Judes, Gaelle; Pajon, Amaury; Penault-Llorca, Frederique; Boiteux, Jean-Paul; Bignon, Yves-Jean; Guy, Laurent; Bernard-Gallon, Dominique J

2014-01-01

Prostate cancer is the most common cancer in men and the second leading cause of cancer deaths in men in France. Apart from the genetic alterations in prostate cancer, epigenetics modifications are involved in the development and progression of this disease. Epigenetic events are the main cause in gene regulation and the three most epigenetic mechanisms studied include DNA methylation, histone modifications and microRNA expression. In this review, we summarized epigenetic mechanisms in prostate cancer. Epigenetic drugs that inhibit DNA methylation, histone methylation and histone acetylation might be able to reactivate silenced gene expression in prostate cancer. However, further understanding of interactions of these enzymes and their effects on transcription regulation in prostate cancer is needed and has become a priority in biomedical research. In this study, we summed up epigenetic changes with emphasis on pharmacologic epigenetic target agents.

An Epigenetic Gateway to Brain Tumor Cell Identity

PubMed Central

Mack, Stephen C.; Hubert, Christopher G.; Miller, Tyler E.; Taylor, Michael D.; Rich, Jeremy N.

2017-01-01

Precise targeting of genetic lesions alone has been insufficient to extend brain tumor patient survival. Brain cancer cells are diverse in their genetic, metabolic, and microenvironmental compositions, accounting for their phenotypic heterogeneity and disparate responses to therapy. These factors converge at the level of the epigenome, representing a unified node that can be disrupted by pharmacologic inhibition. Aberrant epigenomes define many childhood and adult brain cancers, as demonstrated by widespread changes to DNA methylation patterns, redistribution of histone marks, and disruption of chromatin structure. In this review, we describe the convergence of genetic, metabolic, and micro-environmental factors upon mechanisms of epigenetic deregulation in brain cancer. We discuss how aberrant epigenetic pathways identified in brain tumors affect cell identity, cell state, and neoplastic transformation, in addition to the potential to exploit these alterations as novel therapeutic strategies for the treatment of brain cancer. PMID:26713744

Transcriptomic analysis highlights epigenetic and transcriptional regulation during zygotic embryo development of Pinus pinaster.

PubMed

de Vega-Bartol, José J; Simões, Marta; Lorenz, W Walter; Rodrigues, Andreia S; Alba, Rob; Dean, Jeffrey F D; Miguel, Célia M

2013-08-30

It is during embryogenesis that the plant body plan is established and the meristems responsible for all post-embryonic growth are specified. The molecular mechanisms governing conifer embryogenesis are still largely unknown. Their elucidation may contribute valuable information to clarify if the distinct features of embryo development in angiosperms and gymnosperms result from differential gene regulation. To address this issue, we have performed the first transcriptomic analysis of zygotic embryo development in a conifer species (Pinus pinaster) focusing our study in particular on regulatory genes playing important roles during plant embryo development, namely epigenetic regulators and transcription factors. Microarray analysis of P. pinaster zygotic embryogenesis was performed at five periods of embryo development from early developing to mature embryos. Our results show that most changes in transcript levels occurred in the first and the last embryo stage-to-stage transitions, namely early to pre-cotyledonary embryo and cotyledonary to mature embryo. An analysis of functional categories for genes that were differentially expressed through embryogenesis highlighted several epigenetic regulation mechanisms. While putative orthologs of transcripts associated with mechanisms that target transposable elements and repetitive sequences were strongly expressed in early embryogenesis, PRC2-mediated repression of genes seemed more relevant during late embryogenesis. On the other hand, functions related to sRNA pathways appeared differentially regulated across all stages of embryo development with a prevalence of miRNA functions in mid to late embryogenesis. Identification of putative transcription factor genes differentially regulated between consecutive embryo stages was strongly suggestive of the relevance of auxin responses and regulation of auxin carriers during early embryogenesis. Such responses could be involved in establishing embryo patterning. Later in

Epigenetics primer: why the clinician should care about epigenetics.

PubMed

Duarte, Julio D

2013-12-01

Epigenetics describes heritable alterations of gene expression that do not involve DNA sequence variation and are changeable throughout an organism's lifetime. Not only can epigenetic status influence drug response, but it can also be modulated by drugs. In this review, the three major epigenetic mechanisms are described: covalent DNA modification, histone protein modification, and regulation by noncoding RNA. Further, this review describes how drug therapy can influence, and be influenced by, these mechanisms. Drugs with epigenetic mechanisms are already in use, with many more likely to be approved within the next few years. As the understanding of epigenetic processes improves, so will the ability to use these data in the clinic to improve patient care. © 2013 Pharmacotherapy Publications, Inc.

KNOX1 is expressed and epigenetically regulated during in vitro conditions in Agave spp

PubMed Central

2012-01-01

Background The micropropagation is a powerful tool to scale up plants of economical and agronomical importance, enhancing crop productivity. However, a small but growing body of evidence suggests that epigenetic mechanisms, such as DNA methylation and histone modifications, can be affected under the in vitro conditions characteristic of micropropagation. Here, we tested whether the adaptation to different in vitro systems (Magenta boxes and Bioreactors) modified epigenetically different clones of Agave fourcroydes and A. angustifolia. Furthermore, we assessed whether these epigenetic changes affect the regulatory expression of KNOTTED1-like HOMEOBOX (KNOX) transcription factors. Results To gain a better understanding of epigenetic changes during in vitro and ex vitro conditions in Agave fourcroydes and A. angustifolia, we analyzed global DNA methylation, as well as different histone modification marks, in two different systems: semisolid in Magenta boxes (M) and temporary immersion in modular Bioreactors (B). No significant difference was found in DNA methylation in A. fourcroydes grown in either M or B. However, when A. fourcroydes was compared with A. angustifolia, there was a two-fold difference in DNA methylation between the species, independent of the in vitro system used. Furthermore, we detected an absence or a low amount of the repressive mark H3K9me2 in ex vitro conditions in plants that were cultured earlier either in M or B. Moreover, the expression of AtqKNOX1 and AtqKNOX2, on A. fourcroydes and A. angustifolia clones, is affected during in vitro conditions. Therefore, we used Chromatin ImmunoPrecipitation (ChIP) to know whether these genes were epigenetically regulated. In the case of AtqKNOX1, the H3K4me3 and H3K9me2 were affected during in vitro conditions in comparison with AtqKNOX2. Conclusions Agave clones plants with higher DNA methylation during in vitro conditions were better adapted to ex vitro conditions. In addition, A. fourcroydes and A

Epigenetic Regulation in Particulate Matter-Mediated Cardiopulmonary Toxicities: A Systems Biology Perspective.

PubMed

Wang, Ting; Garcia, Joe Gn; Zhang, Wei

2012-12-01

Particulate matter (PM) air pollution exerts significant adverse health effects in global populations, particularly in developing countries with extensive air pollution. Understanding of the mechanisms of PM-induced health effects including the risk for cardiovascular diseases remains limited. In addition to the direct cellular physiological responses such as mitochondrial dysfunction and oxidative stress, PM mediates remarkable dysregulation of gene expression, especially in cardiovascular tissues. The PM-mediated gene dysregulation is likely to be a complex mechanism affected by various genetic and non-genetic factors. Notably, PM is known to alter epigenetic markers (e.g., DNA methylation and histone modifications), which may contribute to air pollution-mediated health consequences including the risk for cardiovascular diseases. Notably, epigenetic changes induced by ambient PM exposure have emerged to play a critical role in gene regulation. Though the underlying mechanism(s) are not completely clear, the available evidence suggests that the modulated activities of DNA methyltransferase (DNMT), histone acetylase (HAT) and histone deacetylase (HDAC) may contribute to the epigenetic changes induced by PM or PM-related chemicals. By employing genome-wide epigenomic and systems biology approaches, PM toxicogenomics could conceivably progress greatly with the potential identification of individual epigenetic loci associated with dysregulated gene expression after PM exposure, as well the interactions between epigenetic pathways and PM. Furthermore, novel therapeutic targets based on epigenetic markers could be identified through future epigenomic studies on PM-mediated cardiopulmonary toxicities. These considerations collectively inform the future population health applications of genomics in developing countries while benefiting global personalized medicine at the same time.

Epigenetic regulation of left-right asymmetry by DNA methylation.

PubMed

Wang, Lu; Liu, Zhibin; Lin, Hao; Ma, Dongyuan; Tao, Qinghua; Liu, Feng

2017-10-16

DNA methylation is a major epigenetic modification; however, the precise role of DNA methylation in vertebrate development is still not fully understood. Here, we show that DNA methylation is essential for the establishment of the left-right (LR) asymmetric body plan during vertebrate embryogenesis. Perturbation of DNA methylation by depletion of DNA methyltransferase 1 ( dnmt1 ) or dnmt3bb.1 in zebrafish embryos leads to defects in dorsal forerunner cell (DFC) specification or collective migration, laterality organ malformation, and disruption of LR patterning. Knockdown of dnmt1 in Xenopus embryos also causes similar defects. Mechanistically, loss of dnmt1 function induces hypomethylation of the lefty2 gene enhancer and promotes lefty2 expression, which consequently represses Nodal signaling in zebrafish embryos. We also show that Dnmt3bb.1 regulates collective DFC migration through cadherin 1 (Cdh1). Taken together, our data uncover dynamic DNA methylation as an epigenetic mechanism to control LR determination during early embryogenesis in vertebrates. © 2017 The Authors.

NFIB-mediated repression of the epigenetic factor Ezh2 regulates cortical development.

PubMed

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.

Maternal stress and diet may influence affective behavior and stress-response in offspring via epigenetic regulation of central peptidergic function.

PubMed

Thorsell, Annika; Nätt, Daniel

2016-08-01

It has been shown that maternal stress and malnutrition, or experience of other adverse events, during the perinatal period may alter susceptibility in the adult offspring in a time-of-exposure dependent manner. The mechanism underlying this may be epigenetic in nature. Here, we summarize some recent findings on the effects on gene-regulation following maternal malnutrition, focusing on epigenetic regulation of peptidergic activity. Numerous neuropeptides within the central nervous system are crucial components in regulation of homeostatic energy-balance, as well as affective health (i.e. health events related to affective disorders, psychiatric disorders also referred to as mood disorders). It is becoming evident that expression, and function, of these neuropeptides can be regulated via epigenetic mechanisms during fetal development, thereby contributing to the development of the adult phenotype and, possibly, modulating disease susceptibility. Here, we focus on two such neuropeptides, neuropeptide Y (NPY) and corticotropin-releasing hormone (CRH), both involved in regulation of endocrine function, energy homeostasis, as well as affective health. While a number of published studies indicate the involvement of epigenetic mechanisms in CRH-dependent regulation of the offspring adult phenotype, NPY has been much less studied in this context and needs further work.

Epigenetics Advancing Personalized Nanomedicine in Cancer Therapy

PubMed Central

Liu, Shujun

2012-01-01

Personalized medicine aims to deliver the right drug to a right patient at the right time. It offers unique opportunities to integrate new technologies and concepts to disease prognosis, diagnosis and therapeutics. While selective personalized therapies are conceptually impressive, the majority of cancer therapies have dismal outcome. Such therapeutic failure could result from no response, drug resistance, disease relapse or severe side effect from improper drug delivery. Nanomedicine, the application of nanotechnology in medicine, has a potential to advance the identification of diagnostic and prognostic biomarkers and the delivery of right drug to disease sites. Epigenetic aberrations dynamically contribute to cancer pathogenesis. Given the individualized traits of epigenetic biomarkers, epigenetic considerations would significantly refine personalized nanomedicine. This review aims to dissect the interface of personalized medicine with nanomedicine and epigenetics. I will outline the progress and highlight challenges and areas that can be further explored perfecting the personalized health care. PMID:22921595

Two decades of leukemia oncoprotein epistasis: the MLL1 paradigm for epigenetic deregulation in leukemia

PubMed Central

Li, Bin E.; Ernst, Patricia

2015-01-01

MLL1, located on human chromosome 11, is disrupted in distinct recurrent chromosomal translocations in several leukemia subsets. Studying the MLL1 gene and its oncogenic variants has provided a paradigm for understanding cancer initiation and maintenance through aberrant epigenetic gene regulation. Here we review the historical development of model systems to recapitulate oncogenic MLL1-rearrangement (MLL-r) alleles encoding mixed-lineage leukemia fusion proteins (MLL-FPs) or internal gene rearrangement products. These largely mouse and human cell/xenograft systems have been generated and used to understand how MLL-r alleles affect diverse pathways to result in a highly penetrant, drug-resistant leukemia. The particular features of the animal models influenced the conclusions of mechanisms of transformation. We discuss significant downstream enablers, inhibitors, effectors, and collaborators of MLL-r leukemia, including molecules that directly interact with MLL-FPs and endogenous mixed-lineage leukemia protein, direct target genes of MLL-FPs, and other pathways that have proven to be influential in supporting or suppressing the leukemogenic activity of MLL-FPs. The use of animal models has been complemented with patient sample, genome-wide analyses to delineate the important genomic and epigenomic changes that occur in distinct subsets of MLL-r leukemia. Collectively, these studies have resulted in rapid progress toward developing new strategies for targeting MLL-r leukemia and general cell-biological principles that may broadly inform targeting aberrant epigenetic regulators in other cancers. PMID:25264566

Epigenetics in women's health care.

PubMed

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.

Epigenetic Regulation of the Sex Determination Gene MeGI in Polyploid Persimmon.

PubMed

Akagi, Takashi; Henry, Isabelle M; Kawai, Takashi; Comai, Luca; Tao, Ryutaro

2016-12-01

Epigenetic regulation can add a flexible layer to genetic variation, potentially enabling long-term but reversible cis-regulatory changes to an allele while maintaining its DNA sequence. Here, we present a case in which alternative epigenetic states lead to reversible sex determination in the hexaploid persimmon Diospyros kaki Previously, we elucidated the molecular mechanism of sex determination in diploid persimmon and demonstrated the action of a Y-encoded sex determinant pseudogene called OGI, which produces small RNAs targeting the autosomal gene MeGI, resulting in separate male and female individuals (dioecy). We contrast these findings with the discovery, in hexaploid persimmon, of an additional layer of regulation in the form of DNA methylation of the MeGI promoter associated with the production of both male and female flowers in genetically male trees. Consistent with this model, developing male buds exhibited higher methylation levels across the MeGI promoter than developing female flowers from either monoecious or female trees. Additionally, a DNA methylation inhibitor induced developing male buds to form feminized flowers. Concurrently, in Y-chromosome-carrying trees, the expression of OGI is silenced by the presence of a SINE (short interspersed nuclear element)-like insertion in the OGI promoter. Our findings provide an example of an adaptive scenario involving epigenetic plasticity. © 2016 American Society of Plant Biologists. All rights reserved.

Transcriptomic analysis highlights epigenetic and transcriptional regulation during zygotic embryo development of Pinus pinaster

PubMed Central

2013-01-01

Background It is during embryogenesis that the plant body plan is established and the meristems responsible for all post-embryonic growth are specified. The molecular mechanisms governing conifer embryogenesis are still largely unknown. Their elucidation may contribute valuable information to clarify if the distinct features of embryo development in angiosperms and gymnosperms result from differential gene regulation. To address this issue, we have performed the first transcriptomic analysis of zygotic embryo development in a conifer species (Pinus pinaster) focusing our study in particular on regulatory genes playing important roles during plant embryo development, namely epigenetic regulators and transcription factors. Results Microarray analysis of P. pinaster zygotic embryogenesis was performed at five periods of embryo development from early developing to mature embryos. Our results show that most changes in transcript levels occurred in the first and the last embryo stage-to-stage transitions, namely early to pre-cotyledonary embryo and cotyledonary to mature embryo. An analysis of functional categories for genes that were differentially expressed through embryogenesis highlighted several epigenetic regulation mechanisms. While putative orthologs of transcripts associated with mechanisms that target transposable elements and repetitive sequences were strongly expressed in early embryogenesis, PRC2-mediated repression of genes seemed more relevant during late embryogenesis. On the other hand, functions related to sRNA pathways appeared differentially regulated across all stages of embryo development with a prevalence of miRNA functions in mid to late embryogenesis. Identification of putative transcription factor genes differentially regulated between consecutive embryo stages was strongly suggestive of the relevance of auxin responses and regulation of auxin carriers during early embryogenesis. Such responses could be involved in establishing embryo patterning

Epigenetic Disregulation in Oral Cancer

PubMed Central

Mascolo, Massimo; Siano, Maria; Ilardi, Gennaro; Russo, Daniela; Merolla, Francesco; De Rosa, Gaetano; Staibano, Stefania

2012-01-01

Squamous cell carcinoma of the oral region (OSCC) is one of the most common and highly aggressive malignancies worldwide, despite the fact that significant results have been achieved during the last decades in its detection, prevention and treatment. Although many efforts have been made to define the molecular signatures that identify the clinical outcome of oral cancers, OSCC still lacks reliable prognostic molecular markers. Scientific evidence indicates that transition from normal epithelium to pre-malignancy, and finally to oral carcinoma, depends on the accumulation of genetic and epigenetic alterations in a multistep process. Unlike genetic alterations, epigenetic changes are heritable and potentially reversible. The most common examples of such changes are DNA methylation, histone modification, and small non-coding RNAs. Although several epigenetic changes have been currently linked to OSCC initiation and progression, they have been only partially characterized. Over the last decade, it has been demonstrated that especially aberrant DNA methylation plays a critical role in oral cancer. The major goal of the present paper is to review the recent literature about the epigenetic modifications contribution in early and later phases of OSCC malignant transformation; in particular we point out the current evidence of epigenetic marks as novel markers for early diagnosis and prognosis as well as potential therapeutic targets in oral cancer. PMID:22408457

Copy number rather than epigenetic alterations are the major dictator of imprinted methylation in tumors.

PubMed

Martin-Trujillo, Alex; Vidal, Enrique; Monteagudo-Sa Nchez, Ana; Sanchez-Delgado, Marta; Moran, Sebastian; Hernandez Mora, Jose Ramon; Heyn, Holger; Guitart, Miriam; Esteller, Manel; Monk, David

2017-09-07

It has been postulated that imprinting aberrations are common in tumors. To understand the role of imprinting in cancer, we have characterized copy-number and methylation in over 280 cancer cell lines and confirm our observations in primary tumors. Imprinted differentially methylated regions (DMRs) regulate parent-of-origin monoallelic expression of neighboring transcripts in cis. Unlike single-copy CpG islands that may be prone to hypermethylation, imprinted DMRs can either loose or gain methylation during tumorigenesis. Here, we show that methylation profiles at imprinted DMRs often not represent genuine epigenetic changes but simply the accumulation of underlying copy-number aberrations (CNAs), which is independent of the genome methylation state inferred from cancer susceptible loci. Our results reveal that CNAs also influence allelic expression as loci with copy-number neutral loss-of-heterozygosity or amplifications may be expressed from the appropriate parental chromosomes, which is indicative of maintained imprinting, although not observed as a single expression foci by RNA FISH.Altered genomic imprinting is frequently reported in cancer. Here, the authors analyze copy number and methylation in cancer cell lines and primary tumors to show that imprinted methylation profiles represent the accumulation of copy number alteration, rather than epigenetic alterations.

Epigenetic Regulation of the Sex Determination Gene MeGI in Polyploid Persimmon[OPEN

PubMed Central

Kawai, Takashi; Tao, Ryutaro

2016-01-01

Epigenetic regulation can add a flexible layer to genetic variation, potentially enabling long-term but reversible cis-regulatory changes to an allele while maintaining its DNA sequence. Here, we present a case in which alternative epigenetic states lead to reversible sex determination in the hexaploid persimmon Diospyros kaki. Previously, we elucidated the molecular mechanism of sex determination in diploid persimmon and demonstrated the action of a Y-encoded sex determinant pseudogene called OGI, which produces small RNAs targeting the autosomal gene MeGI, resulting in separate male and female individuals (dioecy). We contrast these findings with the discovery, in hexaploid persimmon, of an additional layer of regulation in the form of DNA methylation of the MeGI promoter associated with the production of both male and female flowers in genetically male trees. Consistent with this model, developing male buds exhibited higher methylation levels across the MeGI promoter than developing female flowers from either monoecious or female trees. Additionally, a DNA methylation inhibitor induced developing male buds to form feminized flowers. Concurrently, in Y-chromosome-carrying trees, the expression of OGI is silenced by the presence of a SINE (short interspersed nuclear element)-like insertion in the OGI promoter. Our findings provide an example of an adaptive scenario involving epigenetic plasticity. PMID:27956470

Deoxynivalenol exposure induces autophagy/apoptosis and epigenetic modification changes during porcine oocyte maturation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Han, Jun; Wang, Qiao-Chu; Zhu, Cheng-Cheng

Deoxynivalenol (DON) is a widespread trichothecene mycotoxin which contaminates agricultural staples and elicits a complex spectrum of toxic effects on humans and animals. It has been shown that DON impairs oocyte maturation, reproductive function and causes abnormal fetal development in mammals; however, the mechanisms remain unclear. In the present study, we investigate the possible reasons of the toxic effects of DON on porcine oocytes. Our results showed that DON significantly inhibited porcine oocyte maturation and disrupted meiotic spindle by reducing p-MAPK protein level, which caused retardation of cell cycle progression. In addition, up-regulated LC3 protein expression and aberrant Lamp2, LC3more » and mTOR mRNA levels were observed with DON exposure, together with Annexin V-FITC staining assay analysis, these results indicated that DON treatment induced autophagy/apoptosis in porcine oocytes. We also showed that DON exposure increased DNA methylation level in porcine oocytes through altering DNMT3A mRNA levels. Histone methylation levels were also changed showing with increased H3K27me3 and H3K4me2 protein levels, and mRNA levels of their relative methyltransferase genes, indicating that epigenetic modifications were affected. Taken together, our results suggested that DON exposure reduced porcine oocytes maturation capability through affecting cytoskeletal dynamics, cell cycle, autophagy/apoptosis and epigenetic modifications. - Highlights: • DON exposure disrupted meiotic spindle by reducing p-MAPK expression. • DON exposure caused retardation of cell cycle progression in porcine oocytes. • DON triggered autophagy and early-apoptosis in porcine oocytes. • DON exposure led to aberrant epigenetic modifications in porcine oocytes.« less

Genetic and epigenetic alteration of the NF2 gene in sporadic meningiomas.

PubMed

Lomas, Jesus; Bello, M Josefa; Arjona, Dolores; Alonso, M Eva; Martinez-Glez, Victor; Lopez-Marin, Isabel; Amiñoso, Cinthia; de Campos, Jose M; Isla, Alberto; Vaquero, Jesus; Rey, Juan A

2005-03-01

The role of the NF2 gene in the development of meningiomas has recently been documented; inactivating mutations plus allelic loss at 22q, the site of this gene (at 22q12), have been identified in both sporadic and neurofibromatosis type 2-associated tumors. Although epigenetic inactivation through aberrant CpG island methylation of the NF2 5' flanking region has been documented in schwannoma (another NF2-associated neoplasm), data on participation of this epigenetic modification in meningiomas are not yet widely available. Using methylation-specific PCR (MSP) plus sequencing, we assessed the presence of aberrant promoter NF2 methylation in a series of 88 meningiomas (61 grade I, 24 grade II, and 3 grade III), in which the allelic constitution at 22q and the NF2 mutational status also were determined by RFLP/microsatellite and PCR-SSCP analyses. Chromosome 22 allelic loss, NF2 gene mutation, and aberrant NF2 promoter methylation were detected in 49%, 24%, and 26% of cases, respectively. Aberrant NF2 methylation with loss of heterozygosity (LOH) at 22q was found in five cases, and aberrant methylation with NF2 mutation in another; LOH 22q and the mutation were found in 16 samples. The aberrant methylation of the NF2 gene also was the sole alteration in 15 samples, most of which were from grade I tumors. These results indicate that aberrant NF2 hypermethylation may participate in the development of a significant proportion of sporadic meningiomas, primarily those of grade I.

Leg regeneration is epigenetically regulated by histone H3K27 methylation in the cricket Gryllus bimaculatus.

PubMed

Hamada, Yoshimasa; Bando, Tetsuya; Nakamura, Taro; Ishimaru, Yoshiyasu; Mito, Taro; Noji, Sumihare; Tomioka, Kenji; Ohuchi, Hideyo

2015-09-01

Hemimetabolous insects such as the cricket Gryllus bimaculatus regenerate lost tissue parts using blastemal cells, a population of dedifferentiated proliferating cells. The expression of several factors that control epigenetic modification is upregulated in the blastema compared with differentiated tissue, suggesting that epigenetic changes in gene expression might control the differentiation status of blastema cells during regeneration. To clarify the molecular basis of epigenetic regulation during regeneration, we focused on the function of the Gryllus Enhancer of zeste [Gb'E(z)] and Ubiquitously transcribed tetratricopeptide repeat gene on the X chromosome (Gb'Utx) homologues, which regulate methylation and demethylation of histone H3 lysine 27 (H3K27), respectively. Methylated histone H3K27 in the regenerating leg was diminished by Gb'E(z)(RNAi) and was increased by Gb'Utx(RNAi). Regenerated Gb'E(z)(RNAi) cricket legs exhibited extra leg segment formation between the tibia and tarsus, and regenerated Gb'Utx(RNAi) cricket legs showed leg joint formation defects in the tarsus. In the Gb'E(z)(RNAi) regenerating leg, the Gb'dac expression domain expanded in the tarsus. By contrast, in the Gb'Utx(RNAi) regenerating leg, Gb'Egfr expression in the middle of the tarsus was diminished. These results suggest that regulation of the histone H3K27 methylation state is involved in the repatterning process during leg regeneration among cricket species via the epigenetic regulation of leg patterning gene expression. © 2015. Published by The Company of Biologists Ltd.

The Epigenetics of Epilepsy and Its Progression.

PubMed

Hauser, Rebecca M; Henshall, David C; Lubin, Farah D

2018-04-01

Epilepsy is a common and devastating neurological disorder characterized by recurrent and unprovoked spontaneous seizures. One leading hypothesis for the development and progression of epilepsy is that large-scale changes in gene transcription and protein expression contribute to aberrant network restructuring and hyperexcitability, resulting in the genesis of repeated seizures. Current research shows that epigenetic mechanisms, including posttranslational alterations to the proteins around which DNA is coiled, chemical modifications to DNA, and the activity of various noncoding RNA molecules exert important influences on these gene networks in experimental epilepsy. Key findings from animal models have been replicated in humans using brain tissue obtained from living patients at the time of neurosurgical resection for pharmacoresistant epilepsy. These findings have spurred efforts to target epigenetic processes to disrupt or modify epilepsy in experimental models with varying degrees of success. In this review, we will (1) summarize the epigenetic mechanisms implicated in epileptogenesis and epilepsy, (2) explore the influence of metabolic factors on epigenetic mechanisms, and (3) assess the potential of using epigenetic markers to support diagnosis and prognosis. Translation of these findings may guide the development of molecular biomarkers and novel therapeutics for prevention or modification of epileptic disorders.

Epigenetic Control of Cytokine Gene Expression: Regulation of the TNF/LT Locus and T Helper Cell Differentiation

PubMed Central

Falvo, James V.; Jasenosky, Luke D.; Kruidenier, Laurens; Goldfeld, Anne E.

2014-01-01

Epigenetics encompasses transient and heritable modifications to DNA and nucleosomes in the native chromatin context. For example, enzymatic addition of chemical moieties to the N-terminal “tails” of histones, particularly acetylation and methylation of lysine residues in the histone tails of H3 and H4, plays a key role in regulation of gene transcription. The modified histones, which are physically associated with gene regulatory regions that typically occur within conserved noncoding sequences, play a functional role in active, poised, or repressed gene transcription. The “histone code” defined by these modifications, along with the chromatin-binding acetylases, deacetylases, methylases, demethylases, and other enzymes that direct modifications resulting in specific patterns of histone modification, shows considerable evolutionary conservation from yeast to humans. Direct modifications at the DNA level, such as cytosine methylation at CpG motifs that represses promoter activity, are another highly conserved epigenetic mechanism of gene regulation. Furthermore, epigenetic modifications at the nucleosome or DNA level can also be coupled with higher-order intra- or interchromosomal interactions that influence the location of regulatory elements and that can place them in an environment of specific nucleoprotein complexes associated with transcription. In the mammalian immune system, epigenetic gene regulation is a crucial mechanism for a range of physiological processes, including the innate host immune response to pathogens and T cell differentiation driven by specific patterns of cytokine gene expression. Here, we will review current findings regarding epigenetic regulation of cytokine genes important in innate and/or adaptive immune responses, with a special focus upon the tumor necrosis factor/lymphotoxin locus and cytokine-driven CD4+ T cell differentiation into the Th1, Th2, and Th17 lineages. PMID:23683942

Age-related epigenetic drift and phenotypic plasticity loss: implications in prevention of age-related human diseases

PubMed Central

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

Identification by high-throughput imaging of the histone methyltransferase EHMT2 as an epigenetic regulator of VEGFA alternative splicing

PubMed Central

Salton, Maayan; Voss, Ty C.; Misteli, Tom

2014-01-01

Recent evidence points to a role of chromatin in regulation of alternative pre-mRNA splicing (AS). In order to identify novel chromatin regulators of AS, we screened an RNAi library of chromatin proteins using a cell-based high-throughput in vivo assay. We identified a set of chromatin proteins that regulate AS. Using simultaneous genome-wide expression and AS analysis, we demonstrate distinct and non-overlapping functions of these chromatin modifiers on transcription and AS. Detailed mechanistic characterization of one dual function chromatin modifier, the H3K9 methyltransferase EHMT2 (G9a), identified VEGFA as a major chromatin-mediated AS target. Silencing of EHMT2, or its heterodimer partner EHMT1, affects AS by promoting exclusion of VEGFA exon 6a, but does not alter total VEGFA mRNA levels. The epigenetic regulatory mechanism of AS by EHMT2 involves an adaptor system consisting of the chromatin modulator HP1γ, which binds methylated H3K9 and recruits splicing regulator SRSF1. The epigenetic regulation of VEGFA is physiologically relevant since EHMT2 is transcriptionally induced in response to hypoxia and triggers concomitant changes in AS of VEGFA. These results characterize a novel epigenetic regulatory mechanism of AS and they demonstrate separate roles of epigenetic modifiers in transcription and alternative splicing. PMID:25414343

Nimbolide epigenetically regulates autophagy and apoptosis in breast cancer.

PubMed

Pooladanda, Venkatesh; Bandi, Soumya; Mondi, Sandhya Rani; Gottumukkala, Krishna Mohan; Godugu, Chandraiah

2018-09-01

Autophagy is a critical regulator of cellular homeostasis and its dysregulation often results in various disease manifestations, including cancer. Nimbolide, an active chemical constituent of neem (Azadirachta indica) exhibits potent anticancer effects. Although, nimbolide mediated apoptosis activation in breast cancer cells is well known. Nevertheless, its role in autophagy induction mechanism and epigenetic alteration is not explored previously. Our current study intended to bridge the gaps in the existing research by exploring the potential of nimbolide in inducing autophagy, which could counter regulate the transformations in breast cancer. In our studies, nimbolide significantly inhibited the cell proliferation of MDA-MB-231 and MCF-7 cells with IC 50 values of 1.97 ± 0.24 and 5.04 ± 0.25 μM, respectively. Nimbolide markedly arrested the cell cycle progression and cell survival with loss of mitochondrial membrane potential by reducing Bcl-2 concomitantly inducing Bax and caspases protein expression with modulation of HDAC-2 and H3K27Ac expression. Consequently, characteristic autophagolysosome accumulation was observed by acridine orange, monodansylcadaverine (MDC) and Lysotracker Red staining. Moreover, nimbolide induced autophagy signaling by increasing Beclin 1 and LC3B along with decreased p62 and mTOR protein expression. Thus, our findings imply that nimbolide induces autophagy mediated apoptotic cell death in breast cancer with epigenetic modifications. Copyright © 2018 Elsevier Ltd. All rights reserved.

Epigenetic perturbations in the pathogenesis of mustard toxicity; hypothesis and preliminary results

PubMed Central

Korkmaz, Ahmet; Yaren, Hakan; Kunak, Z. Ilker; Uysal, Bulent; Kurt, Bulent; Topal, Turgut; Kenar, Levent; Ucar, Ergun; Oter, Sukru

2008-01-01

Among the most readily available chemical warfare agents, sulfur mustard (SM), also known as mustard gas, has been the most widely used chemical weapon. SM causes debilitating effects that can leave an exposed individual incapacitated for days to months; therefore delayed SM toxicity is of much greater importance than its ability to cause lethality. Although not fully understood, acute toxicity of SM is related to reactive oxygen and nitrogen species, oxidative stress, DNA damage, poly(ADP-ribose) polymerase (PARP) activation and energy depletion within the affected cell. Therefore several antioxidants and PARP inhibitors show beneficial effects against acute SM toxicity. The delayed toxicity of SM however, currently has no clear mechanistic explanation. One third of the 100,000 Iranian casualties are still suffering from the detrimental effects of SM in spite of the extensive treatment. We, therefore, made an attempt whether epigenetic aberrations may contribute to pathogenesis of mustard poisoning. Preliminary evidence reveals that mechlorethamine (a nitrogen mustard derivative) exposure may not only cause oxidative stress, DNA damage, but epigenetic perturbations as well. Epigenetic refers to the study of changes that influence the phenotype without causing alteration of the genotype. It involves changes in the properties of a cell that are inherited but do not involve a change in DNA sequence. It is now known that in addition to mutations, epimutations contribute to a variety of human diseases. Under light of preliminary results, the current hypothesis will focus on epigenetic regulations to clarify mustard toxicity and the use of drugs to correct possible epigenetic defects. PMID:21218122

Epigenetic modifiers in immunotherapy: a focus on checkpoint inhibitors.

PubMed

Terranova-Barberio, Manuela; Thomas, Scott; Munster, Pamela N

2016-06-01

Immune surveillance should be directed to suppress tumor development and progression, involving a balance of coinhibitory and costimulatory signals that amplify immune response without overwhelming the host. Immunotherapy confers durable clinical benefit in 'immunogenic tumors', whereas in other tumors the responses are modest. Thus, immune checkpoint inhibitors may need to be combined with strategies to boost immune response or increase the tumor immune profile. Epigenetic aberrations contribute significantly to carcinogenesis. Recent findings suggest that epigenetic drugs prime the immune response by increasing expression of tumor-associated antigens and immune-related genes, as well as modulating chemokines and cytokines involved in immune system activation. This review describes our current understanding regarding epigenetic and immunotherapy combination, focusing on immune response priming to checkpoint blockade.

Nuclear sensing of viral DNA, epigenetic regulation of herpes simplex virus infection, and innate immunity

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

Epigenetic regulation of oligodendrocyte identity

PubMed Central

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

Epigenetic synergies between biotin and folate in the regulation of pro-inflammatory cytokines and repeats

PubMed Central

Xue, Jing; Zempleni, Janos

2013-01-01

The protein biotin ligase, holocarboxylase synthetase (HLCS), is a chromatin protein that interacts physically with the DNA methyltransferase DNMT1, the methylated cytosine binding protein MeCP2, and the histone H3 K9-methyltransferase EHMT1, all of which participate in folate-dependent gene repression. Here we tested the hypothesis that biotin and folate synergize in the repression of pro-inflammatory cytokines and long-terminal repeats (LTRs), mediated by interactions between HLCS and other chromatin proteins. Biotin and folate supplementation could compensate for each other’s deficiency in the repression of LTRs in Jurkat and U937 cells. For example, when biotin-deficient Jurkat cells were supplemented with folate, the expression of LTRs decreased by >70%. Epigenetic synergies were more complex in the regulation of cytokines compared with LTRs. For example, the abundance of TNF-α was 100% greater in folate- and biotin-supplemented U937 cells compared with biotin-deficient and folate-supplemented cells. The NF-κB inhibitor curcumin abrogated the effects of folate and biotin in cytokine regulation, suggesting that transcription factor signaling adds an extra layer of complexity to the regulation of cytokine genes by epigenetic phenomena. We conclude that biotin and folate synergize in the repression of LTRs and that these interactions are probably mediated by HLCS-dependent epigenetic mechanisms. In contrast, synergies between biotin and folate in the regulation of cytokines need to be interpreted in the context of transcription factor signaling. PMID:24007195

Epigenetic changes in fetal hypothalamic energy regulating pathways are associated with maternal undernutrition and twinning

PubMed Central

Begum, Ghazala; Stevens, Adam; Smith, Emma Bolton; Connor, Kristin; Challis, John R. G.; Bloomfield, Frank; White, Anne

2012-01-01

Undernutrition during pregnancy is implicated in the programming of offspring for the development of obesity and diabetes. We hypothesized that maternal programming causes epigenetic changes in fetal hypothalamic pathways regulating metabolism. This study used sheep to examine the effect of moderate maternal undernutrition (60 d before to 30 d after mating) and twinning to investigate changes in the key metabolic regulators proopiomelanocortin (POMC) and the glucocorticoid receptor (GR) in fetal hypothalami. Methylation of the fetal hypothalamic POMC promoter was reduced in underfed singleton, fed twin, and underfed twin groups (60, 73, and 63% decrease, respectively). This was associated with reduced DNA methyltransferase activity and altered histone methylation and acetylation. Methylation of the hypothalamic GR promoter was decreased in both twin groups and in maternally underfed singleton fetuses (52, 65, and 55% decrease, respectively). This correlated with changes in histone methylation and acetylation and increased GR mRNA expression in the maternally underfed singleton group. Alterations in GR were hypothalamic specific, with no changes in hippocampi. Unaltered levels of OCT4 promoter methylation indicated gene-specific effects. In conclusion, twinning and periconceptional undernutrition are associated with epigenetic changes in fetal hypothalamic POMC and GR genes, potentially resulting in altered energy balance regulation in the offspring.—Begum, G., Stevens, A., Smith, E. B., Connor, K., Challis, J. R. G., Bloomfield, F., White, A. Epigenetic changes in fetal hypothalamic energy regulating pathways are associated with maternal undernutrition and twinning. PMID:22223754

Epigenetics and epilepsy.

PubMed

Pulido Fontes, L; Quesada Jimenez, P; Mendioroz Iriarte, M

2015-03-01

Epigenetics is the study of heritable modifications in gene expression that do not change the DNA nucleotide sequence. Some of the most thoroughly studied epigenetic mechanisms at present are DNA methylation, post-transcriptional modifications of histones, and the effect of non-coding RNA molecules. Gene expression is regulated by means of these mechanisms and disruption of these molecular pathways may elicit development of diseases. We describe the main epigenetic regulatory mechanisms and review the most recent literature about epigenetic mechanisms and how those mechanisms are involved in different epileptic syndromes. Identifying the epigenetic mechanisms involved in epilepsy is a promising line of research that will deliver more in-depth knowledge of epilepsy pathophysiology and treatments. Copyright © 2014 Sociedad Española de Neurología. Published by Elsevier Espana. All rights reserved.

Epigenetic regulation of TTF-I-mediated promoter–terminator interactions of rRNA genes

PubMed Central

Németh, Attila; Guibert, Sylvain; Tiwari, Vijay Kumar; Ohlsson, Rolf; Längst, Gernot

2008-01-01

Ribosomal RNA synthesis is the eukaryotic cell's main transcriptional activity, but little is known about the chromatin domain organization and epigenetics of actively transcribed rRNA genes. Here, we show epigenetic and spatial organization of mouse rRNA genes at the molecular level. TTF-I-binding sites subdivide the rRNA transcription unit into functional chromatin domains and sharply delimit transcription factor occupancy. H2A.Z-containing nucleosomes occupy the spacer promoter next to a newly characterized TTF-I-binding site. The spacer and the promoter proximal TTF-I-binding sites demarcate the enhancer. DNA from both the enhancer and the coding region is hypomethylated in actively transcribed repeats. 3C analysis revealed an interaction between promoter and terminator regions, which brings the beginning and end of active rRNA genes into close contact. Reporter assays show that TTF-I mediates this interaction, thereby linking topology and epigenetic regulation of the rRNA genes. PMID:18354495

Epigenetic Drug Repositioning for Alzheimer's Disease Based on Epigenetic Targets in Human Interactome.

PubMed

Chatterjee, Paulami; Roy, Debjani; Rathi, Nitin

2018-01-01

Epigenetics has emerged as an important field in drug discovery. Alzheimer's disease (AD), the leading neurodegenerative disorder throughout the world, is shown to have an epigenetic basis. Currently, there are very few effective epigenetic drugs available for AD. In this work, for the first time we have proposed 14 AD repositioning epigenetic drugs and identified their targets from extensive human interactome. Interacting partners of the AD epigenetic proteins were identified from the extensive human interactome to construct Epigenetic Protein-Protein Interaction Network (EP-PPIN). Epigenetic Drug-Target Network (EP-DTN) was constructed with the drugs associated with the proteins of EP-PPIN. Regulation of non-coding RNAs associated with the target proteins of these drugs was also studied. AD related target proteins, epigenetic targets, enriched pathways, and functional categories of the proposed repositioning drugs were also studied. The proposed 14 AD epigenetic repositioning drugs have overlapping targets and miRs with known AD epigenetic targets and miRs. Furthermore, several shared functional categories and enriched pathways were obtained for these drugs with FDA approved epigenetic drugs and known AD drugs. The findings of our work might provide insight into future AD epigenetic-therapeutics.

Identification by high-throughput imaging of the histone methyltransferase EHMT2 as an epigenetic regulator of VEGFA alternative splicing.

PubMed

Salton, Maayan; Voss, Ty C; Misteli, Tom

2014-12-16

Recent evidence points to a role of chromatin in regulation of alternative pre-mRNA splicing (AS). In order to identify novel chromatin regulators of AS, we screened an RNAi library of chromatin proteins using a cell-based high-throughput in vivo assay. We identified a set of chromatin proteins that regulate AS. Using simultaneous genome-wide expression and AS analysis, we demonstrate distinct and non-overlapping functions of these chromatin modifiers on transcription and AS. Detailed mechanistic characterization of one dual function chromatin modifier, the H3K9 methyltransferase EHMT2 (G9a), identified VEGFA as a major chromatin-mediated AS target. Silencing of EHMT2, or its heterodimer partner EHMT1, affects AS by promoting exclusion of VEGFA exon 6a, but does not alter total VEGFA mRNA levels. The epigenetic regulatory mechanism of AS by EHMT2 involves an adaptor system consisting of the chromatin modulator HP1γ, which binds methylated H3K9 and recruits splicing regulator SRSF1. The epigenetic regulation of VEGFA is physiologically relevant since EHMT2 is transcriptionally induced in response to hypoxia and triggers concomitant changes in AS of VEGFA. These results characterize a novel epigenetic regulatory mechanism of AS and they demonstrate separate roles of epigenetic modifiers in transcription and alternative splicing. Published by Oxford University Press on behalf of Nucleic Acids Research 2014. This work is written by US Government employees and is in the public domain in the US.

Non-coding RNAs as regulators of gene expression and epigenetics

PubMed Central

Kaikkonen, Minna U.; Lam, Michael T.Y.; Glass, Christopher K.

2011-01-01

Genome-wide studies have revealed that mammalian genomes are pervasively transcribed. This has led to the identification and isolation of novel classes of non-coding RNAs (ncRNAs) that influence gene expression by a variety of mechanisms. Here we review the characteristics and functions of regulatory ncRNAs in chromatin remodelling and at multiple levels of transcriptional and post-transcriptional regulation. We also describe the potential roles of ncRNAs in vascular biology and in mediating epigenetic modifications that might play roles in cardiovascular disease susceptibility. The emerging recognition of the diverse functions of ncRNAs in regulation of gene expression suggests that they may represent new targets for therapeutic intervention. PMID:21558279

Role of Oxidative Stress in Epigenetic Modification in Endometriosis.

PubMed

Ito, Fuminori; Yamada, Yuki; Shigemitsu, Aiko; Akinishi, Mika; Kaniwa, Hiroko; Miyake, Ryuta; Yamanaka, Shoichiro; Kobayashi, Hiroshi

2017-11-01

Aberrant DNA methylation and histone modification are associated with an increased risk of reproductive disorders such as endometriosis. However, a cause-effect relationship between epigenetic mechanisms and endometriosis development has not been fully determined. This review provides current information based on oxidative stress in epigenetic modification in endometriosis. This article reviews the English-language literature on epigenetics, DNA methylation, histone modification, and oxidative stress associated with endometriosis in an effort to identify epigenetic modification that causes a predisposition to endometriosis. Oxidative stress, secondary to the influx of hemoglobin, heme, and iron during retrograde menstruation, is involved in the expression of CpG demethylases, ten-eleven translocation, and jumonji (JMJ). Ten-eleven translocation and JMJ recognize a wide range of endogenous DNA methyltransferases (DNMTs). The increased expression levels of DNMTs may be involved in the subsequent downregulation of the decidualization-related genes. This review supports the hypothesis that there are at least 2 distinct phases of epigenetic modification in endometriosis: the initial wave of iron-induced oxidative stress would be followed by the second big wave of epigenetic modulation of endometriosis susceptibility genes. We summarize the recent advances in our understanding of the underlying epigenetic mechanisms focusing on oxidative stress in endometriosis.

Epigenetic transgenerational inheritance of somatic transcriptomes and epigenetic control regions

PubMed Central

2012-01-01

Background Environmentally induced epigenetic transgenerational inheritance of adult onset disease involves a variety of phenotypic changes, suggesting a general alteration in genome activity. Results Investigation of different tissue transcriptomes in male and female F3 generation vinclozolin versus control lineage rats demonstrated all tissues examined had transgenerational transcriptomes. The microarrays from 11 different tissues were compared with a gene bionetwork analysis. Although each tissue transgenerational transcriptome was unique, common cellular pathways and processes were identified between the tissues. A cluster analysis identified gene modules with coordinated gene expression and each had unique gene networks regulating tissue-specific gene expression and function. A large number of statistically significant over-represented clusters of genes were identified in the genome for both males and females. These gene clusters ranged from 2-5 megabases in size, and a number of them corresponded to the epimutations previously identified in sperm that transmit the epigenetic transgenerational inheritance of disease phenotypes. Conclusions Combined observations demonstrate that all tissues derived from the epigenetically altered germ line develop transgenerational transcriptomes unique to the tissue, but common epigenetic control regions in the genome may coordinately regulate these tissue-specific transcriptomes. This systems biology approach provides insight into the molecular mechanisms involved in the epigenetic transgenerational inheritance of a variety of adult onset disease phenotypes. PMID:23034163

Regulation of tumour related genes by dynamic epigenetic alteration at enhancer regions in gastric epithelial cells infected by Epstein-Barr virus.

PubMed

Okabe, Atsushi; Funata, Sayaka; Matsusaka, Keisuke; Namba, Hiroe; Fukuyo, Masaki; Rahmutulla, Bahityar; Oshima, Motohiko; Iwama, Atsushi; Fukayama, Masashi; Kaneda, Atsushi

2017-08-11

Epstein-Barr virus (EBV) infection is associated with tumours such as Burkitt lymphoma, nasopharyngeal carcinoma, and gastric cancer. We previously showed that EBV(+) gastric cancer presents an extremely high-methylation epigenotype and this aberrant DNA methylation causes silencing of multiple tumour suppressor genes. However, the mechanisms that drive EBV infection-mediated tumorigenesis, including other epigenomic alteration, remain unclear. We analysed epigenetic alterations induced by EBV infection especially at enhancer regions, to elucidate their contribution to tumorigenesis. We performed ChIP sequencing on H3K4me3, H3K4me1, H3K27ac, H3K27me3, and H3K9me3 in gastric epithelial cells infected or not with EBV. We showed that repressive marks were redistributed after EBV infection, resulting in aberrant enhancer activation and repression. Enhancer dysfunction led to the activation of pathways related to cancer hallmarks (e.g., resisting cell death, disrupting cellular energetics, inducing invasion, evading growth suppressors, sustaining proliferative signalling, angiogenesis, and tumour-promoting inflammation) and inactivation of tumour suppressive pathways. Deregulation of cancer-related genes in EBV-infected gastric epithelial cells was also observed in clinical EBV(+) gastric cancer specimens. Our analysis showed that epigenetic alteration associated with EBV-infection may contribute to tumorigenesis through enhancer activation and repression.

Epigenetics and Cellular Metabolism

PubMed Central

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

Endocrine control of epigenetic mechanisms in male reproduction.

PubMed

Ankolkar, Mandar; Balasinor, N H

2016-01-01

Endocrine control of reproduction is very well known and has been echoed by many research groups. However, recent developments point to the ability of toxic endocrine disrupting chemicals (EDC) to alter epigenetic information of the gametes which gets transferred to the developing embryo and affects the immediate reproductive outcome or even persists transgenerationally. These epigenetic aberrations contribute to the ensuing pathophysiology of reproductive disorders. Investigations of the female in cases of poor reproductive outcome have been the main strategy towards diagnosis. However, despite the male partner contributing half of his genome to the progeny, thorough investigations in the male have been ignored. Environmental pollutants are all pervading and are encountered in our day-to-day life. Many of these pollutants have potential to disrupt the endocrine system. Here, we discuss how the male gametes (spermatozoa) are susceptible to a myriad of epigenetic insults inflicted by exposure to endocrine disruptors and how important is the contribution of the epigenetic marks of the spermatozoa in healthy reproduction. We advocate that sperm epigenetics should be considered as a significant contributor to reproductive health and should be researched further and be subsequently included in routine diagnostic workup in cases of poor reproductive outcome.

The Epigenetic Factor KDM2B Regulates EMT and Small GTPases in Colon Tumor Cells.

PubMed

Zacharopoulou, Nefeli; Tsapara, Anna; Kallergi, Galatea; Schmid, Evi; Alkahtani, Saad; Alarifi, Saud; Tsichlis, Philip N; Kampranis, Sotirios C; Stournaras, Christos

2018-05-14

The epigenetic factor KDM2B is a histone demethylase expressed in various tumors. Recently, we have shown that KDM2B regulates actin cytoskeleton organization, small Rho GTPases signaling, cell-cell adhesion and migration of prostate tumor cells. In the present study, we addressed its role in regulating EMT and small GTPases expression in colon tumor cells. We used RT-PCR for the transcriptional analysis of various genes, Western blotting for the assessment of protein expression and immunofluorescence microscopy for visualization of fluorescently labeled proteins. We report here that KDM2B regulates EZH2 and BMI1 in HCT116 colon tumor cells. Knockdown of this epigenetic factor induced potent up-regulation of the protein levels of the epithelial markers E-cadherin and ZO-1, while the mesenchymal marker N-cadherin was downregulated. On the other hand, KDM2B overexpression downregulated the levels of both epithelial markers and upregulated the mesenchymal marker, suggesting control of EMT by KDM2B. In addition, RhoA, RhoB and RhoC protein levels diminished upon KDM2B-knockdown, while all three small GTPases became upregulated in KDM2B-overexpressing HCT116 cell clones. Interestingly, Rac1 GTPase level increased upon KDM2B-knockdown and diminished in KDM2B-overexpressing HCT116 colon tumor- and DU-145 prostate cancer cells. These results establish a clear functional role of the epigenetic factor KDM2B in the regulation of EMT and small-GTPases expression in colon tumor cells and further support the recently postulated oncogenic role of this histone demethylase in various tumors. © 2018 The Author(s). Published by S. Karger AG, Basel.

Chromatin and epigenetics in all their states: Meeting report of the first conference on Epigenetic and Chromatin Regulation of Plant Traits - January 14 - 15, 2016 - Strasbourg, France.

PubMed

Bey, Till; Jamge, Suraj; Klemme, Sonja; Komar, Dorota Natalia; Le Gall, Sabine; Mikulski, Pawel; Schmidt, Martin; Zicola, Johan; Berr, Alexandre

2016-08-02

In January 2016, the first Epigenetic and Chromatin Regulation of Plant Traits conference was held in Strasbourg, France. An all-star lineup of speakers, a packed audience of 130 participants from over 20 countries, and a friendly scientific atmosphere contributed to make this conference a meeting to remember. In this article we summarize some of the new insights into chromatin, epigenetics, and epigenomics research and highlight nascent ideas and emerging concepts in this exciting area of research.

The complexity of epigenetic diseases.

PubMed

Brazel, Ailbhe Jane; Vernimmen, Douglas

2016-01-01

Over the past 30 years, a plethora of pathogenic mutations affecting enhancer regions and epigenetic regulators have been identified. Coupled with more recent genome-wide association studies (GWAS) and epigenome-wide association studies (EWAS) implicating major roles for regulatory mutations in disease, it is clear that epigenetic mechanisms represent important biomarkers for disease development and perhaps even therapeutic targets. Here, we discuss the diversity of disease-causing mutations in enhancers and epigenetic regulators, with a particular focus on cancer. © 2015 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Epigenetic Modifications in Essential Hypertension

PubMed Central

Wise, Ingrid A.; Charchar, Fadi J.

2016-01-01

Essential hypertension (EH) is a complex, polygenic condition with no single causative agent. Despite advances in our understanding of the pathophysiology of EH, hypertension remains one of the world’s leading public health problems. Furthermore, there is increasing evidence that epigenetic modifications are as important as genetic predisposition in the development of EH. Indeed, a complex and interactive genetic and environmental system exists to determine an individual’s risk of EH. Epigenetics refers to all heritable changes to the regulation of gene expression as well as chromatin remodelling, without involvement of nucleotide sequence changes. Epigenetic modification is recognized as an essential process in biology, but is now being investigated for its role in the development of specific pathologic conditions, including EH. Epigenetic research will provide insights into the pathogenesis of blood pressure regulation that cannot be explained by classic Mendelian inheritance. This review concentrates on epigenetic modifications to DNA structure, including the influence of non-coding RNAs on hypertension development. PMID:27023534

Aberrant Epigenetic Alterations of Glutathione-S-Transferase P1 in Age-Related Nuclear Cataract.

PubMed

Chen, Jia; Zhou, Jing; Wu, Jian; Zhang, Guowei; Kang, Lihua; Ben, Jindong; Wang, Yong; Qin, Bai; Guan, Huaijin

2017-03-01

Oxidative damage of lens tissue contributes to the formation of age-related cataract. Pi-class glutathione-S-transferase (GSTP1) plays a role in the removal of oxidative adducts by transferring them to glutathione. To assess epigenetic regulation of GSTP1 and its potential role in age-related nuclear cataract (ARNC) pathogenesis, we evaluated GSTP1 mRNA expression, methylation, and chromatin modifications in lenses from ARNC patients. The mRNA and protein of lens GSTP1 were assayed by relative quantitative real-time polymerase chain reaction (qRT-PCR) and Western blots. Methylation of the GSTP1 promoter was determined by bisulfite genomic sequencing. Chromatin modification was detected by chromatin immunoprecipitation. DNA methyltransferase (DNMT) and histone deacetylase (HDAC) activities were also assayed by enzyme-linked immunosorbent assay (ELISA)-like reaction. To assess the effect of DNA methylation on the mRNA expression of GSTP1, human lens epithelium HLE-B3 cells were treated with the demethylation compound 5-aza-dC, followed by qRT-PCR assay. GSTP1 mRNA and protein levels were significantly reduced in lens epithelium and cortex of ARNC cases versus age-matched controls. The changes corresponded to hypermethylation of the GSTP1 promoter CpG islands. The loss of GSTP1 mRNA and protein and the increased DNA promoter methylation might be correlated with the severity of the ARNC. ARNC lenses also had lower acetylation of histone proteins H3, H4, and lower methylation of H3K4, and higher methylation of H3K9. Histone modifications were not correlated with the severity of the ARNCs. DNMT and HDAC were elevated in lenses from ARNCs compared with controls. Demethylation treatment of HLE-B3 cells with 5-aza-dC enhanced the expression of GSTP1. Epigenetic alteration of GSTP1 regulates its expression in lens epithelial and cortical tissues. These changes likely contribute to the pathogenesis of ARNC.

A network of epigenetic regulators guides developmental haematopoiesis in vivo.

PubMed

Huang, Hsuan-Ting; Kathrein, Katie L; Barton, Abby; Gitlin, Zachary; Huang, Yue-Hua; Ward, Thomas P; Hofmann, Oliver; Dibiase, Anthony; Song, Anhua; Tyekucheva, Svitlana; Hide, Winston; Zhou, Yi; Zon, Leonard I

2013-12-01

The initiation of cellular programs is orchestrated by key transcription factors and chromatin regulators that activate or inhibit target gene expression. To generate a compendium of chromatin factors that establish the epigenetic code during developmental haematopoiesis, a large-scale reverse genetic screen was conducted targeting orthologues of 425 human chromatin factors in zebrafish. A set of chromatin regulators was identified that target different stages of primitive and definitive blood formation, including factors not previously implicated in haematopoiesis. We identified 15 factors that regulate development of primitive erythroid progenitors and 29 factors that regulate development of definitive haematopoietic stem and progenitor cells. These chromatin factors are associated with SWI/SNF and ISWI chromatin remodelling, SET1 methyltransferase, CBP-p300-HBO1-NuA4 acetyltransferase, HDAC-NuRD deacetylase, and Polycomb repressive complexes. Our work provides a comprehensive view of how specific chromatin factors and their associated complexes play a major role in the establishment of haematopoietic cells in vivo.

Epigenetic regulation of fetal bone development and placental transfer of nutrients: progress for osteoporosis.

PubMed

Bocheva, Georgeta; Boyadjieva, Nadka

2011-12-01

Osteoporosis is a common age-related disorder and causes acute and long-term disability and economic cost. Many factors influence the accumulation of bone minerals, including heredity, diet, physical activity, gender, endocrine functions, and risk factors such as alcohol, drug abuse, some pharmacological drugs or cigarette smoking. The pathology of bone development during intrauterine life is a factor for osteoporosis. Moreover, the placental transfer of nutrients plays an important role in the building of bones of fetuses. The importance of maternal calcium intake and vitamin D status are highlighted in this review. Various environmental factors including nutrition state or maternal stress may affect the epigenetic state of a number of genes during fetal development of bones. Histone modifications as histone hypomethylation, histone hypermethylation, hypoacetylation, etc. are involved in chromatin remodeling, known to contribute to the epigenetic landscape of chromosomes, and play roles in both fetal bone development and osteoporosis. This review will give an overview of epigenetic modulation of bone development and placental transfer of nutrients. In addition, the data from animal and human studies support the role of epigenetic modulation of calcium and vitamin D in the pathogenesis of osteoporosis. We review the evidence suggesting that various genes are involved in regulation of osteoclast formation and differentiation by osteoblasts and stem cells. Epigenetic changes in growth factors as well as cytokines play a rol in fetal bone development. On balance, the data suggest that there is a link between epigenetic changes in placental transfer of nutrients, including calcium and vitamin D, abnormal intrauterine bone development and pathogenesis of osteoporosis.

Therapeutic modulation of epigenetic drivers of drug resistance in ovarian cancer

PubMed Central

Zeller, Constanze; Brown, Robert

2010-01-01

Epigenetic changes in tumours are associated not only with cancer development and progression, but also with resistance to chemotherapy. Aberrant DNA methylation at CpG islands and associated epigenetic silencing are observed during the acquisition of drug resistance. However, it remains unclear whether all of the observed changes are drivers of drug resistance, causally associated with response of tumours to chemotherapy, or are passenger events representing chance DNA methylation changes. Systematic approaches that link DNA methylation and expression with chemosensitivity will be required to identify key drivers. Such drivers will be important prognostic or predicitive biomarkers, both to existing chemotherapies, but also to epigenetic therapies used to modulate drug resistance. PMID:21789144

Redox regulation of genome stability by effects on gene expression, epigenetic pathways and DNA damage/repair

PubMed Central

Mikhed, Yuliya; Görlach, Agnes; Knaus, Ulla G.; Daiber, Andreas

2015-01-01

Reactive oxygen and nitrogen species (e.g. H2O2, nitric oxide) confer redox regulation of essential cellular signaling pathways such as cell differentiation, proliferation, migration and apoptosis. In addition, classical regulation of gene expression or activity, including gene transcription to RNA followed by translation to the protein level, by transcription factors (e.g. NF-κB, HIF-1α) and mRNA binding proteins (e.g. GAPDH, HuR) is subject to redox regulation. This review will give an update of recent discoveries in this field, and specifically highlight the impact of reactive oxygen and nitrogen species on DNA repair systems that contribute to genomic stability. Emphasis will be placed on the emerging role of redox mechanisms regulating epigenetic pathways (e.g. miRNA, DNA methylation and histone modifications). By providing clinical correlations we discuss how oxidative stress can impact on gene regulation/activity and vise versa, how epigenetic processes, other gene regulatory mechanisms and DNA repair can influence the cellular redox state and contribute or prevent development or progression of disease. PMID:26079210

Epigenetic regulation in myelodysplastic syndromes: implications for therapy.

PubMed

Vigna, Ernesto; Recchia, Anna Grazia; Madeo, Antonio; Gentile, Massimo; Bossio, Sabrina; Mazzone, Carla; Lucia, Eugenio; Morabito, Lucio; Gigliotti, Vincenzo; Stefano, Laura De; Caruso, Nadia; Servillo, Pasquale; Franzese, Stefania; Fimognari, Filippo; Bisconte, Maria Grazia; Gentile, Carlo; Morabito, Fortunato

2011-04-01

Myelodysplastic syndromes (MDS), characterized by ineffective hematopoiesis and dysplasia in one or more lineages, produce life-threatening cytopenias and progress to acute myeloid leukemia (AML). Growing evidence suggests that targeting epigenetic mechanisms improves MDS/AML pathophysiology. This review provides an understanding of studies investigating novel agents published up to January 2011 aimed at normalizing and monitoring the epigenetic profile of the MDS cancer cell. The authors discuss how non-intensive epigenetic therapy can 're-programme' gene expression patterns of abnormal hematopoiesis in MDS. Recently FDA-approved DNA-methyltransferase inhibitors, 5-azacytidine and 5-aza-2'-deoxycytidine or decitabine, represent frontline nonablative treatments, while combinations with histone deacetylase inhibitors show promising synergism in preclinical and Phase I/II trials in tumor suppressor gene re-expression and overall survival. Additional epigenetic mechanisms including non-encoding transcripts with inhibitory posttranscriptional regulatory functions, such as microRNAs, though not fully understood, present novel molecular and clinical implications in these disorders. Alongside current single-agent epigenetic regimens, combination therapies represent potentially effective options for intermediate-2 and high-risk MDS. Methylation profiles and gene mutation predictors provide promising areas of development for monitoring MDS disease progression and outcome, while targeting microRNA dysregulation represents an important therapeutic goal.

Apicidin sensitizes pancreatic cancer cells to gemcitabine by epigenetically regulating MUC4 expression.

PubMed

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.

The epigenetic basis of memory formation and storage.

PubMed

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.

Dietary Sulforaphane in Cancer Chemoprevention: The Role of Epigenetic Regulation and HDAC Inhibition.

PubMed

Tortorella, Stephanie M; Royce, Simon G; Licciardi, Paul V; Karagiannis, Tom C

2015-06-01

Sulforaphane, produced by the hydrolytic conversion of glucoraphanin after ingestion of cruciferous vegetables, particularly broccoli and broccoli sprouts, has been extensively studied due to its apparent health-promoting properties in disease and limited toxicity in normal tissue. Recent Studies: Recent identification of a sub-population of tumor cells with stem cell-like self-renewal capacity that may be responsible for relapse, metastasis, and resistance, as a potential target of the dietary compound, may be an important aspect of sulforaphane chemoprevention. Evidence also suggests that sulforaphane may target the epigenetic alterations observed in specific cancers, reversing aberrant changes in gene transcription through mechanisms of histone deacetylase inhibition, global demethylation, and microRNA modulation. In this review, we discuss the biochemical and biological properties of sulforaphane with a particular emphasis on the anticancer properties of the dietary compound. Sulforaphane possesses the capacity to intervene in multistage carcinogenesis through the modulation and/or regulation of important cellular mechanisms. The inhibition of phase I enzymes that are responsible for the activation of pro-carcinogens, and the induction of phase II enzymes that are critical in mutagen elimination are well-characterized chemopreventive properties. Furthermore, sulforaphane mediates a number of anticancer pathways, including the activation of apoptosis, induction of cell cycle arrest, and inhibition of NFκB. Further characterization of the chemopreventive properties of sulforaphane and its capacity to be selectively toxic to malignant cells are warranted to potentially establish the clinical utility of the dietary compound as an anti-cancer compound alone, and in combination with clinically relevant therapeutic and management strategies.

Epigenetic regulation of depot-specific gene expression in adipose tissue.

PubMed

Gehrke, Sandra; Brueckner, Bodo; Schepky, Andreas; Klein, Johannes; Iwen, Alexander; Bosch, Thomas C G; Wenck, Horst; Winnefeld, Marc; Hagemann, Sabine

2013-01-01

In humans, adipose tissue is distributed in subcutaneous abdominal and subcutaneous gluteal depots that comprise a variety of functional differences. Whereas energy storage in gluteal adipose tissue has been shown to mediate a protective effect, an increase of abdominal adipose tissue is associated with metabolic disorders. However, the molecular basis of depot-specific characteristics is not completely understood yet. Using array-based analyses of transcription profiles, we identified a specific set of genes that was differentially expressed between subcutaneous abdominal and gluteal adipose tissue. To investigate the role of epigenetic regulation in depot-specific gene expression, we additionally analyzed genome-wide DNA methylation patterns in abdominal and gluteal depots. By combining both data sets, we identified a highly significant set of depot-specifically expressed genes that appear to be epigenetically regulated. Interestingly, the majority of these genes form part of the homeobox gene family. Moreover, genes involved in fatty acid metabolism were also differentially expressed. Therefore we suppose that changes in gene expression profiles might account for depot-specific differences in lipid composition. Indeed, triglycerides and fatty acids of abdominal adipose tissue were more saturated compared to triglycerides and fatty acids in gluteal adipose tissue. Taken together, our results uncover clear differences between abdominal and gluteal adipose tissue on the gene expression and DNA methylation level as well as in fatty acid composition. Therefore, a detailed molecular characterization of adipose tissue depots will be essential to develop new treatment strategies for metabolic syndrome associated complications.

Epigenetic mediated transcriptional activation of WNT5A participates in arsenical-associated malignant transformation

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

Dietary factors and epigenetic regulation for prostate cancer prevention.

PubMed

Ho, Emily; Beaver, Laura M; Williams, David E; Dashwood, Roderick H

2011-11-01

The role of epigenetic alterations in various human chronic diseases has gained increasing attention and has resulted in a paradigm shift in our understanding of disease susceptibility. In the field of cancer research, e.g., genetic abnormalities/mutations historically were viewed as primary underlying causes; however, epigenetic mechanisms that alter gene expression without affecting DNA sequence are now recognized as being of equal or greater importance for oncogenesis. Methylation of DNA, modification of histones, and interfering microRNA (miRNA) collectively represent a cadre of epigenetic elements dysregulated in cancer. Targeting the epigenome with compounds that modulate DNA methylation, histone marks, and miRNA profiles represents an evolving strategy for cancer chemoprevention, and these approaches are starting to show promise in human clinical trials. Essential micronutrients such as folate, vitamin B-12, selenium, and zinc as well as the dietary phytochemicals sulforaphane, tea polyphenols, curcumin, and allyl sulfur compounds are among a growing list of agents that affect epigenetic events as novel mechanisms of chemoprevention. To illustrate these concepts, the current review highlights the interactions among nutrients, epigenetics, and prostate cancer susceptibility. In particular, we focus on epigenetic dysregulation and the impact of specific nutrients and food components on DNA methylation and histone modifications that can alter gene expression and influence prostate cancer progression.

Implication of epigenetics in pancreas development and disease.

PubMed

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.

Cancer Development, Progression, and Therapy: An Epigenetic Overview

PubMed Central

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

Chromatin and epigenetics in all their states: Meeting report of the first conference on Epigenetic and Chromatin Regulation of Plant Traits - January 14 – 15, 2016 - Strasbourg, France

PubMed Central

Bey, Till; Jamge, Suraj; Klemme, Sonja; Komar, Dorota Natalia; Le Gall, Sabine; Mikulski, Pawel; Schmidt, Martin; Zicola, Johan; Berr, Alexandre

2016-01-01

ABSTRACT In January 2016, the first Epigenetic and Chromatin Regulation of Plant Traits conference was held in Strasbourg, France. An all-star lineup of speakers, a packed audience of 130 participants from over 20 countries, and a friendly scientific atmosphere contributed to make this conference a meeting to remember. In this article we summarize some of the new insights into chromatin, epigenetics, and epigenomics research and highlight nascent ideas and emerging concepts in this exciting area of research. PMID:27184433

Prostacyclin synthase expression and epigenetic regulation in nonsmall cell lung cancer.

PubMed

Cathcart, Mary-Clare; Gray, Steven G; Baird, Anne-Marie; Boyle, Elaine; Gately, Kathy; Kay, Elaine; Cummins, Robert; Pidgeon, Graham P; O'Byrne, Kenneth J

2011-11-15

Prostacyclin synthase (PGIS) metabolizes prostaglandin H(2), into prostacyclin. This study aimed to determine the expression profile of PGIS in nonsmall cell lung cancer (NSCLC) and examine potential mechanisms involved in PGIS regulation. PGIS expression was examined in human NSCLC and matched controls by reverse transcriptase polymerase chain reaction (RT-PCR), Western analysis, and immunohistochemistry. A 204-patient NSCLC tissue microarray was stained for PGIS and cyclooxygenase 2 (COX2) expression. Staining intensity was correlated with clinical parameters. Epigenetic mechanisms underpinning PGIS promoter expression were examined using RT-PCR, methylation-specific PCR, and chromatin immunoprecipitation analysis. PGIS expression was reduced/absent in human NSCLC protein samples (P < .0001), but not mRNA relative to matched controls. PGIS tissue expression was higher in squamous cell carcinoma (P = .004) and in male patients (P < .05). No significant correlation of PGIS or COX2 expression with overall patient survival was observed, although COX2 was prognostic for short-term (2-year) survival (P < .001). PGIS mRNA expression was regulated by DNA CpG methylation and histone acetylation in NSCLC cell lines, with chromatin remodeling taking place directly at the PGIS gene. PGIS mRNA expression was increased by both demethylation agents and histone deacetylase inhibitors. Protein levels were unaffected by demethylation agents, whereas PGIS protein stability was negatively affected by histone deacetylase inhibitors. PGIS protein expression is reduced in NSCLC, and does not correlate with overall patient survival. PGIS expression is regulated through epigenetic mechanisms. Differences in expression patterns between mRNA and protein levels suggest that PGIS expression and protein stability are regulated post-translationally. PGIS protein stability may have an important therapeutic role in NSCLC. Copyright © 2011 American Cancer Society.

Epigenetic regulation of REG1A and chemosensitivity of cutaneous melanoma

PubMed Central

Sato, Yusuke; Marzese, Diego M; Ohta, Katsuya; Huang, Sharon K; Sim, Myung Shin; Chong, Kelly; Hoon, Dave SB

2013-01-01

Regenerating gene 1A (REG1A) plays an important role in tissue regeneration and in cell proliferation in epithelium origin tumors; however, its role in melanoma has not been explored in details. The objective of this study was to identify whether REG1A is expressed in cutaneous melanoma and if REG1A expression status can predict prognosis in cutaneous melanoma patients with metastasis. We also determined whether epigenetic regulation of the promoter region regulates REG1A expression. AJCC stage III cutaneous melanoma specimens with clinically well annotated stage III lymph node melanoma metastasis tissue microarray were assessed by IHC. MALDI-TOF-mass spectrometry and HM450K array were used to identify REG1A promoter region CpG site methylation. Chemotherapeutic agent response by melanoma cells as related to REG1A protein expression was assessed. Post-surgery melanoma patients followed by adjuvant chemotherapy with high REG1A expression had a significantly better prognosis (disease-specific survival) compared with patients with low REG1A expression (log rank test; p = 0.0013). The demethylating reagent 5-Aza-2′-deoxycytidine activated REG1A promoter region resulting in enhanced REG1A mRNA and protein expression in melanoma cell lines. Promoter region CpG methylation was shown to regulate REG1A expression in melanoma cells. Moreover, melanoma lines with high REG1A mRNA expression were more susceptible to Dacarbazine and Cisplatin, as compared with those with low REG1A mRNA expression. In conclusion, REG1A expression status may be useful as a biomarker in melanoma patients for sensitivity to these chemotherapeutic agents. The epigenetic regulation of the REG1A promoter region may offer a potential therapeutic approach to improve chemotherapy for metastatic melanoma patients. PMID:23903855

Identification of the epigenetic reader CBX2 as a potential drug target in advanced prostate cancer.

PubMed

Clermont, Pier-Luc; Crea, Francesco; Chiang, Yan Ting; Lin, Dong; Zhang, Amy; Wang, James Z L; Parolia, Abhijit; Wu, Rebecca; Xue, Hui; Wang, Yuwei; Ding, Jiarui; Thu, Kelsie L; Lam, Wan L; Shah, Sohrab P; Collins, Colin C; Wang, Yuzhuo; Helgason, Cheryl D

2016-01-01

While localized prostate cancer (PCa) can be effectively cured, metastatic disease inevitably progresses to a lethal state called castration-resistant prostate cancer (CRPC). Emerging evidence suggests that aberrant epigenetic repression by the polycomb group (PcG) complexes fuels PCa progression, providing novel therapeutic opportunities. In the search for potential epigenetic drivers of CRPC, we analyzed the molecular profile of PcG members in patient-derived xenografts and clinical samples. Overall, our results identify the PcG protein and methyl-lysine reader CBX2 as a potential therapeutic target in advanced PCa. We report that CBX2 was recurrently up-regulated in metastatic CRPC and that elevated CBX2 expression was correlated with poor clinical outcome in PCa cohorts. Furthermore, CBX2 depletion abrogated cell viability and induced caspase 3-mediated apoptosis in metastatic PCa cell lines. Mechanistically explaining this phenotype, microarray analysis in CBX2-depleted cells revealed that CBX2 controls the expression of many key regulators of cell proliferation and metastasis. Taken together, this study provides the first evidence that CBX2 inhibition induces cancer cell death, positioning CBX2 as an attractive drug target in lethal CRPC.

Epigenetic regulation of the DRD4 gene and dimensions of attention-deficit/hyperactivity disorder in children.

PubMed

Dadds, Mark R; Schollar-Root, Olivia; Lenroot, Rhoshel; Moul, Caroline; Hawes, David J

2016-10-01

Recent evidence suggests that epigenetic regulation of the DRD4 gene may characterise specific aspects of ADHD symptomology. We tested associations between ADHD symptoms and epigenetic changes to the DRD4 gene in DNA extracted from blood and saliva in N = 330 children referred for a variety of behavioural and emotional problems. ADHD was indexed using DSM diagnoses as well as mother, father, and teacher reports. Methylation levels were assayed for the island of 18 CpG sites in the DRD4 receptor gene. A nearby SNP, rs3758653, was also genotyped as it has previously been shown to influence methylation levels. There was high consistency of methylation levels across CpG sites and tissue sources, and higher methylation levels were associated with the major allele of SNP rs3758653. Higher methylation levels were associated with more severe ADHD independent of SNP status, tissue source, ethnicity, environmental adversity, and comorbid conduct problems. The association applied specifically to the cognitive/attentional, rather than hyperactivity problems that characterise ADHD. The results indicate that epigenetic regulation of the DRD4 gene in the form of increased methylation is associated with the cognitive/attentional deficits in ADHD.

Epigenetic Mechanisms of Memory Formation and Reconsolidation

PubMed Central

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

Genetic and epigenetic factors underlying sex differences in the regulation of gene expression in the brain

PubMed Central

Ratnu, Vikram S.; Emami, Michael R.; Bredy, Timothy W.

2016-01-01

There are inherent biological differences between males and females that contribute to sex differences in brain function and to many sex-specific illnesses and disorders. Traditionally, it has been thought that such differences are largely due to hormonal regulation; however, there are also genetic and epigenetic effects caused by the inheritance and unequal dosage of genes located on the X- and Y-chromosomes. Here we discuss the evidence in favor of a genetic and epigenetic basis for sexually dimorphic behavior, as a consequence of underlying differences in the regulation of genes that drive brain function. A better understanding of sex-specific molecular processes in the brain will provide further insight for the development of novel therapeutic approaches for the treatment of neuropsychiatric disorders characterized by gender/sex differences. PMID:27870402

Epigenetics and the Developmental Origins of Health and ...

EPA Pesticide Factsheets

Epigenetic programming is likely to be an important mechanism underlying the lasting influence of the developmental environment on lifelong health, a concept known as the Developmental Origins of Health and Disease (DOHaD). DNA methylation, posttranslational histone protei n modifications, noncoding RNAs and recruited protein complexes are elements of the epigenetic regulation of gene transcription. These heritable but reversible changes in gene function are dynamic and labile during specific stages of the reproductive cycle and development. Epigenetic marks may be maintained throughout an individual's lifespan and can alter the life-long risk of disease; the nature of these epigenetic marks and their potential alteration by environmental factors is an area of active research. This chapter provides an overview of epigenetic regulation, particularly as it occurs as an essential component of embryo-fetal development. In this chapter we will present key features of DNA methylation and histone protein modifications, including the enzymes involved and the effects of these modifications on gene transcription. We will discuss the interplay of these dynamic modifications and the emerging role of noncoding RNAs in epigenetic gene regulation.

Interplay between the miRNome and the epigenetic machinery: Implications in health and disease.

PubMed

Poddar, Shagun; Kesharwani, Devesh; Datta, Malabika

2017-11-01

Epigenetics refers to functionally relevant genomic changes that do not involve changes in the basic nucleotide sequence. Majorly, these are of two types: DNA methylation and histone modifications. Small RNA molecules called miRNAs are often thought to mediate post-transcriptional epigenetic changes by mRNA degradation or translational attenuation. While DNA methylation and histone modifications have their own independent effects on various cellular events, several reports are suggestive of an obvious interplay between these phenomena and the miRNA regulatory program within the cell. Several miRNAs like miR-375, members of miR-29 family, miR-34, miR-200, and others are regulated by DNA methylation and histone modifications in various types of cancers and metabolic diseases. On the other hand, miRNAs like miR-449a, miR-148, miR-101, miR-214, and miR-128 target members of the epigenetic machinery and their dysregulation leads to diverse cellular aberrations. In spite of being independent cellular events, emergence of such reports that suggest a connection between DNA methylation, histone modification, and miRNA function in several diseases indicate that this connecting axis offers a valuable target with great therapeutic potential that might be exploited for disease management. We review the current status of crosstalk between the major epigenetic modifications and the miRNA machinery and discuss this in the context of health and disease. © 2017 Wiley Periodicals, Inc.

Epigenetics and maternal nutrition: nature v. nurture.

PubMed

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.

Epigenetic regulation of RGS2 (Regulator of G-protein signaling 2) in chemoresistant ovarian cancer cells.

PubMed

Cacan, Ercan

2017-06-01

Regulator of G-protein signaling 2 (RGS2) is a GTPase-activating protein functioning as an inhibitor of G-protein coupled receptors (GPCRs). RGS2 dysregulation was implicated in solid tumour development and RGS2 downregulation has been reported in prostate and ovarian cancer progression. However, the molecular mechanism by which RGS2 expression is suppressed in ovarian cancer remains unknown. The expression and epigenetic regulation of RGS2 in chemosensitive and chemoresistant ovarian cancer cells were determined by qRT-PCR and chromatin immunoprecipitation assays, respectively. In the present study, the molecular mechanisms contributing to the loss of RGS2 expression were determined in ovarian cancer. The data indicated that suppression of RGS2 gene in chemoresistant ovarian cancer cells, in part, due to accumulation of histone deacetylases (HDACs) and DNA methyltransferase I (DNMT1) at the promoter region of RGS2. Inhibition of HDACs or DNMTs significantly increases RGS2 expression. These results suggest that epigenetic changes in histone modifications and DNA methylation may contribute to the loss of RGS2 expression in chemoresistant ovarian cancer cells. The results further suggest that class I HDACs and DNMT1 contribute to the suppression of RGS2 during acquired chemoresistance and support growing evidence that inhibition of HDACs/DNMTs represents novel therapeutic approaches to overcome ovarian cancer chemoresistance.

Epigenetics and Psychoneuroimmunology: Mechanisms and Models

PubMed Central

Mathews, Herbert L.; Janusek, Linda Witek

2010-01-01

In this Introduction to the Named Series “Epigenetics, Brain, Behavior, and Immunity” an overview of epigenetics is provided with a consideration of the nature of epigenetic regulation including DNA methylation, histone modification and chromatin remodeling. Illustrative examples of recent scientific developments are highlighted to demonstrate the influence of epigenetics in areas of research relevant to those who investigate phenomena within the scientific discipline of psychoneuroimmunology. These examples are presented in order to provide a perspective on how epigenetic analysis will add insight into the molecular processes that connect the brain with behavior, neuroendocrine responsivity and immune outcome. PMID:20832468

Epigenetic impact of endocrine disrupting chemicals on lipid homeostasis and atherosclerosis: a pregnane X receptor-centric view.

PubMed

Helsley, Robert N; Zhou, Changcheng

2017-10-01

Despite the major advances in developing diagnostic techniques and effective treatments, atherosclerotic cardiovascular disease (CVD) is still the leading cause of mortality and morbidity worldwide. While considerable progress has been achieved to identify gene variations and environmental factors that contribute to CVD, much less is known about the role of "gene-environment interactions" in predisposing individuals to CVD. Our chemical environment has significantly changed in the last few decades, and there are more than 100,000 synthetic chemicals in the market. Recent large-scale human population studies have associated exposure to certain chemicals including many endocrine disrupting chemicals (EDCs) with increased CVD risk, and animal studies have also confirmed that some EDCs can cause aberrant lipid homeostasis and increase atherosclerosis. However, the underlying mechanisms of how exposure to those EDCs influences CVD risk remain elusive. Numerous EDCs can activate the nuclear receptor pregnane X receptor (PXR) that functions as a xenobiotic sensor to regulate host xenobiotic metabolism. Recent studies have demonstrated the novel functions of PXR in lipid homeostasis and atherosclerosis. In addition to directly regulating transcription, PXR has been implicated in the epigenetic regulation of gene transcription. Exposure to many EDCs can also induce epigenetic modifications, but little is known about how the changes relate to the onset or progression of CVD. In this review, we will discuss recent research on PXR and EDCs in the context of CVD and propose that PXR may play a previously unrealized role in EDC-mediated epigenetic modifications that affect lipid homeostasis and atherosclerosis.

Epigenetic Regulation of Learning and Memory by Drosophila EHMT/G9a

PubMed Central

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

IFN-α potentiates the direct and immune-mediated antitumor effects of epigenetic drugs on both metastatic and stem cells of colorectal cancer.

PubMed

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.

IFN-α potentiates the direct and immune-mediated antitumor effects of epigenetic drugs on both metastatic and stem cells of colorectal cancer

PubMed Central

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

Epigenetics meets endocrinology

PubMed Central

Zhang, Xiang; Ho, Shuk-Mei

2014-01-01

Although genetics determines endocrine phenotypes, it cannot fully explain the great variability and reversibility of the system in response to environmental changes. Evidence now suggests that epigenetics, i.e. heritable but reversible changes in gene function without changes in nucleotide sequence, links genetics and environment in shaping endocrine function. Epigenetic mechanisms, including DNA methylation, histone modification, and microRNA, partition the genome into active and inactive domains based on endogenous and exogenous environmental changes and developmental stages, creating phenotype plasticity that can explain interindividual and population endocrine variability. We will review the current understanding of epigenetics in endocrinology, specifically, the regulation by epigenetics of the three levels of hormone action (synthesis and release, circulating and target tissue levels, and target-organ responsiveness) and the epigenetic action of endocrine disruptors. We will also discuss the impacts of hormones on epigenetics. We propose a three-dimensional model (genetics, environment, and developmental stage) to explain the phenomena related to progressive changes in endocrine functions with age, the early origin of endocrine disorders, phenotype discordance between monozygotic twins, rapid shifts in disease patterns among populations experiencing major lifestyle changes such as immigration, and the many endocrine disruptions in contemporary life. We emphasize that the key for understanding epigenetics in endocrinology is the identification, through advanced high-throughput screening technologies, of plasticity genes or loci that respond directly to a specific environmental stimulus. Investigations to determine whether epigenetic changes induced by today's lifestyles or environmental `exposures' can be inherited and are reversible should open doors for applying epigenetics to the prevention and treatment of endocrine disorders. PMID:21322125

Novel multiple sclerosis susceptibility loci implicated in epigenetic regulation.

PubMed

Andlauer, Till F M; Buck, Dorothea; Antony, Gisela; Bayas, Antonios; Bechmann, Lukas; Berthele, Achim; Chan, Andrew; Gasperi, Christiane; Gold, Ralf; Graetz, Christiane; Haas, Jürgen; Hecker, Michael; Infante-Duarte, Carmen; Knop, Matthias; Kümpfel, Tania; Limmroth, Volker; Linker, Ralf A; Loleit, Verena; Luessi, Felix; Meuth, Sven G; Mühlau, Mark; Nischwitz, Sandra; Paul, Friedemann; Pütz, Michael; Ruck, Tobias; Salmen, Anke; Stangel, Martin; Stellmann, Jan-Patrick; Stürner, Klarissa H; Tackenberg, Björn; Then Bergh, Florian; Tumani, Hayrettin; Warnke, Clemens; Weber, Frank; Wiendl, Heinz; Wildemann, Brigitte; Zettl, Uwe K; Ziemann, Ulf; Zipp, Frauke; Arloth, Janine; Weber, Peter; Radivojkov-Blagojevic, Milena; Scheinhardt, Markus O; Dankowski, Theresa; Bettecken, Thomas; Lichtner, Peter; Czamara, Darina; Carrillo-Roa, Tania; Binder, Elisabeth B; Berger, Klaus; Bertram, Lars; Franke, Andre; Gieger, Christian; Herms, Stefan; Homuth, Georg; Ising, Marcus; Jöckel, Karl-Heinz; Kacprowski, Tim; Kloiber, Stefan; Laudes, Matthias; Lieb, Wolfgang; Lill, Christina M; Lucae, Susanne; Meitinger, Thomas; Moebus, Susanne; Müller-Nurasyid, Martina; Nöthen, Markus M; Petersmann, Astrid; Rawal, Rajesh; Schminke, Ulf; Strauch, Konstantin; Völzke, Henry; Waldenberger, Melanie; Wellmann, Jürgen; Porcu, Eleonora; Mulas, Antonella; Pitzalis, Maristella; Sidore, Carlo; Zara, Ilenia; Cucca, Francesco; Zoledziewska, Magdalena; Ziegler, Andreas; Hemmer, Bernhard; Müller-Myhsok, Bertram

2016-06-01

We conducted a genome-wide association study (GWAS) on multiple sclerosis (MS) susceptibility in German cohorts with 4888 cases and 10,395 controls. In addition to associations within the major histocompatibility complex (MHC) region, 15 non-MHC loci reached genome-wide significance. Four of these loci are novel MS susceptibility loci. They map to the genes L3MBTL3, MAZ, ERG, and SHMT1. The lead variant at SHMT1 was replicated in an independent Sardinian cohort. Products of the genes L3MBTL3, MAZ, and ERG play important roles in immune cell regulation. SHMT1 encodes a serine hydroxymethyltransferase catalyzing the transfer of a carbon unit to the folate cycle. This reaction is required for regulation of methylation homeostasis, which is important for establishment and maintenance of epigenetic signatures. Our GWAS approach in a defined population with limited genetic substructure detected associations not found in larger, more heterogeneous cohorts, thus providing new clues regarding MS pathogenesis.

Novel multiple sclerosis susceptibility loci implicated in epigenetic regulation

PubMed Central

Andlauer, Till F. M.; Buck, Dorothea; Antony, Gisela; Bayas, Antonios; Bechmann, Lukas; Berthele, Achim; Chan, Andrew; Gasperi, Christiane; Gold, Ralf; Graetz, Christiane; Haas, Jürgen; Hecker, Michael; Infante-Duarte, Carmen; Knop, Matthias; Kümpfel, Tania; Limmroth, Volker; Linker, Ralf A.; Loleit, Verena; Luessi, Felix; Meuth, Sven G.; Mühlau, Mark; Nischwitz, Sandra; Paul, Friedemann; Pütz, Michael; Ruck, Tobias; Salmen, Anke; Stangel, Martin; Stellmann, Jan-Patrick; Stürner, Klarissa H.; Tackenberg, Björn; Then Bergh, Florian; Tumani, Hayrettin; Warnke, Clemens; Weber, Frank; Wiendl, Heinz; Wildemann, Brigitte; Zettl, Uwe K.; Ziemann, Ulf; Zipp, Frauke; Arloth, Janine; Weber, Peter; Radivojkov-Blagojevic, Milena; Scheinhardt, Markus O.; Dankowski, Theresa; Bettecken, Thomas; Lichtner, Peter; Czamara, Darina; Carrillo-Roa, Tania; Binder, Elisabeth B.; Berger, Klaus; Bertram, Lars; Franke, Andre; Gieger, Christian; Herms, Stefan; Homuth, Georg; Ising, Marcus; Jöckel, Karl-Heinz; Kacprowski, Tim; Kloiber, Stefan; Laudes, Matthias; Lieb, Wolfgang; Lill, Christina M.; Lucae, Susanne; Meitinger, Thomas; Moebus, Susanne; Müller-Nurasyid, Martina; Nöthen, Markus M.; Petersmann, Astrid; Rawal, Rajesh; Schminke, Ulf; Strauch, Konstantin; Völzke, Henry; Waldenberger, Melanie; Wellmann, Jürgen; Porcu, Eleonora; Mulas, Antonella; Pitzalis, Maristella; Sidore, Carlo; Zara, Ilenia; Cucca, Francesco; Zoledziewska, Magdalena; Ziegler, Andreas; Hemmer, Bernhard; Müller-Myhsok, Bertram

2016-01-01

We conducted a genome-wide association study (GWAS) on multiple sclerosis (MS) susceptibility in German cohorts with 4888 cases and 10,395 controls. In addition to associations within the major histocompatibility complex (MHC) region, 15 non-MHC loci reached genome-wide significance. Four of these loci are novel MS susceptibility loci. They map to the genes L3MBTL3, MAZ, ERG, and SHMT1. The lead variant at SHMT1 was replicated in an independent Sardinian cohort. Products of the genes L3MBTL3, MAZ, and ERG play important roles in immune cell regulation. SHMT1 encodes a serine hydroxymethyltransferase catalyzing the transfer of a carbon unit to the folate cycle. This reaction is required for regulation of methylation homeostasis, which is important for establishment and maintenance of epigenetic signatures. Our GWAS approach in a defined population with limited genetic substructure detected associations not found in larger, more heterogeneous cohorts, thus providing new clues regarding MS pathogenesis. PMID:27386562

Regulators of gene expression as biomarkers for prostate cancer

PubMed Central

Willard, Stacey S; Koochekpour, Shahriar

2012-01-01

Recent technological advancements in gene expression analysis have led to the discovery of a promising new group of prostate cancer (PCa) biomarkers that have the potential to influence diagnosis and the prediction of disease severity. The accumulation of deleterious changes in gene expression is a fundamental mechanism of prostate carcinogenesis. Aberrant gene expression can arise from changes in epigenetic regulation or mutation in the genome affecting either key regulatory elements or gene sequences themselves. At the epigenetic level, a myriad of abnormal histone modifications and changes in DNA methylation are found in PCa patients. In addition, many mutations in the genome have been associated with higher PCa risk. Finally, over- or underexpression of key genes involved in cell cycle regulation, apoptosis, cell adhesion and regulation of transcription has been observed. An interesting group of biomarkers are emerging from these studies which may prove more predictive than the standard prostate specific antigen (PSA) serum test. In this review, we discuss recent results in the field of gene expression analysis in PCa including the most promising biomarkers in the areas of epigenetics, genomics and the transcriptome, some of which are currently under investigation as clinical tests for early detection and better prognostic prediction of PCa. PMID:23226612

Epigenetic modifications: basic mechanisms and role in cardiovascular disease (2013 Grover Conference series).

PubMed

Loscalzo, Joseph; Handy, Diane E

2014-06-01

Epigenetics refers to heritable traits that are not a consequence of DNA sequence. Three classes of epigenetic regulation exist: DNA methylation, histone modification, and noncoding RNA action. In the cardiovascular system, epigenetic regulation affects development, differentiation, and disease propensity or expression. Defining the determinants of epigenetic regulation offers opportunities for novel strategies for disease prevention and treatment.

Epigenetic regulation of metalloproteinases and their inhibitors in rotator cuff tears

PubMed Central

Caires dos Santos, Leonardo; Martins de Oliveira, Adrielle; Santoro Belangero, Paulo; Antônio Figueiredo, Eduardo; Cohen, Carina; de Seixas Alves, Felipe; Hiromi Yanaguizawa, Wânia; Vicente Andreoli, Carlos; de Castro Pochini, Alberto; Ejnisman, Benno; Cardoso Smith, Marília; de Seixas Alves, Maria Teresa; Cohen, Moises

2017-01-01

Rotator cuff tear is a common orthopedic condition. Metalloproteinases (MMP) and their inhibitors (TIMP) seem to play a role in the development of joint injuries and in the failure of tissue healing. However, the mechanisms of regulation of gene expression in tendons are still unknown. Epigenetic mechanisms, such as DNA methylation and microRNAs regulation, are involved in the dynamic control of gene expression. Here, the mRNA expression and DNA methylation status of MMPs (MMP1, MMP2, MMP3, MMP9, MMP13, and MMP14) and TIMPs (TIMP1-3) and the expression of miR-29 family members in ruptured supraspinatus tendons were compared with non-injured tendons of individuals without this lesion. Additionally, the gene expression and methylation status at the edge of the ruptured tendon were compared with macroscopically non-injured rotator cuff tendon samples from the anterior and posterior regions of patients with tendon tears. Moreover, the possible associations between the molecular alterations and the clinical and histologic characteristics were investigated. Dysregulated expression and DNA methylation of MMP and TIMP genes were found across the rotator cuff tendon samples of patients with supraspinatus tears. These alterations were influenced at least in part by age at surgery, sex, smoking habit, tear size, and duration of symptoms. Alterations in the studied MMP and TIMP genes may contribute to the presence of microcysts, fissures, necrosis, and neovascularization in tendons and may thus be involved in the tendon healing process. In conclusion, MMPs and their inhibitors are regulated by epigenetic modifications and may play a role in rotator cuff tears. PMID:28902861

Epigenetic Effects of Cannabis Exposure.

PubMed

Szutorisz, Henrietta; Hurd, Yasmin L

2016-04-01

The past decade has witnessed a number of societal and political changes that have raised critical questions about the long-term impact of marijuana (Cannabis sativa) that are especially important given the prevalence of its abuse and that potential long-term effects still largely lack scientific data. Disturbances of the epigenome have generally been hypothesized as the molecular machinery underlying the persistent, often tissue-specific transcriptional and behavioral effects of cannabinoids that have been observed within one's lifetime and even into the subsequent generation. Here, we provide an overview of the current published scientific literature that has examined epigenetic effects of cannabinoids. Though mechanistic insights about the epigenome remain sparse, accumulating data in humans and animal models have begun to reveal aberrant epigenetic modifications in brain and the periphery linked to cannabis exposure. Expansion of such knowledge and causal molecular relationships could help provide novel targets for future therapeutic interventions. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Epigenetic Effects of Cannabis Exposure

PubMed Central

Szutorisz, Henrietta; Hurd, Yasmin L.

2015-01-01

The past decade has witnessed a number of societal and political changes that have raised critical questions about the long-term impact of marijuana (Cannabis sativa) that are especially important given the prevalence of its abuse and that potential long-term effects still largely lack scientific data. Disturbances of the epigenome have generally been hypothesized as the molecular machinery underlying the persistent, often tissue-specific transcriptional and behavioral effects of cannabinoids that have been observed within one’s lifetime and even into the subsequent generation. Here, we provide an overview of the current published scientific literature that examined epigenetic effects of cannabinoids. Though mechanistic insights about the epigenome remain sparse, accumulating data in humans and animal models have begun to reveal aberrant epigenetic modifications in brain and the periphery linked to cannabis exposure. Expansion of such knowledge and causal molecular relationships could help provide novel targets for future therapeutic interventions. PMID:26546076

Epigenetic stress responses induce muscle stem-cell ageing by Hoxa9 developmental signals.

PubMed

Schwörer, Simon; Becker, Friedrich; Feller, Christian; Baig, Ali H; Köber, Ute; Henze, Henriette; Kraus, Johann M; Xin, Beibei; Lechel, André; Lipka, Daniel B; Varghese, Christy S; Schmidt, Manuel; Rohs, Remo; Aebersold, Ruedi; Medina, Kay L; Kestler, Hans A; Neri, Francesco; von Maltzahn, Julia; Tümpel, Stefan; Rudolph, K Lenhard

2016-12-15

The functionality of stem cells declines during ageing, and this decline contributes to ageing-associated impairments in tissue regeneration and function. Alterations in developmental pathways have been associated with declines in stem-cell function during ageing, but the nature of this process remains poorly understood. Hox genes are key regulators of stem cells and tissue patterning during embryogenesis with an unknown role in ageing. Here we show that the epigenetic stress response in muscle stem cells (also known as satellite cells) differs between aged and young mice. The alteration includes aberrant global and site-specific induction of active chromatin marks in activated satellite cells from aged mice, resulting in the specific induction of Hoxa9 but not other Hox genes. Hoxa9 in turn activates several developmental pathways and represents a decisive factor that separates satellite cell gene expression in aged mice from that in young mice. The activated pathways include most of the currently known inhibitors of satellite cell function in ageing muscle, including Wnt, TGFβ, JAK/STAT and senescence signalling. Inhibition of aberrant chromatin activation or deletion of Hoxa9 improves satellite cell function and muscle regeneration in aged mice, whereas overexpression of Hoxa9 mimics ageing-associated defects in satellite cells from young mice, which can be rescued by the inhibition of Hoxa9-targeted developmental pathways. Together, these data delineate an altered epigenetic stress response in activated satellite cells from aged mice, which limits satellite cell function and muscle regeneration by Hoxa9-dependent activation of developmental pathways.

Epigenetic mechanisms of memory formation and reconsolidation.

PubMed

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.

Epigenetic Mechanisms Underlie Genome Development

ERIC Educational Resources Information Center

Lamm, Ehud

2013-01-01

Technological and methodological advances, in particular next-generation sequencing and chromatin profiling, has led to a deluge of data on epigenetic mechanisms and processes. Epigenetic regulation in the brain is no exception. In this commentary, Ehud Lamm writes that extending existing frameworks for thinking about psychological development to…

Epigenetic Regulation of Axonal Growth of Drosophila Pacemaker Cells by Histone Acetyltransferase Tip60 Controls Sleep

PubMed Central

Pirooznia, Sheila K.; Chiu, Kellie; Chan, May T.; Zimmerman, John E.; Elefant, Felice

2012-01-01

Tip60 is a histone acetyltransferase (HAT) enzyme that epigenetically regulates genes enriched for neuronal functions through interaction with the amyloid precursor protein (APP) intracellular domain. However, whether Tip60-mediated epigenetic dysregulation affects specific neuronal processes in vivo and contributes to neurodegeneration remains unclear. Here, we show that Tip60 HAT activity mediates axonal growth of the Drosophila pacemaker cells, termed “small ventrolateral neurons” (sLNvs), and their production of the neuropeptide pigment-dispersing factor (PDF) that functions to stabilize Drosophila sleep–wake cycles. Using genetic approaches, we show that loss of Tip60 HAT activity in the presence of the Alzheimer’s disease-associated APP affects PDF expression and causes retraction of the sLNv synaptic arbor required for presynaptic release of PDF. Functional consequence of these effects is evidenced by disruption of the sleep–wake cycle in these flies. Notably, overexpression of Tip60 in conjunction with APP rescues these sleep–wake disturbances by inducing overelaboration of the sLNv synaptic terminals and increasing PDF levels, supporting a neuroprotective role for dTip60 in sLNv growth and function under APP-induced neurodegenerative conditions. Our findings reveal a novel mechanism for Tip60 mediated sleep–wake regulation via control of axonal growth and PDF levels within the sLNv-encompassing neural network and provide insight into epigenetic-based regulation of sleep disturbances observed in neurodegenerative diseases like Alzheimer’s disease. PMID:22982579

Epigenetic hierarchy governing Nestin expression.

PubMed

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.

Epigenetic regulation of transcription and possible functions of mammalian short interspersed elements, SINEs.

PubMed

Ichiyanagi, Kenji

2013-01-01

Short interspersed elements (SINEs) are a class of retrotransposons, which amplify their copy numbers in their host genomes by retrotransposition. More than a million copies of SINEs are present in a mammalian genome, constituting over 10% of the total genomic sequence. In contrast to the other two classes of retrotransposons, long interspersed elements (LINEs) and long terminal repeat (LTR) elements, SINEs are transcribed by RNA polymerase III. However, like LINEs and LTR elements, the SINE transcription is likely regulated by epigenetic mechanisms such as DNA methylation, at least for human Alu and mouse B1. Whereas SINEs and other transposable elements have long been thought as selfish or junk DNA, recent studies have revealed that they play functional roles at their genomic locations, for example, as distal enhancers, chromatin boundaries and binding sites of many transcription factors. These activities imply that SINE retrotransposition has shaped the regulatory network and chromatin landscape of their hosts. Whereas it is thought that the epigenetic mechanisms were originated as a host defense system against proliferation of parasitic elements, this review discusses a possibility that the same mechanisms are also used to regulate the SINE-derived functions.

Dynamic epigenetic regulation of glioblastoma tumorigenicity through LSD1 modulation of MYC expression

PubMed Central

Kozono, David; Li, Jie; Nitta, Masayuki; Sampetrean, Oltea; Gonda, David; Kushwaha, Deepa S.; Merzon, Dmitry; Ramakrishnan, Valya; Zhu, Shan; Zhu, Kaya; Matsui, Hiroko; Harismendy, Olivier; Hua, Wei; Mao, Ying; Kwon, Chang-Hyuk; Saya, Hideyuki; Nakano, Ichiro; Pizzo, Donald P.; VandenBerg, Scott R.; Chen, Clark C.

2015-01-01

The available evidence suggests that the lethality of glioblastoma is driven by small subpopulations of cells that self-renew and exhibit tumorigenicity. It remains unclear whether tumorigenicity exists as a static property of a few cells or as a dynamically acquired property. We used tumor-sphere and xenograft formation as assays for tumorigenicity and examined subclones isolated from established and primary glioblastoma lines. Our results indicate that glioblastoma tumorigenicity is largely deterministic, yet the property can be acquired spontaneously at low frequencies. Further, these dynamic transitions are governed by epigenetic reprogramming through the lysine-specific demethylase 1 (LSD1). LSD depletion increases trimethylation of histone 3 lysine 4 at the avian myelocytomatosis viral oncogene homolog (MYC) locus, which elevates MYC expression. MYC, in turn, regulates oligodendrocyte lineage transcription factor 2 (OLIG2), SRY (sex determining region Y)-box 2 (SOX2), and POU class 3 homeobox 2 (POU3F2), a core set of transcription factors required for reprogramming glioblastoma cells into stem-like states. Our model suggests epigenetic regulation of key transcription factors governs transitions between tumorigenic states and provides a framework for glioblastoma therapeutic development. PMID:26159421

Emergence of the Noncoding Cancer Genome: A Target of Genetic and Epigenetic Alterations.

PubMed

Zhou, Stanley; Treloar, Aislinn E; Lupien, Mathieu

2016-11-01

The emergence of whole-genome annotation approaches is paving the way for the comprehensive annotation of the human genome across diverse cell and tissue types exposed to various environmental conditions. This has already unmasked the positions of thousands of functional cis-regulatory elements integral to transcriptional regulation, such as enhancers, promoters, and anchors of chromatin interactions that populate the noncoding genome. Recent studies have shown that cis-regulatory elements are commonly the targets of genetic and epigenetic alterations associated with aberrant gene expression in cancer. Here, we review these findings to showcase the contribution of the noncoding genome and its alteration in the development and progression of cancer. We also highlight the opportunities to translate the biological characterization of genetic and epigenetic alterations in the noncoding cancer genome into novel approaches to treat or monitor disease. The majority of genetic and epigenetic alterations accumulate in the noncoding genome throughout oncogenesis. Discriminating driver from passenger events is a challenge that holds great promise to improve our understanding of the etiology of different cancer types. Advancing our understanding of the noncoding cancer genome may thus identify new therapeutic opportunities and accelerate our capacity to find improved biomarkers to monitor various stages of cancer development. Cancer Discov; 6(11); 1215-29. ©2016 AACR. ©2016 American Association for Cancer Research.

Understanding Neurological Disease Mechanisms in the Era of Epigenetics

PubMed Central

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

Parvovirus B19 DNA CpG Dinucleotide Methylation and Epigenetic Regulation of Viral Expression

PubMed Central

Bonvicini, Francesca; Manaresi, Elisabetta; Di Furio, Francesca; De Falco, Luisa; Gallinella, Giorgio

2012-01-01

CpG DNA methylation is one of the main epigenetic modifications playing a role in the control of gene expression. For DNA viruses whose genome has the ability to integrate in the host genome or to maintain as a latent episome, a correlation has been found between the extent of DNA methylation and viral quiescence. No information is available for Parvovirus B19, a human pathogenic virus, which is capable of both lytic and persistent infections. Within Parvovirus B19 genome, the inverted terminal regions display all the characteristic signatures of a genomic CpG island; therefore we hypothesised a role of CpG dinucleotide methylation in the regulation of viral genome expression. The analysis of CpG dinucleotide methylation of Parvovirus B19 DNA was carried out by an aptly designed quantitative real-time PCR assay on bisulfite-modified DNA. The effects of CpG methylation on the regulation of viral genome expression were first investigated by transfection of either unmethylated or in vitro methylated viral DNA in a model cell line, showing that methylation of viral DNA was correlated to lower expression levels of the viral genome. Then, in the course of in vitro infections in different cellular environments, it was observed that absence of viral expression and genome replication were both correlated to increasing levels of CpG methylation of viral DNA. Finally, the presence of CpG methylation was documented in viral DNA present in bioptic samples, indicating the occurrence and a possible role of this epigenetic modification in the course of natural infections. The presence of an epigenetic level of regulation of viral genome expression, possibly correlated to the silencing of the viral genome and contributing to the maintenance of the virus in tissues, can be relevant to the balance and outcome of the different types of infection associated to Parvovirus B19. PMID:22413013

Dietary Sulforaphane in Cancer Chemoprevention: The Role of Epigenetic Regulation and HDAC Inhibition

PubMed Central

Tortorella, Stephanie M.; Royce, Simon G.; Licciardi, Paul V.

2015-01-01

Abstract Significance: Sulforaphane, produced by the hydrolytic conversion of glucoraphanin after ingestion of cruciferous vegetables, particularly broccoli and broccoli sprouts, has been extensively studied due to its apparent health-promoting properties in disease and limited toxicity in normal tissue. Recent Studies: Recent identification of a sub-population of tumor cells with stem cell-like self-renewal capacity that may be responsible for relapse, metastasis, and resistance, as a potential target of the dietary compound, may be an important aspect of sulforaphane chemoprevention. Evidence also suggests that sulforaphane may target the epigenetic alterations observed in specific cancers, reversing aberrant changes in gene transcription through mechanisms of histone deacetylase inhibition, global demethylation, and microRNA modulation. Critical Issues: In this review, we discuss the biochemical and biological properties of sulforaphane with a particular emphasis on the anticancer properties of the dietary compound. Sulforaphane possesses the capacity to intervene in multistage carcinogenesis through the modulation and/or regulation of important cellular mechanisms. The inhibition of phase I enzymes that are responsible for the activation of pro-carcinogens, and the induction of phase II enzymes that are critical in mutagen elimination are well-characterized chemopreventive properties. Furthermore, sulforaphane mediates a number of anticancer pathways, including the activation of apoptosis, induction of cell cycle arrest, and inhibition of NFκB. Future Directions: Further characterization of the chemopreventive properties of sulforaphane and its capacity to be selectively toxic to malignant cells are warranted to potentially establish the clinical utility of the dietary compound as an anti-cancer compound alone, and in combination with clinically relevant therapeutic and management strategies. Antioxid. Redox Signal. 22, 1382–1424. PMID:25364882

BORIS/CTCFL mRNA isoform expression and epigenetic regulation in epithelial ovarian cancer

PubMed Central

Link, Petra A.; Zhang, Wa; Odunsi, Kunle; Karpf, Adam R.

2013-01-01

Cancer germline (CG) genes are normally expressed in germ cells and aberrantly expressed in a variety of cancers; their immunogenicity has led to the widespread development of cancer vaccines targeting these antigens. BORIS/CTCFL is an autosomal CG antigen and promising cancer vaccine target. BORIS is the only known paralog of CTCF, a gene intimately involved in genomic imprinting, chromatin insulation, and nuclear regulation. We have previously shown that BORIS is expressed in epithelial ovarian cancer (EOC) and that its expression coincides with promoter and global DNA hypomethylation. Recently, 23 different BORIS mRNA variants have been described, and have been functionally grouped into six BORIS isoform families (sf1–sf6). In the present study, we have characterized the expression of BORIS isoform families in normal ovary (NO) and EOC, the latter of which were selected to include two groups with widely varying global DNA methylation status. We find selective expression of BORIS isoform families in NO, which becomes altered in EOC, primarily by the activation of BORIS sf1 in EOC. When comparing EOC samples based on methylation status, we find that BORIS sf1 and sf2 isoform families are selectively activated in globally hypomethylated tumors. In contrast, CTCF is downregulated in EOC, and the ratio of BORIS sf1, sf2, and sf6 isoform families as a function of CTCF is elevated in hypomethylated tumors. Finally, the expression of all BORIS isoform families was induced to varying extents by epigenetic modulatory drugs in EOC cell lines, particularly when DNMT and HDAC inhibitors were used in combination. PMID:23390377

Genome-wide loss of 5-hmC is a novel epigenetic feature of Huntington's disease.

PubMed

Wang, Fengli; Yang, Yeran; Lin, Xiwen; Wang, Jiu-Qiang; Wu, Yong-Sheng; Xie, Wenjuan; Wang, Dandan; Zhu, Shu; Liao, You-Qi; Sun, Qinmiao; Yang, Yun-Gui; Luo, Huai-Rong; Guo, Caixia; Han, Chunsheng; Tang, Tie-Shan

2013-09-15

5-Hydroxymethylcytosine (5-hmC) may represent a new epigenetic modification of cytosine. While the dynamics of 5-hmC during neurodevelopment have recently been reported, little is known about its genomic distribution and function(s) in neurodegenerative diseases such as Huntington's disease (HD). We here observed a marked reduction of the 5-hmC signal in YAC128 (yeast artificial chromosome transgene with 128 CAG repeats) HD mouse brain tissues when compared with age-matched wild-type (WT) mice, suggesting a deficiency of 5-hmC reconstruction in HD brains during postnatal development. Genome-wide distribution analysis of 5-hmC further confirmed the diminishment of the 5-hmC signal in striatum and cortex in YAC128 HD mice. General genomic features of 5-hmC are highly conserved, not being affected by either disease or brain regions. Intriguingly, we have identified disease-specific (YAC128 versus WT) differentially hydroxymethylated regions (DhMRs), and found that acquisition of DhmRs in gene body is a positive epigenetic regulator for gene expression. Ingenuity pathway analysis (IPA) of genotype-specific DhMR-annotated genes revealed that alternation of a number of canonical pathways involving neuronal development/differentiation (Wnt/β-catenin/Sox pathway, axonal guidance signaling pathway) and neuronal function/survival (glutamate receptor/calcium/CREB, GABA receptor signaling, dopamine-DARPP32 feedback pathway, etc.) could be important for the onset of HD. Our results indicate that loss of the 5-hmC marker is a novel epigenetic feature in HD, and that this aberrant epigenetic regulation may impair the neurogenesis, neuronal function and survival in HD brain. Our study also opens a new avenue for HD treatment; re-establishing the native 5-hmC landscape may have the potential to slow/halt the progression of HD.

Epigenetic mechanisms in memory and synaptic function

PubMed Central

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

Association of Smoking, Alcohol Use, and Betel Quid Chewing with Epigenetic Aberrations in Cancers.

PubMed

Wang, Tong-Hong; Hsia, Shih-Min; Shih, Yin-Hwa; Shieh, Tzong-Ming

2017-06-06

Numerous environmental factors such as diet, alcohol use, stress, and environmental chemicals are known to elicit epigenetic changes, leading to increased rates of cancers and other diseases. The incidence of head and neck cancer, one of the most common cancers in Taiwanese males, is increasing: oral cancer and nasopharyngeal carcinoma are ranked fourth and tenth respectively, among the top ten cancers in this group, and a major cause of cancer-related deaths in Taiwanese males. Previous studies have identified smoking, alcohol use, and betel quid chewing as the three major causes of head and neck cancers; these three social habits are commonly observed in Taiwanese males, resulting in an increasing morbidity rate of head and neck cancers in this population. In this literature review, we discuss the association between specific components of betel quid, alcohol, and tobacco, and the occurrence of head and neck cancers, lung cancer, gastrointestinal cancers, and urethral cancer. We focus on regulatory mechanisms at the epigenetic level and their oncogenic effects. The review further discusses the application of FDA-approved epigenetic drugs as therapeutic strategies against cancer.

Neurological and Epigenetic Implications of Nutritional Deficiencies on Psychopathology: Conceptualization and Review of Evidence

PubMed Central

Liu, Jianghong; Zhao, Sophie R.; Reyes, Teresa

2015-01-01

In recent years, a role for epigenetic modifications in the pathophysiology of disease has received significant attention. Many studies are now beginning to explore the gene–environment interactions, which may mediate early-life exposure to risk factors, such as nutritional deficiencies and later development of behavioral problems in children and adults. In this paper, we review the current literature on the role of epigenetics in the development of psychopathology, with a specific focus on the potential for epigenetic modifications to link nutrition and brain development. We propose a conceptual framework whereby epigenetic modifications (e.g., DNA methylation) mediate the link between micro- and macro-nutrient deficiency early in life and brain dysfunction (e.g., structural aberration, neurotransmitter perturbation), which has been linked to development of behavior problems later on in life. PMID:26251900

Regulation of disease-responsive genes mediated by epigenetic factors: interaction of Arabidopsis-Pseudomonas.

PubMed

De-La-Peña, Clelia; Rangel-Cano, Alicia; Alvarez-Venegas, Raúl

2012-05-01

Genes in eukaryotic organisms function within the context of chromatin, and the mechanisms that modulate the structure of chromatin are defined as epigenetic. In Arabidopsis, pathogen infection induces the expression of at least one histone deacetylase, suggesting that histone acetylation/deacetylation has an important role in the pathogenic response in plants. How/whether histone methylation affects gene response to pathogen infection is unknown. To gain a better understanding of the epigenetic mechanisms regulating the interaction between Pseudomonas syringae and Arabidopsis thaliana, we analysed three different Arabidopsis ash1-related (absent, small or homeotic discs 1) mutants. We found that the loss of function of ASHH2 and ASHR1 resulted in faster hypersensitive responses (HRs) to both mutant (hrpA) and pathogenic (DC3000) strains of P. syringae, whereas control (Col-0) and ashr3 mutants appeared to be more resistant to the infection after 2 days. Furthermore, we showed that, in the ashr3 background, the PR1 gene (PATHOGENESIS-RELATED GENE 1) displayed the highest expression levels on infection with DC3000, correlating with increased resistance against this pathogen. Our results show that, in both the ashr1 and ashh2 backgrounds, the histone H3 lysine 4 dimethylation (H3K4me2) levels decreased at the promoter region of PR1 on infection with the DC3000 strain, suggesting that an epigenetically regulated PR1 expression is involved in the plant defence. Our results suggest that histone methylation in response to pathogen infection may be a critical component in the signalling and defence processes occurring between plants and microbes. © 2011 THE AUTHORS. MOLECULAR PLANT PATHOLOGY © 2011 BSPP AND BLACKWELL PUBLISHING LTD.

Epigenetic-induced alterations in sex-ratios in response to climate change: An epigenetic trap?

PubMed

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.

Epigenetic regulation in murine offspring as a novel mechanism for transmaternal asthma protection induced by microbes

USDA-ARS?s Scientific Manuscript database

Bronchial asthma is a chronic inflammatory disease resulting from complex gene-environment interactions. Natural microbial exposure has been identified as an important environmental condition that provides asthma protection in a prenatal window of opportunity. Epigenetic regulation is an important m...

Epigenetics and Bruxism: Possible Role of Epigenetics in the Etiology of Bruxism.

PubMed

Čalić, Aleksandra; Peterlin, Borut

2015-01-01

Bruxism is defined as a repetitive jaw muscle activity characterized by clenching or grinding of the teeth and/or bracing or thrusting of the mandible. There are two distinct circadian phenotypes for bruxism: sleep bruxism (SB) and awake bruxism, which are considered separate entities due to the putative difference in their etiology and phenotypic variance. The detailed etiology of bruxism so far remains unknown. Recent theories suggest the central regulation of certain pathophysiological or psychological pathways. Current proposed causes of bruxism appear to be a combination of genetic and environmental (G×E) factors, with epigenetics providing a robust framework for investigating G×E interactions, and their involvement in bruxism makes it a suitable candidate for epigenetic research. Both types of bruxism are associated with certain epigenetically determined disorders, such as Rett syndrome (RTT), Prader-Willi syndrome (PWS), and Angelman syndrome (AS), and these associations suggest a mechanistic link between epigenetic deregulation and bruxism. The present article reviews the possible role of epigenetic mechanisms in the etiology of both types of bruxism based on the epigenetic pathways involved in the pathophysiology of RTT, PWS, and AS, and on other epigenetic disruptions associated with risk factors for bruxism, including sleep disorders, altered stress response, and psychopathology.

The omniscient placenta: Metabolic and epigenetic regulation of fetal programming

PubMed Central

Nugent, Bridget M.; Bale, Tracy L.

2015-01-01

Fetal development could be considered a sensitive period wherein exogenous insults and changes to the maternal milieu can have long-term impacts on developmental programming. The placenta provides the fetus with protection and necessary nutrients for growth, and responds to maternal cues and changes in nutrient signaling through multiple epigenetic mechanisms. The X-linked enzyme O-linked-N-acetylglucosamine transferase (OGT) acts as a nutrient sensor that modifies numerous proteins to alter various cellular signals, including major epigenetic processes. This review describes epigenetic alterations in the placenta in response to insults during pregnancy, the potential links of OGT as a nutrient sensor to placental epigenetics, and the implications of placental epigenetics in long-term neurodevelopmental programming. We describe the role of placental OGT in the sex-specific programming of hypothalamic-pituitary-adrenal (HPA) axis programming deficits by early prenatal stress as an example of how placental signaling can have long-term effects on neurodevelopment. PMID:26368654

Androgen receptor mediated epigenetic regulation of CRISP3 promoter in prostate cancer cells.

PubMed

Pathak, Bhakti R; Breed, Ananya A; Deshmukh, Priyanka; Mahale, Smita D

2018-07-01

Cysteine-rich secretory protein 3 (CRISP3) is one of the most upregulated genes in prostate cancer. Androgen receptor (AR) plays an important role not only in initial stages of prostate cancer development but also in the advanced stage of castration-resistant prostate cancer (CRPC). Role of AR in regulation of CRISP3 expression is not yet known. In order to understand the regulation of CRISP3 expression, various overlapping fragments of CRISP3 promoter were cloned in pGL3 luciferase reporter vector. All constructs were transiently and stably transfected in PC3 (CRISP3 negative) and LNCaP (CRISP3 positive) cell lines and promoter activity was measured by luciferase assay. Promoter activity of LNCaP stable clones was significantly higher than PC3 stable clones. Further in CRISP3 negative PC3 and RWPE-1 cells, CRISP3 promoter was shown to be silenced by histone deacetylation. Treatment of LNCaP cells with DHT resulted in increase in levels of CRISP3 transcript and protein. AR dependency of CRISP3 promoter was also evaluated in LNCaP stable clones by luciferase assay. To provide molecular evidence of epigenetic regulation of CRISP3 promoter and its response to DHT, ChIP PCR was performed in PC3 and LNCaP cells. Our results demonstrate that CRISP3 expression in prostate cancer cells is androgen dependent and in AR positive cells, CRISP3 promoter is epigenetically regulated by AR. Copyright © 2018 Elsevier Ltd. All rights reserved.

Aging in the Brain: New Roles of Epigenetics in Cognitive Decline.

PubMed

Barter, Jolie D; Foster, Thomas C

2018-06-01

Gene expression in the aging brain depends on transcription signals generated by senescent physiology, interacting with genetic and epigenetic programs. In turn, environmental factors influence epigenetic mechanisms, such that an epigenetic-environmental link may contribute to the accumulation of cellular damage, susceptibility or resilience to stressors, and variability in the trajectory of age-related cognitive decline. Epigenetic mechanisms, DNA methylation and histone modifications, alter chromatin structure and the accessibility of DNA. Furthermore, small non-coding RNA, termed microRNA (miRNA) bind to messenger RNA (mRNA) to regulate translation. In this review, we examine key questions concerning epigenetic mechanisms in regulating the expression of genes associated with brain aging and age-related cognitive decline. In addition, we highlight the interaction of epigenetics with senescent physiology and environmental factors in regulating transcription.

BRDT is an essential epigenetic regulator for proper chromatin organization, silencing of sex chromosomes and crossover formation in male meiosis

PubMed Central

Oh, Min Young; Garyn, Corey

2018-01-01

The double bromodomain and extra-terminal domain (BET) proteins are critical epigenetic readers that bind to acetylated histones in chromatin and regulate transcriptional activity and modulate changes in chromatin structure and organization. The testis-specific BET member, BRDT, is essential for the normal progression of spermatogenesis as mutations in the Brdt gene result in complete male sterility. Although BRDT is expressed in both spermatocytes and spermatids, loss of the first bromodomain of BRDT leads to severe defects in spermiogenesis without overtly compromising meiosis. In contrast, complete loss of BRDT blocks the progression of spermatocytes into the first meiotic division, resulting in a complete absence of post-meiotic cells. Although BRDT has been implicated in chromatin remodeling and mRNA processing during spermiogenesis, little is known about its role in meiotic processes. Here we report that BRDT is an essential regulator of chromatin organization and reprograming during prophase I of meiosis. Loss of BRDT function disrupts the epigenetic state of the meiotic sex chromosome inactivation in spermatocytes, affecting the synapsis and silencing of the X and Y chromosomes. We also found that BRDT controls the global chromatin organization and histone modifications of the chromatin attached to the synaptonemal complex. Furthermore, the homeostasis of crossover formation and localization during pachynema was altered, underlining a possible epigenetic mechanism by which crossovers are regulated and differentially established in mammalian male genomes. Our observations reveal novel findings about the function of BRDT in meiosis and provide insight into how epigenetic regulators modulate the progression of male mammalian meiosis and the formation of haploid gametes. PMID:29513658

Twin methodology in epigenetic studies.

PubMed

Tan, Qihua; Christiansen, Lene; von Bornemann Hjelmborg, Jacob; Christensen, Kaare

2015-01-01

Since the final decades of the last century, twin studies have made a remarkable contribution to the genetics of human complex traits and diseases. With the recent rapid development in modern biotechnology of high-throughput genetic and genomic analyses, twin modelling is expanding from analysis of diseases to molecular phenotypes in functional genomics especially in epigenetics, a thriving field of research that concerns the environmental regulation of gene expression through DNA methylation, histone modification, microRNA and long non-coding RNA expression, etc. The application of the twin method to molecular phenotypes offers new opportunities to study the genetic (nature) and environmental (nurture) contributions to epigenetic regulation of gene activity during developmental, ageing and disease processes. Besides the classical twin model, the case co-twin design using identical twins discordant for a trait or disease is becoming a popular and powerful design for epigenome-wide association study in linking environmental exposure to differential epigenetic regulation and to disease status while controlling for individual genetic make-up. It can be expected that novel uses of twin methods in epigenetic studies are going to help with efficiently unravelling the genetic and environmental basis of epigenomics in human complex diseases. © 2015. Published by The Company of Biologists Ltd.

Genomic imprinting—an epigenetic gene-regulatory model

PubMed Central

Koerner, Martha V; Barlow, Denise P

2010-01-01

Epigenetic mechanisms (Box 1) are considered to play major gene-regulatory roles in development, differentiation and disease. However, the relative importance of epigenetics in defining the mammalian transcriptome in normal and disease states is unknown. The mammalian genome contains only a few model systems where epigenetic gene regulation has been shown to play a major role in transcriptional control. These model systems are important not only to investigate the biological function of known epigenetic modifications but also to identify new and unexpected epigenetic mechanisms in the mammalian genome. Here we review recent progress in understanding how epigenetic mechanisms control imprinted gene expression. PMID:20153958

Epigenetic down-regulated DDX10 promotes cell proliferation through Akt/NF-κB pathway in ovarian cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gai, Muhuizi; Bo, Qifang; Qi, Lixia, E-mail: lixiaqi_dph@sina.com

Ovarian cancer contributes to the majority of ovarian cancer, while the molecular mechanisms remain elusive. Recently, some DEAD box protein 1 has been reported play a tumor suppressor role in ovarian cancer progression. However, the functions of DEAD box protein (DDX) members in ovarian cancer development remain largely unknown. In current study, we retrieved GEO databases and surprisingly found that DDX10 is significantly down-regulated in ovarian cancer tissues compared with normal ovary. These findings suggest that DDX10 might also play a suppressive role in ovarian cancer. We then validated the down-regulated expression pattern of DDX10 in fresh ovarian cancer tissues.more » Furthermore, both loss- and gain-functions assays reveal that the down-regulated DDX10 could promote ovarian cancer proliferation in vitro and the xenograft subcutaneous tumor formation assays confirmed these findings in vivo. In addition, we found that DDX10 is epigenetic silenced by miR-155-5p in ovarian cancer. Moreover, we further preliminary illustrated that down-regulated DDX10 promotes ovarian cancer cell proliferation through Akt/NF-κB pathway. Taken together, in current study, we found a novel tumor suppressor, DDX10, is epigenetic silenced by miR-155-5p in ovarian cancer, and the down-regulated expression pattern of DDX10 promotes ovarian cancer proliferation through Akt/NF-κB pathway. Our findings shed the light that DDX families might be a novel for ovarian cancer treatment. - Highlights: • A novel DEAD box protein, DDX10 is significantly down-regulated in ovarian cancer tissues. • Down-regulated DDX10 promotes ovarian cancer cell proliferation and growth both in vitro and in vivo. • miR-155-5p is highly expressed in ovarian cancer tissues and epigenetically targets DDX10. • DDX10 and miR-155-5p regulates Akt/p65 axis in ovarian cancer cells.« less

Targeting epigenetics for the treatment of prostate cancer: recent progress and future directions.

PubMed

Lin, Jianqing; Wang, Chenguang; Kelly, Wm Kevin

2013-06-01

Epigenetic aberrations contribute to prostate cancer carcinogenesis and disease progression. Efforts have been made to target DNA methyltransferase and histone deacetylases (HDACs) in prostate cancer and other solid tumors but have not had the success that was seen in the hematologic malignancies. Oral, less toxic, and more specific agents are being developed in solid tumors including prostate cancer. Combinations of epigenetic agents alone or with a targeted agent such as androgen receptor signaling inhibitors are promising approaches and will be discussed further. Copyright © 2013 Elsevier Inc. All rights reserved.

[Epigenetics in atherosclerosis].

PubMed

Guardiola, Montse; Vallvé, Joan C; Zaina, Silvio; Ribalta, Josep

2016-01-01

The association studies based on candidate genes carried on for decades have helped in visualizing the influence of the genetic component in complex diseases such as atherosclerosis, also showing the interaction between different genes and environmental factors. Even with all the knowledge accumulated, there is still some way to go to decipher the individual predisposition to disease, and if we consider the great influence that environmental factors play in the development and progression of atherosclerosis, epigenetics is presented as a key element in trying to expand our knowledge on individual predisposition to atherosclerosis and cardiovascular disease. Epigenetics can be described as the discipline that studies the mechanisms of transcriptional regulation, independent of changes in the sequence of DNA, and mostly induced by environmental factors. This review aims to describe what epigenetics is and how epigenetic mechanisms are involved in atherosclerosis. Copyright © 2015 Sociedad Española de Arteriosclerosis. Published by Elsevier España. All rights reserved.

Epigenetic Regulation of ZBTB18 Promotes Glioblastoma Progression.

PubMed

Fedele, Vita; Dai, Fangping; Masilamani, Anie P; Heiland, Dieter H; Kling, Eva; Gätjens-Sanchez, Ana M; Ferrarese, Roberto; Platania, Leonardo; Soroush, Doostkam; Kim, Hyunsoo; Nelander, Sven; Weyerbrock, Astrid; Prinz, Marco; Califano, Andrea; Iavarone, Antonio; Bredel, Markus; Carro, Maria S

2017-08-01

Glioblastoma (GBM) comprises distinct subtypes characterized by their molecular profile. Mesenchymal identity in GBM has been associated with a comparatively unfavorable prognosis, primarily due to inherent resistance of these tumors to current therapies. The identification of molecular determinants of mesenchymal transformation could potentially allow for the discovery of new therapeutic targets. Zinc Finger and BTB Domain Containing 18 (ZBTB18/ZNF238/RP58) is a zinc finger transcriptional repressor with a crucial role in brain development and neuronal differentiation. Here, ZBTB18 is primarily silenced in the mesenchymal subtype of GBM through aberrant promoter methylation. Loss of ZBTB18 contributes to the aggressive phenotype of glioblastoma through regulation of poor prognosis-associated signatures. Restitution of ZBTB18 expression reverses the phenotype and impairs tumor-forming ability. These results indicate that ZBTB18 functions as a tumor suppressor in GBM through the regulation of genes associated with phenotypically aggressive properties. Implications: This study characterizes the role of the putative tumor suppressor ZBTB18 and its regulation by promoter hypermethylation, which appears to be a common mechanism to silence ZBTB18 in the mesenchymal subtype of GBM and provides a new mechanistic opportunity to specifically target this tumor subclass. Mol Cancer Res; 15(8); 998-1011. ©2017 AACR . ©2017 American Association for Cancer Research.

Epigenetic Regulation of ZBTB18 Promotes Glioblastoma Progression

PubMed Central

Fedele, Vita; Dai, Fangping; Masilamani, Anie Priscilla; Heiland, Dieter Henrik; Kling, Eva; Gätjens-Sanchez, Ana Maria; Ferrarese, Roberto; Platania, Leonardo; Soroush, Doostkam; Kim, Hyunsoo; Nelander, Sven; Weyerbrock, Astrid; Prinz, Marco; Califano, Andrea; Iavarone, Antonio; Bredel, Markus; Carro, Maria Stella

2018-01-01

Glioblastoma (GBM) is comprised of distinct subtypes characterized by their molecular profile. Mesenchymal identity in GBM has been associated with a comparatively unfavorable prognosis, primarily due to inherent resistance of these tumors to current therapies. The identification of molecular determinants of mesenchymal transformation could potentially allow for the discovery of new therapeutic targets. Zinc Finger and BTB Domain Containing 18 (ZBTB18/ZNF238/RP58) is a zinc finger transcriptional repressor with a crucial role in brain development and neuronal differentiation. Here, ZBTB18 is primarily silenced in the mesenchymal subtype of GBM through aberrant promoter methylation. Loss of ZBTB18 contributes to the aggressive phenotype of glioblastoma through regulation of poor prognosis-associated signatures. Restitution of ZBTB18 expression reverses the phenotype and impairs tumor-forming ability. These results indicate that ZBTB18 functions as a tumor suppressor in GBM through the regulation of genes associated with phenotypically aggressive properties. Implications This study characterizes the role of the putative tumor suppressor ZBTB18 and its regulation by promoter hypermethylation, which appears to be a common mechanism to silence ZBTB18 in the mesenchymal subtype of GBM and provides a new mechanistic opportunity to specifically target this tumor subclass. PMID:28512252

The danger of epigenetics misconceptions (epigenetics and stuff…).

PubMed

Georgel, Philippe T

2015-12-01

Within the past two decades, the fields of chromatin structure and function and transcription regulation research started to fuse and overlap, as evidence mounted to support a very strong regulatory role in gene expression that was associated with histone post-translational modifications, DNA methylation, as well as various chromatin-associated proteins (the pillars of the "Epigenetics" building). The fusion and convergence of these complementary fields is now often simply referred to as "Epigenetics". During these same 20 years, numerous new research groups have started to recognize the importance of chromatin composition, conformation, and its plasticity. However, as the field started to grow exponentially, its growth came with the spreading of several important misconceptions, which have unfortunately led to improper or hasty conclusions. The goal of this short "opinion" piece is to attempt to minimize future misinterpretations of experimental results and ensure that the right sets of experiment are used to reach the proper conclusion, at least as far as epigenetic mechanisms are concerned.

Epigenetic modulation of homer1a transcription regulation in amygdala and hippocampus with Pavlovian fear conditioning

PubMed Central

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

Epigenetics: a lasting impression?

PubMed

Biddie, Simon C; Lightman, Stafford L

2011-02-01

Epigenetics is the term that has been classically used to describe inheritable nongenetic factors that regulate genes. Although these factors were originally thought to act in a long time domain only, it is now clear that they can also be highly dynamic, changing over minutes. Transcription factors, including the glucocorticoid, oestrogen and androgen receptors, interact with these epigenetic mechanisms in a very dynamic manner to modify transcription of genes and consequently contribute to physiological processes, health and disease. Modern usage of the term epigenetics encompasses both longer-term and transient changes and is relevant to multiple biological systems. © 2011 The Authors. Journal of Neuroendocrinology © 2011 Blackwell Publishing Ltd.

Noncoding transcripts in sense and antisense orientation regulate the epigenetic state of ribosomal RNA genes.

PubMed

Bierhoff, H; Schmitz, K; Maass, F; Ye, J; Grummt, I

2010-01-01

Alternative transcription of the same gene in sense and antisense orientation regulates expression of protein-coding genes. Here we show that noncoding RNA (ncRNA) in sense and antisense orientation also controls transcription of rRNA genes (rDNA). rDNA exists in two types of chromatin--a euchromatic conformation that is permissive to transcription and a heterochromatic conformation that is transcriptionally silent. Silencing of rDNA is mediated by NoRC, a chromatin-remodeling complex that triggers heterochromatin formation. NoRC function requires RNA that is complementary to the rDNA promoter (pRNA). pRNA forms a DNA:RNA triplex with a regulatory element in the rDNA promoter, and this triplex structure is recognized by DNMT3b. The results imply that triplex-mediated targeting of DNMT3b to specific sequences may be a common pathway in epigenetic regulation. We also show that rDNA is transcribed in antisense orientation. The level of antisense RNA (asRNA) is down-regulated in cancer cells and up-regulated in senescent cells. Ectopic asRNA triggers trimethylation of histone H4 at lysine 20 (H4K20me3), suggesting that antisense transcripts guide the histone methyltransferase Suv4-20 to rDNA. The results reveal that noncoding RNAs in sense and antisense orientation are important determinants of the epigenetic state of rDNA.

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.

Epigenetic Regulation of Chromatin States in Schizosaccharomyces pombe

PubMed Central

Allshire, Robin C.; Ekwall, Karl

2015-01-01

This article discusses the advances made in epigenetic research using the model organism fission yeast Schizosaccharomyces pombe. S. pombe has been used for epigenetic research since the discovery of position effect variegation (PEV). This is a phenomenon in which a transgene inserted within heterochromatin is variably expressed, but can be stably inherited in subsequent cell generations. PEV occurs at centromeres, telomeres, ribosomal DNA (rDNA) loci, and mating-type regions of S. pombe chromosomes. Heterochromatin assembly in these regions requires enzymes that modify histones and the RNA interference (RNAi) machinery. One of the key histone-modifying enzymes is the lysine methyltransferase Clr4, which methylates histone H3 on lysine 9 (H3K9), a classic hallmark of heterochromatin. The kinetochore is assembled on specialized chromatin in which histone H3 is replaced by the variant CENP-A. Studies in fission yeast have contributed to our understanding of the establishment and maintenance of CENP-A chromatin and the epigenetic activation and inactivation of centromeres. PMID:26134317

New Insights into Somatic Embryogenesis: LEAFY COTYLEDON1, BABY BOOM1 and WUSCHEL-RELATED HOMEOBOX4 Are Epigenetically Regulated in Coffea canephora

PubMed Central

Nic-Can, Geovanny I.; López-Torres, Adolfo; Barredo-Pool, Felipe; Wrobel, Kazimierz; Loyola-Vargas, Víctor M.; Rojas-Herrera, Rafael; De-la-Peña, Clelia

2013-01-01

Plant cells have the capacity to generate a new plant without egg fertilization by a process known as somatic embryogenesis (SE), in which differentiated somatic cells can form somatic embryos able to generate a functional plant. Although there have been advances in understanding the genetic basis of SE, the epigenetic mechanism that regulates this process is still unknown. Here, we show that the embryogenic development of Coffea canephora proceeds through a crosstalk between DNA methylation and histone modifications during the earliest embryogenic stages of SE. We found that low levels of DNA methylation, histone H3 lysine 9 dimethylation (H3K9me2) and H3K27me3 change according to embryo development. Moreover, the expression of LEAFY COTYLEDON1 (LEC1) and BABY BOOM1 (BBM1) are only observed after SE induction, whereas WUSCHEL-RELATED HOMEOBOX4 (WOX4) decreases its expression during embryo maturation. Using a pharmacological approach, it was found that 5-Azacytidine strongly inhibits the embryogenic response by decreasing both DNA methylation and gene expression of LEC1 and BBM1. Therefore, in order to know whether these genes were epigenetically regulated, we used Chromatin Immunoprecipitation (ChIP) assays. It was found that WOX4 is regulated by the repressive mark H3K9me2, while LEC1 and BBM1 are epigenetically regulated by H3K27me3. We conclude that epigenetic regulation plays an important role during somatic embryogenic development, and a molecular mechanism for SE is proposed. PMID:23977240

Microbiota and epigenetic regulation of inflammatory mediators in type 2 diabetes and obesity.

PubMed

Remely, M; Aumueller, E; Jahn, D; Hippe, B; Brath, H; Haslberger, A G

2014-03-01

Metabolic syndrome is associated with alterations in the structure of the gut microbiota leading to low-grade inflammatory responses. An increased penetration of the impaired gut membrane by bacterial components is believed to induce this inflammation, possibly involving epigenetic alteration of inflammatory molecules such as Toll-like receptors (TLRs). We evaluated changes of the gut microbiota and epigenetic DNA methylation of TLR2 and TLR4 in three groups of subjects: type 2 diabetics under glucagon-like peptide-1 agonist therapy, obese individuals without established insulin resistance, and a lean control group. Clostridium cluster IV, Clostridium cluster XIVa, lactic acid bacteria, Faecalibacterium prausnitzii and Bacteroidetes abundances were analysed by PCR and 454 high-throughput sequencing. The epigenetic methylation in the regulatory region of TLR4 and TLR2 was analysed using bisulfite conversion and pyrosequencing. We observed a significantly higher ratio of Firmicutes/ Bacteroidetes in type 2 diabetics compared to lean controls and obese. Major differences were shown in lactic acid bacteria, with the highest abundance in type 2 diabetics, followed by obese and lean participants. In comparison, F. prausnitzii was least abundant in type 2 diabetics, and most abundant in lean controls. Methylation analysis of four CpGs in the first exon of TLR4 showed significantly lower methylation in obese individuals, but no significant difference between type 2 diabetics and lean controls. Methylation of seven CpGs in the promoter region of TLR2 was significantly lower in type 2 diabetics compared to obese subjects and lean controls. The methylation levels of both TLRs were significantly correlated with body mass index. Our data suggest that changes in gut microbiota and thus cell wall components are involved in the epigenetic regulation of inflammatory reactions. An improved diet targeted to induce gut microbial balance and in the following even epigenetic changes of

Epigenetic regulation of BDNF in the learned helplessness-induced animal model of depression.

PubMed

Su, Chun-Lin; Su, Chun-Wei; Hsiao, Ya-Hsin; Gean, Po-Wu

2016-05-01

Major depressive disorder (MDD), one of the most common mental disorders, is a significant risk factor for suicide and causes a low quality of life for many people. However, the causes and underlying mechanism of depression remain elusive. In the current work, we investigated epigenetic regulation of BDNF in the learned helplessness-induced animal model of depression. Mice were exposed to inescapable stress and divided into learned helplessness (LH) and resilient (LH-R) groups depending on the number they failed to escape. We found that the LH group had longer immobility duration in the forced swimming test (FST) and tail suspension tests (TST), which is consistent with a depression-related phenotype. Western blotting analysis and enzyme-linked immunosorbent assay (ELISA) revealed that the LH group had lower BDNF expression than that of the LH-R group. The LH group consistently had lower BDNF mRNA levels, as detected by qPCR assay. In addition, we found BDNF exon IV was down-regulated in the LH group. Intraperitoneal injection of imipramine or histone deacetylase inhibitors (HDACi) to the LH mice for 14 consecutive days ameliorated depression-like behaviors and reversed the decrease in BDNF. The expression of HDAC5 was up-regulated in the LH mice, and a ChIP assay revealed that the level of HDAC5 binding to the promoter region of BDNF exon IV was higher than that seen in other groups. Knockdown of HDAC5 reduced depression-like behaviors in the LH mice. Taken together, these results suggest that epigenetic regulation of BDNF by HDAC5 plays an important role in the learned helplessness model of depression. Copyright © 2016 Elsevier Ltd. All rights reserved.

Epigenetic Regulation of the Nitrosative Stress Response and Intracellular Macrophage Survival by Extraintestinal Pathogenic Escherichia coli

PubMed Central

Bateman, Stacey L.; Seed, Patrick C.

2013-01-01

Summary Extraintestinal pathogenic Escherichia coli (ExPEC) reside in the enteric tract as a commensal reservoir, but can transition to a pathogenic state by invading normally sterile niches, establishing infection, and disseminating to invasive sites like the bloodstream. Macrophages are required for ExPEC dissemination, suggesting the pathogen has developed mechanisms to persist within professional phagocytes. Here, we report that FimX, an ExPEC-associated DNA invertase that regulates the major virulence factor type 1 pili (T1P), is also an epigenetic regulator of a LuxR-like response regulator HyxR. FimX regulated hyxR expression through bidirectional phase inversion of its promoter region at sites different from the type 1 pili promoter and independent of integration host factor IHF. In vitro, transition from high to low HyxR expression produced enhanced tolerance of reactive nitrogen intermediates (RNI), primarily through de-repression of hmpA, encoding a nitric oxide detoxifying flavohemoglobin. However, in the macrophage, HyxR produced large effects on intracellular survival in the presence and absence of RNI and independent of Hmp. Collectively, we have shown that the ability of ExPEC to survive in macrophages is contingent upon the proper transition from high to low HyxR expression through epigenetic regulatory control by FimX. PMID:22221182

Molecular and epigenetic regulations and functions of the LAFL transcriptional regulators that control seed development.

PubMed

Lepiniec, L; Devic, M; Roscoe, T J; Bouyer, D; Zhou, D-X; Boulard, C; Baud, S; Dubreucq, B

2018-05-24

The LAFL (i.e. LEC1, ABI3, FUS3, and LEC2) master transcriptional regulators interact to form different complexes that induce embryo development and maturation, and inhibit seed germination and vegetative growth in Arabidopsis. Orthologous genes involved in similar regulatory processes have been described in various angiosperms including important crop species. Consistent with a prominent role of the LAFL regulators in triggering and maintaining embryonic cell fate, their expression appears finely tuned in different tissues during seed development and tightly repressed in vegetative tissues by a surprisingly high number of genetic and epigenetic factors. Partial functional redundancies and intricate feedback regulations of the LAFL have hampered the elucidation of the underpinning molecular mechanisms. Nevertheless, genetic, genomic, cellular, molecular, and biochemical analyses implemented during the last years have greatly improved our knowledge of the LALF network. Here we summarize and discuss recent progress, together with current issues required to gain a comprehensive insight into the network, including the emerging function of LEC1 and possibly LEC2 as pioneer transcription factors.

Radiation-induced genomic instability: Are epigenetic mechanisms the missing link?

DOE Office of Scientific and Technical Information (OSTI.GOV)

Aypar, Umut; Morgan, William F.; Baulch, Janet E.

Purpose: This review examines the evidence for the hypothesis that epigenetics are involved in the initiation and perpetuation of radiation-induced genomic instability (RIGI). Conclusion: In addition to the extensively studied targeted effects of radiation, it is now apparent that non-targeted delayed effects such as RIGI are also important post-irradiation outcomes. In RIGI, unirradiated progeny cells display phenotypic changes at delayed times after radiation of the parental cell. RIGI is thought to be important in the process of carcinogenesis, however, the mechanism by which this occurs remains to be elucidated. In the genomically unstable clones developed by Morgan and colleagues, radiation-inducedmore » mutations, double-strand breaks, or changes in mRNA levels alone could not account for the initiation or perpetuation of RIGI. Since changes in the DNA sequence could not fully explain the mechanism of RIGI, inherited epigenetic changes may be involved. Epigenetics are known to play an important role in many cellular processes and epigenetic aberrations can lead to carcinogenesis. Recent studies in the field of radiation biology suggest that the changes in methylation patterns may be involved in RIGI. Together these clues have led us to hypothesize that epigenetics may be the missing link in understanding the mechanism behind RIGI.« less

Acute and Chronic Electroconvulsive Seizures (ECS) Differentially Regulate the Expression of Epigenetic Machinery in the Adult Rat Hippocampus.

PubMed

Pusalkar, Madhavi; Ghosh, Shreya; Jaggar, Minal; Husain, Basma Fatima Anwar; Galande, Sanjeev; Vaidya, Vidita A

2016-09-01

Electroconvulsive seizure treatment is a fast-acting antidepressant therapy that evokes rapid transcriptional, neurogenic, and behavioral changes. Epigenetic mechanisms contribute to altered gene regulation, which underlies the neurogenic and behavioral effects of electroconvulsive seizure. We hypothesized that electroconvulsive seizure may modulate the expression of epigenetic machinery, thus establishing potential alterations in the epigenetic landscape. We examined the influence of acute and chronic electroconvulsive seizure on the gene expression of histone modifiers, namely histone acetyltransferases, histone deacetylases, histone methyltransferases, and histone (lysine) demethylases as well as DNA modifying enzymes, including DNA methyltransferases, DNA demethylases, and methyl-CpG-binding proteins in the hippocampi of adult male Wistar rats using quantitative real time-PCR analysis. Further, we examined the influence of acute and chronic electroconvulsive seizure on global and residue-specific histone acetylation and methylation levels within the hippocampus, a brain region implicated in the cellular and behavioral effects of electroconvulsive seizure. Acute and chronic electroconvulsive seizure induced a primarily unique, and in certain cases bidirectional, regulation of histone and DNA modifiers, and methyl-CpG-binding proteins, with an overlapping pattern of gene regulation restricted to Sirt4, Mll3, Jmjd3, Gadd45b, Tet2, and Tet3. Global histone acetylation and methylation levels were predominantly unchanged, with the exception of a significant decline in H3K9 acetylation in the hippocampus following chronic electroconvulsive seizure. Electroconvulsive seizure treatment evokes the transcriptional regulation of several histone and DNA modifiers, and methyl-CpG-binding proteins within the hippocampus, with a predominantly distinct pattern of regulation induced by acute and chronic electroconvulsive seizure. © The Author 2016. Published by Oxford

Acute and Chronic Electroconvulsive Seizures (ECS) Differentially Regulate the Expression of Epigenetic Machinery in the Adult Rat Hippocampus

PubMed Central

Pusalkar, Madhavi; Ghosh, Shreya; Jaggar, Minal; Husain, Basma Fatima Anwar; Galande, Sanjeev

2016-01-01

Background: Electroconvulsive seizure treatment is a fast-acting antidepressant therapy that evokes rapid transcriptional, neurogenic, and behavioral changes. Epigenetic mechanisms contribute to altered gene regulation, which underlies the neurogenic and behavioral effects of electroconvulsive seizure. We hypothesized that electroconvulsive seizure may modulate the expression of epigenetic machinery, thus establishing potential alterations in the epigenetic landscape. Methods: We examined the influence of acute and chronic electroconvulsive seizure on the gene expression of histone modifiers, namely histone acetyltransferases, histone deacetylases, histone methyltransferases, and histone (lysine) demethylases as well as DNA modifying enzymes, including DNA methyltransferases, DNA demethylases, and methyl-CpG-binding proteins in the hippocampi of adult male Wistar rats using quantitative real time-PCR analysis. Further, we examined the influence of acute and chronic electroconvulsive seizure on global and residue-specific histone acetylation and methylation levels within the hippocampus, a brain region implicated in the cellular and behavioral effects of electroconvulsive seizure. Results: Acute and chronic electroconvulsive seizure induced a primarily unique, and in certain cases bidirectional, regulation of histone and DNA modifiers, and methyl-CpG-binding proteins, with an overlapping pattern of gene regulation restricted to Sirt4, Mll3, Jmjd3, Gadd45b, Tet2, and Tet3. Global histone acetylation and methylation levels were predominantly unchanged, with the exception of a significant decline in H3K9 acetylation in the hippocampus following chronic electroconvulsive seizure. Conclusions: Electroconvulsive seizure treatment evokes the transcriptional regulation of several histone and DNA modifiers, and methyl-CpG-binding proteins within the hippocampus, with a predominantly distinct pattern of regulation induced by acute and chronic electroconvulsive seizure. PMID

MicroRNAs as New Characters in the Plot between Epigenetics and Prostate Cancer.

PubMed

Paone, Alessio; Galli, Roberta; Fabbri, Muller

2011-01-01

Prostate cancer (PCA) still represents a leading cause of death. An increasing number of studies have documented that microRNAs (miRNAs), a subgroup of non-coding RNAs with gene regulatory functions, are differentially expressed in PCA respect to the normal tissue counterpart, suggesting their involvement in prostate carcinogenesis and dissemination. Interestingly, it has been shown that miRNAs undergo the same regulatory mechanisms than any other protein coding gene, including epigenetic regulation. In turn, miRNAs can also affect the expression of oncogenes and tumor suppressor genes by targeting effectors of the epigenetic machinery, therefore indirectly affecting the epigenetic controls on these genes. Among the genes that undergo this complex regulation, there is the androgen receptor (AR), a key therapeutic target for PCA. This review will focus on the role of epigenetically regulated and epigenetically regulating miRNAs in PCA and on the fine regulation of AR expression, as mediated by this miRNA-epigenetics interaction.

Epigenetic reprogramming in mammalian species after SCNT-based cloning.

PubMed

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.

Epigenetic changes in fetal hypothalamic energy regulating pathways are associated with maternal undernutrition and twinning.

PubMed

Begum, Ghazala; Stevens, Adam; Smith, Emma Bolton; Connor, Kristin; Challis, John R G; Bloomfield, Frank; White, Anne

2012-04-01

Undernutrition during pregnancy is implicated in the programming of offspring for the development of obesity and diabetes. We hypothesized that maternal programming causes epigenetic changes in fetal hypothalamic pathways regulating metabolism. This study used sheep to examine the effect of moderate maternal undernutrition (60 d before to 30 d after mating) and twinning to investigate changes in the key metabolic regulators proopiomelanocortin (POMC) and the glucocorticoid receptor (GR) in fetal hypothalami. Methylation of the fetal hypothalamic POMC promoter was reduced in underfed singleton, fed twin, and underfed twin groups (60, 73, and 63% decrease, respectively). This was associated with reduced DNA methyltransferase activity and altered histone methylation and acetylation. Methylation of the hypothalamic GR promoter was decreased in both twin groups and in maternally underfed singleton fetuses (52, 65, and 55% decrease, respectively). This correlated with changes in histone methylation and acetylation and increased GR mRNA expression in the maternally underfed singleton group. Alterations in GR were hypothalamic specific, with no changes in hippocampi. Unaltered levels of OCT4 promoter methylation indicated gene-specific effects. In conclusion, twinning and periconceptional undernutrition are associated with epigenetic changes in fetal hypothalamic POMC and GR genes, potentially resulting in altered energy balance regulation in the offspring.

Epigenetic medicine and fetal alcohol spectrum disorders

PubMed Central

Resendiz, Marisol; Chen, Yuanyuan; Öztürk, Nail C; Zhou, Feng C

2013-01-01

Epigenetic medicine is still in its infancy. To date, only a handful of diseases have documented epigenetic correlates upstream of gene regulation including cancer, developmental syndromes and late-onset diseases. The finding that epigenetic markers are dynamic and heterogeneous at tissue and cellular levels, combined with recent identification of a new form of functionally distinct DNA methylation has opened a wider window for investigators to pry into the epigenetic world. It is anticipated that many diseases will be elucidated through this epigenetic inquiry. In this review, we discuss the normal course of DNA methylation during development, taking alcohol as a demonstrator of the epigenetic impact of environmental factors in disease etiology, particularly the growth retardation and neurodevelopmental deficits of fetal alcohol spectrum disorders. PMID:23414322

(Bis)urea and (Bis)thiourea Inhibitors of Lysine-Specific Demethylase 1 as Epigenetic Modulators

PubMed Central

Sharma, Shiv K.; Wu, Yu; Steinbergs, Nora; Crowley, Michael L.; Hanson, Allison S.; Casero, Robert A.; Woster, Patrick M.

2010-01-01

The recently discovered enzyme lysine-specific demethylase 1 (LSD1) plays an important role in the epigenetic control of gene expression, and aberrant gene silencing secondary to LSD1 over expression is thought to contribute to the development of cancer. We recently reported a series of (bis)guanidines and (bis)biguanides that are potent inhibitors of LSD1, and induce the re-expression of aberrantly silenced tumor suppressor genes in tumor cells in vitro. We now report a series of isosteric ureas and thioureas that are also potent inhibitors of LSD1. These compounds induce increases in methylation at the histone 3 lysine 4 (H3K4) chromatin mark, a specific target of LSD1, in Calu-6 lung carcinoma cells. In addition, these analogues increase cellular levels of secreted frizzle-related proteins (SFRP) 2 and 5, and transcription factor GATA4. These compounds represent an important new series of epigenetic modulators with the potential for use as antitumor agents. PMID:20568780

How to stomach an epigenetic insult: the gastric cancer epigenome.

PubMed

Padmanabhan, Nisha; Ushijima, Toshikazu; Tan, Patrick

2017-08-01

Gastric cancer is a deadly malignancy afflicting close to a million people worldwide. Patient survival is poor and largely due to late diagnosis and suboptimal therapies. Disease heterogeneity is a substantial obstacle, underscoring the need for precision treatment strategies. Studies have identified different subgroups of gastric cancer displaying not just genetic, but also distinct epigenetic hallmarks. Accumulating evidence suggests that epigenetic abnormalities in gastric cancer are not mere bystander events, but rather promote carcinogenesis through active mechanisms. Epigenetic aberrations, induced by pathogens such as Helicobacter pylori, are an early component of gastric carcinogenesis, probably preceding genetic abnormalities. This Review summarizes our current understanding of the gastric cancer epigenome, highlighting key advances in recent years in both tumours and pre-malignant lesions, made possible through targeted and genome-wide technologies. We focus on studies related to DNA methylation and histone modifications, linking these findings to potential therapeutic opportunities. Lessons learned from the gastric cancer epigenome might also prove relevant for other gastrointestinal cancers.

The epigenetic switches for neural development and psychiatric disorders.

PubMed

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.

Epigenetic mechanisms in cerebral ischemia

PubMed Central

Schweizer, Sophie; Meisel, Andreas; Märschenz, Stefanie

2013-01-01

Treatment efficacy for ischemic stroke represents a major challenge. Despite fundamental advances in the understanding of stroke etiology, therapeutic options to improve functional recovery remain limited. However, growing knowledge in the field of epigenetics has dramatically changed our understanding of gene regulation in the last few decades. According to the knowledge gained from animal models, the manipulation of epigenetic players emerges as a highly promising possibility to target diverse neurologic pathologies, including ischemia. By altering transcriptional regulation, epigenetic modifiers can exert influence on all known pathways involved in the complex course of ischemic disease development. Beneficial transcriptional effects range from attenuation of cell death, suppression of inflammatory processes, and enhanced blood flow, to the stimulation of repair mechanisms and increased plasticity. Most striking are the results obtained from pharmacological inhibition of histone deacetylation in animal models of stroke. Multiple studies suggest high remedial qualities even upon late administration of histone deacetylase inhibitors (HDACi). In this review, the role of epigenetic mechanisms, including histone modifications as well as DNA methylation, is discussed in the context of known ischemic pathways of damage, protection, and regeneration. PMID:23756691

Epigenetic regulation of ageing: linking environmental inputs to genomic stability

PubMed Central

Benayoun, Bérénice A.; Pollina, Elizabeth A.; Brunet, Anne

2016-01-01

Preface Ageing is affected by both genetic and non-genetic factors. Here, we review the chromatin-based epigenetic changes that occur during ageing, the role of chromatin modifiers in modulating lifespan and the importance of epigenetic signatures as biomarkers of ageing. We also discuss how epigenome remodeling by environmental stimuli impacts several aspects of transcription and genomic stability, with important consequences on longevity, and outline epigenetic differences between the ‘mortal soma’ and the ‘immortal germline’. Finally, we discuss the inheritance of ageing characteristics and potential chromatin-based strategies to delay or reverse hallmarks of ageing or age-related diseases. PMID:26373265

Therapeutic perspectives of epigenetically active nutrients

PubMed Central

Remely, M; Lovrecic, L; de la Garza, A L; Migliore, L; Peterlin, B; Milagro, F I; Martinez, A J; Haslberger, A G

2015-01-01

Many nutrients are known for a wide range of activities in prevention and alleviation of various diseases. Recently, their potential role in regulating human health through effects on epigenetics has become evident, although specific mechanisms are still unclear. Thus, nutriepigenetics/nutriepigenomics has emerged as a new and promising field in current epigenetics research in the past few years. In particular, polyphenols, as part of the central dynamic interaction between the genome and the environment with specificity at physiological concentrations, are well known to affect mechanisms underlying human health. This review summarizes the effects of dietary compounds on epigenetic mechanisms in the regulation of gene expression including expression of enzymes and other molecules responsible for drug absorption, distribution, metabolism and excretion in cancer, metabolic syndrome, neurodegenerative disorders and hormonal dysfunction. PMID:25046997

Epigenetics of cell fate reprogramming and its implications for neurological disorders modelling.

PubMed

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.

Epigenetics in non-small cell lung cancer: from basics to therapeutics.

PubMed

Ansari, Junaid; Shackelford, Rodney E; El-Osta, Hazem

2016-04-01

Lung cancer remains the number one cause of cancer-related deaths worldwide with 221,200 estimated new cases and 158,040 estimated deaths in 2015. Approximately 80% of cases are non-small cell lung cancer (NSCLC). The diagnosis is usually made at an advanced stage where the prognosis is poor and therapeutic options are limited. The evolution of lung cancer is a multistep process involving genetic, epigenetic, and environmental factor interactions that result in the dysregulation of key oncogenes and tumor suppressor genes, culminating in activation of cancer-related signaling pathways. The past decade has witnessed the discovery of multiple molecular aberrations that drive lung cancer growth, among which are epidermal growth factor receptor (EGFR) mutations and translocations involving the anaplastic lymphoma kinase (ALK) gene. This has translated into therapeutic agent developments that target these molecular alterations. The absence of targetable mutations in 50% of NSCLC cases and targeted therapy resistance development underscores the importance for developing alternative therapeutic strategies for treating lung cancer. Among these strategies, pharmacologic modulation of the epigenome has been used to treat lung cancer. Epigenetics approaches may circumvent the problem of tumor heterogeneity by affecting the expression of multiple tumor suppression genes (TSGs), halting tumor growth and survival. Moreover, it may be effective for tumors that are not driven by currently recognized druggable mutations. This review summarizes the molecular pathology of lung cancer epigenetic aberrations and discusses current efforts to target the epigenome with different pharmacological approaches. Our main focus will be on hypomethylating agents, histone deacetylase (HDAC) inhibitors, microRNA modulations, and the role of novel epigenetic biomarkers. Last, we will address the challenges that face this old-new strategy in treating lung cancer.

Epigenetic Therapeutics: A New Weapon in the War Against Cancer.

PubMed

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.

Epigenetic Effect of Environmental Factors on Neurodevelopmenal Disorders.

PubMed

Kubota, Takeo

2016-01-01

Epigenetics is an important mechanism of gene regulation that is dependent on the chromatin structure, which is determined by the epigenetic chemical modification of DNA and histone proteins. It is known that the failure of epigenetic mechanisms causes congenital neurodevelopmental disorders (NDs), and that early life exposure to mental stress and endocrine disrupting chemicals, such as phthalates, bisphenol A, and tobacco, can change epigenetic mechanism and gene expression in the brain and cause NDs. Moreover, environmentally induced epigenetic changes are not erased during gametogenesis and are transmitted to subsequent generations, leading to changes in behavior phenotypes. However, epigenetics has a reversible nature because it is based on the addition or removal of chemical residues, and thus the original epigenetic status may be restored. Indeed, several drugs used for mental disorders and NDs restore the epigenetic state and gene expression. Improved epigenetic understanding of NDs will provide important clues for the development of new drugs that take advantage of epigenetic reversibility.

Environment, diet and CpG island methylation: epigenetic signals in gastrointestinal neoplasia.

PubMed

Johnson, Ian T; Belshaw, Nigel J

2008-04-01

The epithelial surfaces of the mammalian alimentary tract are characterised by very high rates of cell proliferation and DNA synthesis, and in humans they are highly susceptible to cancer. The role of somatic mutations as drivers of carcinogenesis in the alimentary tract is well established, but the importance of gene silencing by epigenetic mechanisms is increasingly recognised. Methylation of CpG islands is an important component of the epigenetic code that regulates gene expression during development and normal cellular differentiation, and a number of genes are well known to become abnormally methylated during the development of tumours of the oesophagus, stomach and colorectum. Aberrant patterns of DNA methylation develop as a result of pathological processes such as chronic inflammation, and in response to various dietary factors, including imbalances in the supply of methyl donors, particularly folates, and exposure to DNA methyltransferase inhibitors, which include polyphenols and possibly isothiocyanates from plant foods. However the importance of these environmental interactions in human health and disease remains to be established. Recent moves to modify the exposure of human populations to folate, by mandatory supplementation of cereal foods, emphasise the importance of understanding the susceptibility of the human epigenome to dietary and other environmental effects.

Exercise impacts brain-derived neurotrophic factor plasticity by engaging mechanisms of epigenetic regulation.

PubMed

Gomez-Pinilla, F; Zhuang, Y; Feng, J; Ying, Z; Fan, G

2011-02-01

We have evaluated the possibility that the action of voluntary exercise on the regulation of brain-derived neurotrophic factor (BDNF), a molecule important for rat hippocampal learning, could involve mechanisms of epigenetic regulation. We focused the studies on the Bdnf promoter IV, as this region is highly responsive to neuronal activity. We have found that exercise stimulates DNA demethylation in Bdnf promoter IV, and elevates levels of activated methyl-CpG-binding protein 2, as well as BDNF mRNA and protein in the rat hippocampus. Chromatin immunoprecipitation assay showed that exercise increases acetylation of histone H3, and protein assessment showed that exercise elevates the ratio of acetylated :total for histone H3 but had no effects on histone H4 levels. Exercise also reduces levels of the histone deacetylase 5 mRNA and protein implicated in the regulation of the Bdnf gene [N.M. Tsankova et al. (2006)Nat. Neurosci., 9, 519-525], but did not affect histone deacetylase 9. Exercise elevated the phosphorylated forms of calcium/calmodulin-dependent protein kinase II and cAMP response element binding protein, implicated in the pathways by which neural activity influences the epigenetic regulation of gene transcription, i.e. Bdnf. These results showing the influence of exercise on the remodeling of chromatin containing the Bdnf gene emphasize the importance of exercise on the control of gene transcription in the context of brain function and plasticity. Reported information about the impact of a behavior, inherently involved in the daily human routine, on the epigenome opens exciting new directions and therapeutic opportunities in the war against neurological and psychiatric disorders. © 2010 The Authors. European Journal of Neuroscience © 2010 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

The Epigenetic Landscape of Alcoholism

PubMed Central

Krishnan, Harish R.; Sakharkar, Amul J.; Teppen, Tara L.; Berkel, Tiffani D.M.; Pandey, Subhash C.

2015-01-01

Alcoholism is a complex psychiatric disorder that has a multifactorial etiology. Epigenetic mechanisms are uniquely capable of accounting for the multifactorial nature of the disease in that they are highly stable and are affected by environmental factors, including alcohol itself. Chromatin remodeling causes changes in gene expression in specific brain regions contributing to the endophenotypes of alcoholism such as tolerance and dependence. The epigenetic mechanisms that regulate changes in gene expression observed in addictive behaviors respond not only to alcohol exposure, but also to comorbid psychopathology such as the presence of anxiety and stress. This review summarizes recent developments in epigenetic research that may play a role in alcoholism. We propose that pharmacologically manipulating epigenetic targets, as demonstrated in various preclinical models, holds great therapeutic potential in the treatment and prevention of alcoholism. PMID:25131543

Implications of long-term culture for mesenchymal stem cells: genetic defects or epigenetic regulation?

PubMed Central

2012-01-01

Mesenchymal stem cells change dramatically during culture expansion. Long-term culture has been suspected to evoke oncogenic transformation: overall, the genome appears to be relatively stable throughout culture but transient clonal aneuploidies have been observed. Oncogenic transformation does not necessarily entail growth advantage in vitro and, therefore, the available methods - such as karyotypic analysis or genomic profiling - cannot exclude this risk. On the other hand, long-term culture is associated with specific senescence-associated DNA methylation (SA-DNAm) changes, particularly in developmental genes. SA-DNAm changes are highly reproducible and can be used to monitor the state of senescence for quality control. Notably, neither telomere attrition nor SA-DNAm changes occur in pluripotent stem cells, which can evade the 'Hayflick limit'. Long-term culture of mesenchymal stem cells seems to involve a tightly regulated epigenetic program. These epigenetic modifications may counteract dominant clones, which are more prone to transformation. PMID:23257053

Implications of long-term culture for mesenchymal stem cells: genetic defects or epigenetic regulation?

PubMed

Wagner, Wolfgang

2012-12-20

Mesenchymal stem cells change dramatically during culture expansion. Long-term culture has been suspected to evoke oncogenic transformation: overall, the genome appears to be relatively stable throughout culture but transient clonal aneuploidies have been observed. Oncogenic transformation does not necessarily entail growth advantage in vitro and, therefore, the available methods - such as karyotypic analysis or genomic profiling - cannot exclude this risk. On the other hand, long-term culture is associated with specific senescence-associated DNA methylation (SA-DNAm) changes, particularly in developmental genes. SA-DNAm changes are highly reproducible and can be used to monitor the state of senescence for quality control. Notably, neither telomere attrition nor SA-DNAm changes occur in pluripotent stem cells, which can evade the 'Hayflick limit'. Long-term culture of mesenchymal stem cells seems to involve a tightly regulated epigenetic program. These epigenetic modifications may counteract dominant clones, which are more prone to transformation.

Health Promoting Effects of Brassica-Derived Phytochemicals: From Chemopreventive and Anti-Inflammatory Activities to Epigenetic Regulation

PubMed Central

Wagner, Anika Eva; Terschluesen, Anna Maria; Rimbach, Gerald

2013-01-01

A high intake of brassica vegetables may be associated with a decreased chronic disease risk. Health promoting effects of Brassicaceae have been partly attributed to glucosinolates and in particular to their hydrolyzation products including isothiocyanates. In vitro and in vivo studies suggest a chemopreventive activity of isothiocyanates through the redox-sensitive transcription factor Nrf2. Furthermore, studies in cultured cells, in laboratory rodents, and also in humans support an anti-inflammatory effect of brassica-derived phytochemicals. However, the underlying mechanisms of how these compounds mediate their health promoting effects are yet not fully understood. Recent findings suggest that brassica-derived compounds are regulators of epigenetic mechanisms. It has been shown that isothiocyanates may inhibit histone deacetylase transferases and DNA-methyltransferases in cultured cells. Only a few papers have dealt with the effect of brassica-derived compounds on epigenetic mechanisms in laboratory animals, whereas data in humans are currently lacking. The present review aims to summarize the current knowledge regarding the biological activities of brassica-derived phytochemicals regarding chemopreventive, anti-inflammatory, and epigenetic pathways. PMID:24454992

Individual epigenetic variation: When, why, and so what?

USDA-ARS?s Scientific Manuscript database

Epigenetics provides a potential explanation for how environmental factors modify the risk for common diseases among individuals. Interindividual variation in DNA methylation and epigenetic regulation has been reported at specific genomic regions including transposable elements, genomically imprinte...

The Emerging Role of Epigenetics in the Regulation of Female Puberty

PubMed Central

Lomniczi, Alejandro; Ojeda, Sergio R.

2016-01-01

In recent years the pace of discovering the molecular and genetic underpinnings of the pubertal process has accelerated considerably. Genes required for human puberty to occur have been identified and evidence has been provided suggesting that the initiation of puberty requires coordinated changes in the output of a multiplicity of genes organized into functional networks. Recent evidence suggests that a dual mechanism of epigenetic regulation affecting the transcriptional activity of neurons involved in stimulating gonadotropin-releasing hormone release plays a fundamental role in the timing of puberty. The Polycomb group (PcG) of transcriptional silencers appears to be a major component of the repressive arm of this mechanism. PcG proteins prevent the premature initiation of female puberty by silencing the Kiss1 gene in kisspeptin neurons of the arcuate nucleus (ARC) of the hypothalamus. Because the abundance of histone marks either catalyzed by – or associated with – the Trithorax group (TrxG) of transcriptional activators increases at the time when PcG control subsides, it appears that the TrxG complex is the counteracting partner of PcG-mediated gene silencing. In this chapter, we discuss the concept that a switch from epigenetic repression to activation within ARC kisspeptin neurons is a core mechanism underlying the initiation of female puberty. PMID:26680569

Advancements in the delivery of epigenetic drugs

PubMed Central

Cramer, Samantha A.; Adjei, Isaac M.; Labhasetwar, Vinod

2015-01-01

Introduction Advancements in epigenetic treatments are not only coming from new drugs but from modifications or encapsulation of the existing drugs into different formulations leading to greater stability and enhanced delivery to the target site. The epigenome is highly regulated and complex; therefore it is important that off-target effects of epigenetic drugs be minimized. The step from in vitro to in vivo treatment of these drugs often requires development of a method of effective delivery for clinical translation. Areas covered This review covers epigenetic mechanisms such as DNA methylation, chromatin remodeling and small RNA mediated gene regulation. There is a section in the review with examples of diseases where epigenetic alterations lead to impaired pathways, with an emphasis on cancer. Epigenetic drugs, their targets and clinical status are presented. Advantages of using a delivery method for epigenetic drugs as well as examples of current advancements and challenges are also discussed. Expert opinion Epigenetic drugs have the potential to be very effective therapy against a number of diseases, especially cancers and neurological disorders. As with many chemotherapeutics, undesired side effects need to be minimized. Finding a suitable delivery method means reducing side effects and achieving a higher therapeutic index. Each drug may require a unique delivery method exploiting the drug's chemistry or other physical characteristic requiring interdisciplinary participation and would benefit from a better understanding of the mechanisms of action. PMID:25739728

Cooperative STAT/NF-κB signaling regulates lymphoma metabolic reprogramming and aberrant GOT2 expression.

PubMed

Feist, Maren; Schwarzfischer, Philipp; Heinrich, Paul; Sun, Xueni; Kemper, Judith; von Bonin, Frederike; Perez-Rubio, Paula; Taruttis, Franziska; Rehberg, Thorsten; Dettmer, Katja; Gronwald, Wolfram; Reinders, Jörg; Engelmann, Julia C; Dudek, Jan; Klapper, Wolfram; Trümper, Lorenz; Spang, Rainer; Oefner, Peter J; Kube, Dieter

2018-04-17

Knowledge of stromal factors that have a role in the transcriptional regulation of metabolic pathways aside from c-Myc is fundamental to improvements in lymphoma therapy. Using a MYC-inducible human B-cell line, we observed the cooperative activation of STAT3 and NF-κB by IL10 and CpG stimulation. We show that IL10 + CpG-mediated cell proliferation of MYC low cells depends on glutaminolysis. By 13 C- and 15 N-tracing of glutamine metabolism and metabolite rescue experiments, we demonstrate that GOT2 provides aspartate and nucleotides to cells with activated or aberrant Jak/STAT and NF-κB signaling. A model of GOT2 transcriptional regulation is proposed, in which the cooperative phosphorylation of STAT3 and direct joint binding of STAT3 and p65/NF-κB to the proximal GOT2 promoter are important. Furthermore, high aberrant GOT2 expression is prognostic in diffuse large B-cell lymphoma underscoring the current findings and importance of stromal factors in lymphoma biology.

Post transcriptional control of the epigenetic stem cell regulator PLZF by sirtuin and HDAC deacetylases.

PubMed

McConnell, Melanie J; Durand, Laetitia; Langley, Emma; Coste-Sarguet, Lise; Zelent, Arthur; Chomienne, Christine; Kouzarides, Tony; Licht, Jonathan D; Guidez, Fabien

2015-01-01

The transcriptional repressor promyelocytic leukemia zinc finger protein (PLZF) is critical for the regulation of normal stem cells maintenance by establishing specific epigenetic landscape. We have previously shown that CBP/p300 acetyltransferase induces PLZF acetylation in order to increase its deoxynucleotidic acid (DNA) binding activity and to enhance its epigenetic function (repression of PLZF target genes). However, how PLZF is inactivated is not yet understood. In this study, we demonstrate that PLZF is deacetylated by both histone deacetylase 3 and the NAD+ dependent deacetylase silent mating type information regulation 2 homolog 1 (SIRT1). Unlike other PLZF-interacting deacetylases, these two proteins interact with the zinc finger domain of PLZF, where the activating CBP/p300 acetylation site was previously described, inducing deacetylation of lysines 647/650/653. Overexpression of histone deacetylase 3 (HDAC3) and SIRT1 is associated with loss of PLZF DNA binding activity and decreases PLZF transcriptional repression. As a result, the chromatin status of the promoters of PLZF target genes, involved in oncogenesis, shift from a heterochromatin to an open euchromatin environment leading to gene expression even in the presence of PLZF. Consequently, SIRT1 and HDAC3 mediated-PLZF deacetylation provides for rapid control and fine-tuning of PLZF activity through post-transcriptional modification to regulate gene expression and cellular homeostasis.

Epigenetic Regulation of miRNAs and Breast Cancer Stem Cells

PubMed Central

Duru, Nadire; Gernapudi, Ramkishore; Eades, Gabriel; Eckert, Richard; Zhou, Qun

2015-01-01

MicroRNAs have emerged as important targets of chemopreventive strategies in breast cancer. We have found that miRNAs are dysregulated at an early stage in breast cancer, in non-malignant Ductal Carcinoma In Situ. Many dietary chemoprevention agents can act by epigenetically activating miRNA-signaling pathways involved in tumor cell proliferation and invasive progression. In addition, many miRNAs activated via chemopreventive strategies target cancer stem cell signaling and prevent tumor progression or relapse. Specifically, we have found that miRNAs regulate DCIS stem cells, which may play important roles in breast cancer progression to invasive disease. We have shown that chemopreventive agents can directly inhibit DCIS stem cells and block tumor formation in vivo, via activation of tumor suppressor miRNAs. PMID:26052481

Epigenetic Alterations in Cellular Immunity: New Insights into Autoimmune Diseases.

PubMed

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.

Pathway modulations and epigenetic alterations in ovarian tumorbiogenesis

PubMed Central

Saldanha, Sabita N.; Tollefsbol, Trygve O.

2013-01-01

Cellular pathways are numerous and are highly integrated in function in the control of cellular systems. They collectively regulate cell division, proliferation, survival and apoptosis of cells and mutagenesis of key genes that control these pathways can initiate neoplastic transformations. Understanding these pathways is crucial to future therapeutic and preventive strategies of the disease. Ovarian cancers are of three major types; epithelial, germ-cell and stromal. However, ovarian cancers of epithelial origin, arising from the mesothelium, are the predominant form. Of the subtypes of ovarian cancer, the high-grade serous tumors are fatal, with low survival rate due to late detection and poor response to treatments. Close examination of preserved ovarian tissues and in vitro studies have provided insights into the mechanistic changes occurring in cells mediated by a few key genes. This review will focus on pathways and key genes of the pathways that are mutated or have aberrant functions in the pathology of ovarian cancer. Non-genetic mechanisms that are gaining prominence in the pathology of ovarian cancer, miRNAs and epigenetics, will also be discussed in the review. PMID:24105793

Epigenetics in mammary gland biology and cancer

USDA-ARS?s Scientific Manuscript database

In the post genome era, the focus has shifted to understanding the mechanisms that regulate the interpretation of the genetic code. "Epigenetics" as a research field is taking center stage. Epigenetics is a term which is now being used throughout the scientific community in different contexts from p...

The epigenetic landscape of alcoholism.

PubMed

Krishnan, Harish R; Sakharkar, Amul J; Teppen, Tara L; Berkel, Tiffani D M; Pandey, Subhash C

2014-01-01

Alcoholism is a complex psychiatric disorder that has a multifactorial etiology. Epigenetic mechanisms are uniquely capable of accounting for the multifactorial nature of the disease in that they are highly stable and are affected by environmental factors, including alcohol itself. Chromatin remodeling causes changes in gene expression in specific brain regions contributing to the endophenotypes of alcoholism such as tolerance and dependence. The epigenetic mechanisms that regulate changes in gene expression observed in addictive behaviors respond not only to alcohol exposure but also to comorbid psychopathology such as the presence of anxiety and stress. This review summarizes recent developments in epigenetic research that may play a role in alcoholism. We propose that pharmacologically manipulating epigenetic targets, as demonstrated in various preclinical models, hold great therapeutic potential in the treatment and prevention of alcoholism. © 2014 Elsevier Inc. All rights reserved.

Sulfamethazine Suppresses Epigenetic Silencing in Arabidopsis by Impairing Folate Synthesis[W

PubMed Central

Zhang, Huiming; Deng, Xiangyang; Miki, Daisuke; Cutler, Sean; La, Honggui; Hou, Yueh-Ju; Oh, JeeEun; Zhu, Jian-Kang

2012-01-01

DNA methylation is a critical, dynamically regulated epigenetic mark. Small chemicals can be valuable tools in probing cellular processes, but the set of chemicals with broad effects on epigenetic regulation is very limited. Using the Arabidopsis thaliana repressor of silencing1 mutant, in which transgenes are transcriptionally silenced, we performed chemical genetic screens and found sulfamethazine (SMZ) as a chemical suppressor of epigenetic silencing. SMZ treatment released the silencing of transgenes as well as endogenous transposons and other repetitive elements. Plants treated with SMZ exhibit substantially reduced levels of DNA methylation and histone H3 Lys-9 dimethylation, but heterochromatic siRNA levels were not affected. SMZ is a structural analog and competitive antagonist to p-aminobenzoic acid (PABA), which is a precursor of folates. SMZ decreased the plant folate pool size and caused methyl deficiency, as demonstrated by reductions in S-adenosylmethionine levels and in global DNA methylation. Exogenous application of PABA or compounds downstream in the folate biosynthesis pathway restored transcriptional silencing in SMZ-treated plants. Together, our results revealed a novel type of chemical suppressor of epigenetic silencing, which may serve as a valuable tool for studying the roles and mechanisms of epigenetic regulation and underscores an important linkage between primary metabolism and epigenetic gene regulation. PMID:22447685

Regulation of the DNA Methylation Landscape in Human Somatic Cell Reprogramming by the miR-29 Family.

PubMed

Hysolli, Eriona; Tanaka, Yoshiaki; Su, Juan; Kim, Kun-Yong; Zhong, Tianyu; Janknecht, Ralf; Zhou, Xiao-Ling; Geng, Lin; Qiu, Caihong; Pan, Xinghua; Jung, Yong-Wook; Cheng, Jijun; Lu, Jun; Zhong, Mei; Weissman, Sherman M; Park, In-Hyun

2016-07-12

Reprogramming to pluripotency after overexpression of OCT4, SOX2, KLF4, and MYC is accompanied by global genomic and epigenomic changes. Histone modification and DNA methylation states in induced pluripotent stem cells (iPSCs) have been shown to be highly similar to embryonic stem cells (ESCs). However, epigenetic differences still exist between iPSCs and ESCs. In particular, aberrant DNA methylation states found in iPSCs are a major concern when using iPSCs in a clinical setting. Thus, it is critical to find factors that regulate DNA methylation states in reprogramming. Here, we found that the miR-29 family is an important epigenetic regulator during human somatic cell reprogramming. Our global DNA methylation and hydroxymethylation analysis shows that DNA demethylation is a major event mediated by miR-29a depletion during early reprogramming, and that iPSCs derived from miR-29a depletion are epigenetically closer to ESCs. Our findings uncover an important miRNA-based approach to generate clinically robust iPSCs. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

Unexplored Potentials of Epigenetic Mechanisms of Plants and Animals—Theoretical Considerations

PubMed Central

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

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.

Epigenetic regulation of adaptive responses of forest tree species to the environment

PubMed Central

Bräutigam, Katharina; Vining, Kelly J; Lafon-Placette, Clément; Fossdal, Carl G; Mirouze, Marie; Marcos, José Gutiérrez; Fluch, Silvia; Fraga, Mario Fernández; Guevara, M Ángeles; Abarca, Dolores; Johnsen, Øystein; Maury, Stéphane; Strauss, Steven H; Campbell, Malcolm M; Rohde, Antje; Díaz-Sala, Carmen; Cervera, María-Teresa

2013-01-01

Epigenetic variation is likely to contribute to the phenotypic plasticity and adaptative capacity of plant species, and may be especially important for long-lived organisms with complex life cycles, including forest trees. Diverse environmental stresses and hybridization/polyploidization events can create reversible heritable epigenetic marks that can be transmitted to subsequent generations as a form of molecular “memory”. Epigenetic changes might also contribute to the ability of plants to colonize or persist in variable environments. In this review, we provide an overview of recent data on epigenetic mechanisms involved in developmental processes and responses to environmental cues in plant, with a focus on forest tree species. We consider the possible role of forest tree epigenetics as a new source of adaptive traits in plant breeding, biotechnology, and ecosystem conservation under rapid climate change. PMID:23467802

Maternal dietary manganese protects chick embryos against maternal heat stress via epigenetic-activated antioxidant and anti-apoptotic abilities.

PubMed

Zhu, Yongwen; Lu, Lin; Liao, Xiudong; Li, Wenxiang; Zhang, Liyang; Ji, Cheng; Lin, Xi; Liu, Hsiao-Ching; Odle, Jack; Luo, Xugang

2017-10-27

Maternal heat stress induced the aberrant epigenetic patterns resulting in the abnormal development of offspring embryos. It is unclear whether maternal dietary manganese supplementation as an epigenetic modifier could protect the chick embryonic development against maternal heat stress via epigenetic mechanisms. To test this hypothesis using an avian model, a completely randomized design with a 2 (maternal normal and high environmental temperatures of 21 and 32°C, respectively) × 3 (maternal dietary manganese sources, the control diet without manganese supplementation and the control diet + 120 mg/kg as either inorganic or organic manganese) factorial arrangement was adopted. Maternal environmental hyperthermia increased mRNA expressions of heat shock proteins 90 and 70, cyclin-dependent kinase 6 and B-cell CLL/lymphoma 2-associated X protein displaying oxidative damage and apoptosis in the embryonic heart. Maternal environmental hyperthermia impaired the embryonic development associated with the alteration of epigenetic status, as evidenced by global DNA hypomethylation and histone 3 lysine 9 hypoacetylation in the embryonic heart. Maternal dietary manganese supplementation increased the heart anti-apoptotic gene B-cell CLL/lymphoma 2 expressions under maternal environmental hyperthermia and manganese superoxide dismutase enzyme activity in the embryonic heart. Maternal dietary organic Mn supplementation effectively eliminated the impairment of maternal environmental hyperthermia on the embryonic development. Maternal dietary manganese supplementation up-regulated manganese superoxide dismutase mRNA expression by reducing DNA methylation and increasing histone 3 lysine 9 acetylation of its promoter. It is suggested that maternal dietary manganese addition could protect the chick embryonic development against maternal heat stress via enhancing epigenetic-activated antioxidant and anti-apoptotic abilities.

Identification of aberrant gene expression associated with aberrant promoter methylation in primordial germ cells between E13 and E16 rat F3 generation vinclozolin lineage.

PubMed

Taguchi, Y-h

2015-01-01

Transgenerational epigenetics (TGE) are currently considered important in disease, but the mechanisms involved are not yet fully understood. TGE abnormalities expected to cause disease are likely to be initiated during development and to be mediated by aberrant gene expression associated with aberrant promoter methylation that is heritable between generations. However, because methylation is removed and then re-established during development, it is not easy to identify promoter methylation abnormalities by comparing normal lineages with those expected to exhibit TGE abnormalities. This study applied the recently proposed principal component analysis (PCA)-based unsupervised feature extraction to previously reported and publically available gene expression/promoter methylation profiles of rat primordial germ cells, between E13 and E16 of the F3 generation vinclozolin lineage that are expected to exhibit TGE abnormalities, to identify multiple genes that exhibited aberrant gene expression/promoter methylation during development. The biological feasibility of the identified genes were tested via enrichment analyses of various biological concepts including pathway analysis, gene ontology terms and protein-protein interactions. All validations suggested superiority of the proposed method over three conventional and popular supervised methods that employed t test, limma and significance analysis of microarrays, respectively. The identified genes were globally related to tumors, the prostate, kidney, testis and the immune system and were previously reported to be related to various diseases caused by TGE. Among the genes reported by PCA-based unsupervised feature extraction, we propose that chemokine signaling pathways and leucine rich repeat proteins are key factors that initiate transgenerational epigenetic-mediated diseases, because multiple genes included in these two categories were identified in this study.

Identification of aberrant gene expression associated with aberrant promoter methylation in primordial germ cells between E13 and E16 rat F3 generation vinclozolin lineage

PubMed Central

2015-01-01

Background Transgenerational epigenetics (TGE) are currently considered important in disease, but the mechanisms involved are not yet fully understood. TGE abnormalities expected to cause disease are likely to be initiated during development and to be mediated by aberrant gene expression associated with aberrant promoter methylation that is heritable between generations. However, because methylation is removed and then re-established during development, it is not easy to identify promoter methylation abnormalities by comparing normal lineages with those expected to exhibit TGE abnormalities. Methods This study applied the recently proposed principal component analysis (PCA)-based unsupervised feature extraction to previously reported and publically available gene expression/promoter methylation profiles of rat primordial germ cells, between E13 and E16 of the F3 generation vinclozolin lineage that are expected to exhibit TGE abnormalities, to identify multiple genes that exhibited aberrant gene expression/promoter methylation during development. Results The biological feasibility of the identified genes were tested via enrichment analyses of various biological concepts including pathway analysis, gene ontology terms and protein-protein interactions. All validations suggested superiority of the proposed method over three conventional and popular supervised methods that employed t test, limma and significance analysis of microarrays, respectively. The identified genes were globally related to tumors, the prostate, kidney, testis and the immune system and were previously reported to be related to various diseases caused by TGE. Conclusions Among the genes reported by PCA-based unsupervised feature extraction, we propose that chemokine signaling pathways and leucine rich repeat proteins are key factors that initiate transgenerational epigenetic-mediated diseases, because multiple genes included in these two categories were identified in this study. PMID:26677731

Transposon-mediated epigenetic regulation contributes to phenotypic diversity and environmental adaptation in rice.

PubMed

Song, Xianwei; Cao, Xiaofeng

2017-04-01

Transposable elements (TEs) have long been regarded as 'selfish DNA', and are generally silenced by epigenetic mechanisms. However, work in the past decade has identified positive roles for TEs in generating genomic novelty and diversity in plants. In particular, recent studies suggested that TE-induced epigenetic alterations and modification of gene expression contribute to phenotypic variation and adaptation to geography or stress. These findings have led many to regard TEs, not as junk DNA, but as sources of control elements and genomic diversity. As a staple food crop and model system for genomic research on monocot plants, rice (Oryza sativa) has a modest-sized genome that harbors massive numbers of DNA transposons (class II transposable elements) scattered across the genome, which may make TE regulation of genes more prevalent. In this review, we summarize recent progress in research on the functions of rice TEs in modulating gene expression and creating new genes. We also examine the contributions of TEs to phenotypic diversity and adaptation to environmental conditions. Copyright © 2017 Elsevier Ltd. All rights reserved.

Epigenetics: the language of the cell?

PubMed

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.

p38 МАРK is Involved in Regulation of Epigenetic Mechanisms of Food Aversion Learning.

PubMed

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.

Nutritional influences on epigenetics and age-related disease

USDA-ARS?s Scientific Manuscript database

Nutritional epigenetics has emerged as a novel mechanism underlying gene–diet interactions, further elucidating the modulatory role of nutrition in aging and age-related disease development. Epigenetics is defined as a heritable modification to the DNA that regulates chromosome architecture and modu...

[Epigenetics of plant vernalization regulated by non-coding RNAs].

PubMed

Zhang, Shao-Feng; Li, Xiao-Rong; Sun, Chuan-Bao; He, Yu-Ke

2012-07-01

Many higher plants must experience a period of winter cold to accomplish the transition from vegetative to reproductive growth. This biological process is called vernalization. Some crops such as wheat (Triticum aestivum L.) and oilseed rape (Brassica napus L.) produce seeds as edible organs, and therefore special measures of rotation and cultivation are necessary for plants to go through an early vernalization for flower differentiation and development, whereas the other crops such as Chinese cabbage (B rapa ssp. pekinenesis) and cabbage (Brassica napus L.) produce leafy heads as edible organs, and additional practice should be taken to avoid vernalization for a prolonged and fully vegetative growth. Before vernalization, flowering is repressed by the action of a gene called Flowering Locus C (FLC). This paper reviewed the function of non-coding RNAs and some proteins including VRN1, VRN2, and VIN3 in epigenetic regulation of FLC during vernalization.

An epigenetic view of developmental diseases: new targets, new therapies.

PubMed

Xie, Pei; Zang, Li-Qun; Li, Xue-Kun; Shu, Qiang

2016-08-01

Function of epigenetic modifications is one of the most competitive fields in life science. Over the past several decades, it has been revealed that epigenetic modifications play essential roles in development and diseases including developmental diseases. In the present review, we summarize the recent progress about the function of epigenetic regulation, especially DNA and RNA modifications in developmental diseases. Original research articles and literature reviews published in PubMed-indexed journals. DNA modifications including methylation and demethylation can regulate gene expression, and are involved in development and multiple diseases including Rett syndrome, Autism spectrum disorders, congenital heart disease and cancer, etc. RNA methylation and demethylation play important roles in RNA processing, reprogramming, circadian, and neuronal activity, and then modulate development. DNA and RNA modifications play important roles in development and diseases through regulating gene expression. Epigenetic components could serve as novel targets for the treatment of developmental diseases.

Epigenetics in cancer stem cells.

PubMed

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.

Epigenetics of sleep and chronobiology.

PubMed

Qureshi, Irfan A; Mehler, Mark F

2014-03-01

The circadian clock choreographs fundamental biological rhythms. This system is comprised of the master circadian pacemaker in the suprachiasmatic nucleus and associated pacemakers in other tissues that coordinate complex physiological processes and behaviors, such as sleep, feeding, and metabolism. The molecular circuitry that underlies these clocks and orchestrates circadian gene expression has been the focus of intensive investigation, and it is becoming clear that epigenetic factors are highly integrated into these networks. In this review, we draw attention to the fundamental roles played by epigenetic mechanisms in transcriptional and post-transcriptional regulation within the circadian clock system. We also highlight how alterations in epigenetic factors and mechanisms are being linked with sleep-wake disorders. These observations provide important insights into the pathogenesis and potential treatment of these disorders and implicate epigenetic deregulation in the significant but poorly understood interconnections now emerging between circadian processes and neurodegeneration, metabolic diseases, cancer, and aging.

Epigenetic Mechanisms Regulate Innate Immunity against Uropathogenic and Commensal-Like Escherichia coli in the Surrogate Insect Model Galleria mellonella.

PubMed

Heitmueller, Miriam; Billion, André; Dobrindt, Ulrich; Vilcinskas, Andreas; Mukherjee, Krishnendu

2017-10-01

Innate-immunity-related genes in humans are activated during urinary tract infections (UTIs) caused by pathogenic strains of Escherichia coli but are suppressed by commensals. Epigenetic mechanisms play a pivotal role in the regulation of gene expression in response to environmental stimuli. To determine whether epigenetic mechanisms can explain the different behaviors of pathogenic and commensal bacteria, we infected larvae of the greater wax moth, Galleria mellonella , a widely used model insect host, with a uropathogenic E. coli (UPEC) strain that causes symptomatic UTIs in humans or a commensal-like strain that causes asymptomatic bacteriuria (ABU). Infection with the UPEC strain (CFT073) was more lethal to larvae than infection with the attenuated ABU strain (83972) due to the recognition of each strain by different Toll-like receptors, ultimately leading to differential DNA/RNA methylation and histone acetylation. We used next-generation sequencing and reverse transcription (RT)-PCR to correlate epigenetic changes with the induction of innate-immunity-related genes. Transcriptomic analysis of G. mellonella larvae infected with E. coli strains CFT073 and 83972 revealed strain-specific variations in the class and expression levels of genes encoding antimicrobial peptides, cytokines, and enzymes controlling DNA methylation and histone acetylation. Our results provide evidence for the differential epigenetic regulation of transcriptional reprogramming by UPEC and ABU strains of E. coli in G. mellonella larvae, which may be relevant to understanding the different behaviors of these bacterial strains in the human urinary tract. Copyright © 2017 American Society for Microbiology.

Insights into inner ear-specific gene regulation: epigenetics and non-coding RNAs in inner ear development and regeneration

PubMed Central

Avraham, Karen B.

2016-01-01

The vertebrate inner ear houses highly specialized sensory organs, tuned to detect and encode sound, head motion and gravity. Gene expression programs under the control of transcription factors orchestrate the formation and specialization of the non-sensory inner ear labyrinth and its sensory constituents. More recently, epigenetic factors and non-coding RNAs emerged as an additional layer of gene regulation, both in inner ear development and disease. In this review, we provide an overview on how epigenetic modifications and non-coding RNAs, in particular microRNAs (miRNAs), influence gene expression and summarize recent discoveries that highlight their critical role in the proper formation of the inner ear labyrinth and its sensory organs. In contrast to non-mammalian vertebrates, adult mammals lack the ability to regenerate inner ear mechano-sensory hair cells. Finally, we discuss recent insights into how epigenetic factors and miRNAs may facilitate, or in the case of mammals, restrict sensory hair cell regeneration. PMID:27836639

Epigenetic regulation of the expression of WRKY75 transcription factor in response to biotic and abiotic stresses in Solanaceae plants.

PubMed

López-Galiano, María José; González-Hernández, Ana I; Crespo-Salvador, Oscar; Rausell, Carolina; Real, M Dolores; Escamilla, Mónica; Camañes, Gemma; García-Agustín, Pilar; González-Bosch, Carmen; García-Robles, Inmaculada

2018-01-01

SlyWRKY75: gene expression was induced in response to biotic stresses, especially in Botrytis cinerea-infected tomato plants, in which Sly-miR1127-3p is a putative SlyWRKY75 regulator and epigenetic marks were detected. WRKY75 transcription factor involved in Pi homeostasis was recently found also induced in defense against necrotrophic pathogens. In this study, we analyzed by RT-qPCR the expression of SlyWRKY75 gene in tomato plants in response to abiotic stresses (drought or heat) and biotic stresses (Colorado potato beetle larvae infestation, Pseudomonas syringae or Botrytis cinerea infection) being only differentially expressed following biotic stresses, especially upon B. cinerea infection (55-fold induction). JA and JA-Ile levels were significantly increased in tomato plants under biotic stresses compared with control plants, indicating that SlyWRKY75 might be a transcriptional regulator of the JA pathway. The contribution of miRNAs and epigenetic molecular mechanisms to the regulation of this gene in B. cinerea-infected tomato plants was explored. We identified a putative Sly-miR1127-3p miRNA predicted to bind the intronic region of the SlyWRKY75 genomic sequence. Sly-miR1127-3p miRNA was repressed in infected plants (0.4-fold) supporting that it might act as an epigenetic regulation factor of SlyWRKY75 gene expression rather than via the post-transcriptional mechanisms of canonical miRNAs. It has been proposed that certain miRNAs can mediate DNA methylation in the plant nucleus broadening miRNA functions with transcriptional gene silencing by targeting intron-containing pre-mRNAs. Histone modifications analysis by chromatin immunoprecipitation (ChIP) demonstrated the presence of the activator histone modification H3K4me3 on SlyWRKY75 transcription start site and gene body. The induction of this gene in response to B. cinerea correlates with the presence of an activator mark. Thus, miRNAs and chromatin modifications might cooperate as epigenetic factors to

Epigenetic Machinery Regulates Alternative Splicing of Androgen Receptor (AR) Gene in Castration Resistant Prostate Cancer

DTIC Science & Technology

2017-09-01

AWARD NUMBER: W81XWH-16-1-0531 TITLE: Epigenetic machinery regulates alternative splicing of androgen receptor ( AR ) gene in castration...DISTRIBUTION STATEMENT: Approved for Public Release Distribution Unlimited The views, opinions and/or findings contained in this report are those of...One of the reasons for the resistance to ADT and newer anti-androgen drugs is the emergence of constitutively active AR variants ( AR -Vs) such as AR

Epigenetic Control of Stem Cell Potential During Homeostasis, Aging, and Disease

PubMed Central

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

Epigenetic mechanisms in non-alcoholic fatty liver disease: An emerging field.

PubMed

Gallego-Durán, Rocío; Romero-Gómez, Manuel

2015-10-28

Non-alcoholic fatty liver disease (NAFLD) is an emerging health concern in both developed and non-developed world, encompassing from simple steatosis to non-alcoholic steatohepatitis (NASH), cirrhosis and liver cancer. Incidence and prevalence of this disease are increasing due to the socioeconomic transition and change to harmful diet. Currently, gold standard method in NAFLD diagnosis is liver biopsy, despite complications and lack of accuracy due to sampling error. Further, pathogenesis of NAFLD is not fully understood, but is well-known that obesity, diabetes and metabolic derangements played a major role in disease development and progression. Besides, gut microbioma and host genetic and epigenetic background could explain considerable interindividual variability. Knowledge that epigenetics, heritable events not caused by changes in DNA sequence, contribute to development of diseases has been a revolution in the last few years. Recently, evidences are accumulating revealing the important role of epigenetics in NAFLD pathogenesis and in NASH genesis. Histone modifications, changes in DNA methylation and aberrant profiles or microRNAs could boost development of NAFLD and transition into clinical relevant status. PNPLA3 genotype GG has been associated with a more progressive disease and epigenetics could modulate this effect. The impact of epigenetic on NAFLD progression could deserve further applications on therapeutic targets together with future non-invasive methods useful for the diagnosis and staging of NAFLD.

The Emerging Role of Epigenetics in the Regulation of Female Puberty.

PubMed

Lomniczi, Alejandro; Ojeda, Sergio R

2016-01-01

In recent years the pace of discovering the molecular and genetic underpinnings of the pubertal process has accelerated considerably. Genes required for human puberty to occur have been identified and evidence has been provided suggesting that the initiation of puberty requires coordinated changes in the output of a multiplicity of genes organized into functional networks. Recent evidence suggests that a dual mechanism of epigenetic regulation affecting the transcriptional activity of neurons involved in stimulating gonadotropin-releasing hormone release plays a fundamental role in the timing of puberty. The Polycomb group (PcG) of transcriptional silencers appears to be a major component of the repressive arm of this mechanism. PcG proteins prevent the premature initiation of female puberty by silencing the Kiss1 gene in kisspeptin neurons of the arcuate nucleus (ARC) of the hypothalamus. Because the abundance of histone marks either catalyzed by--or associated with--the Trithorax group (TrxG) of transcriptional activators increases at the time when PcG control subsides, it appears that the TrxG complex is the counteracting partner of PcG-mediated gene silencing. In this chapter, we discuss the concept that a switch from epigenetic repression to activation within ARC kisspeptin neurons is a core mechanism underlying the initiation of female puberty. © 2016 S. Karger AG, Basel.

LPS-induced expression of CD14 in the TRIF pathway is epigenetically regulated by sulforaphane in porcine pulmonary alveolar macrophages.

PubMed

Yang, Qin; Pröll, Maren J; Salilew-Wondim, Dessie; Zhang, Rui; Tesfaye, Dawit; Fan, Huitao; Cinar, Mehmet U; Große-Brinkhaus, Christine; Tholen, Ernst; Islam, Mohammad A; Hölker, Michael; Schellander, Karl; Uddin, Muhammad J; Neuhoff, Christiane

2016-11-01

Pulmonary alveolar macrophages (AMs) are important in defense against bacterial lung inflammation. Cluster of differentiation 14 (CD14) is involved in recognizing bacterial lipopolysaccharide (LPS) through MyD88-dependent and TRIF pathways of innate immunity. Sulforaphane (SFN) shows anti-inflammatory activity and suppresses DNA methylation. To identify CD14 epigenetic changes by SFN in the LPS-induced TRIF pathway, an AMs model was investigated in vitro. CD14 gene expression was induced by 5 µg/ml LPS at the time point of 12 h and suppressed by 5 µM SFN. After 12 h of LPS stimulation, gene expression was significantly up-regulated, including TRIF, TRAF6, NF-κB, TRAF3, IRF7, TNF-α, IL-1β, IL-6, and IFN-β. LPS-induced TRAM, TRIF, RIPK1, TRAF3, TNF-α, IL-1β and IFN-β were suppressed by 5 µM SFN. Similarly, DNMT3a expression was increased by LPS but significantly down-regulated by 5 µM SFN. It showed positive correlation of CD14 gene body methylation with in LPS-stimulated AMs, and this methylation status was inhibited by SFN. This study suggests that SFN suppresses CD14 activation in bacterial inflammation through epigenetic regulation of CD14 gene body methylation associated with DNMT3a. The results provide insights into SFN-mediated epigenetic down-regulation of CD14 in LPS-induced TRIF pathway inflammation and may lead to new methods for controlling LPS-induced inflammation in pigs.

Conference scene: Select Biosciences Epigenetics Europe 2010.

PubMed

Razvi, Enal S

2011-02-01

The field of epigenetics is now on a geometric rise, driven in a large part by the realization that modifiers of chromatin are key regulators of biological processes in vivo. The three major classes of epigenetic effectors are DNA methylation, histone post-translational modifications (such as acetylation, methylation or phosphorylation) and small noncoding RNAs (most notably microRNAs). In this article, I report from Select Biosciences Epigenetics Europe 2010 industry conference held on 14-15 September 2010 at The Burlington Hotel, Dublin, Ireland. This industry conference was extremely well attended with a global pool of delegates representing the academic research community, biotechnology companies and pharmaceutical companies, as well as the technology/tool developers. This conference represented the current state of the epigenetics community with cancer/oncology as a key driver. In fact, it has been estimated that approximately 45% of epigenetic researchers today identify cancer/oncology as their main area of focus vis-à-vis their epigenetic research efforts.

Role of Interleukin 10 Transcriptional Regulation in Inflammation and Autoimmune Disease

PubMed Central

Iyer, Shankar Subramanian; Cheng, Genhong

2012-01-01

Interleukin 10 (IL-10) is a cytokine with potent anti-inflammatory properties that plays a central role in limiting host immune response to pathogens, thereby preventing damage to the host and maintaining normal tissue homeostasis. Dysregulation of IL-10 is associated with enhanced immunopathology in response to infection as well as increased risk for development of many autoimmune diseases. Thus a fundamental understanding of IL-10 gene expression is critical for our comprehension of disease progression and resolution of host inflammatory response. In this review, we discuss modes of regulation of IL-10 gene expression in immune effector cell types, including signal transduction, epigenetics, promoter architecture, and post-transcriptional regulation, and how aberrant regulation contributes to immunopathology and disease progression. PMID:22428854

Epigenetic Heterogeneity of B-Cell Lymphoma: Chromatin Modifiers

PubMed Central

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

Epigenetic Regulation of Placental "NR3C1": Mechanism Underlying Prenatal Programming of Infant Neurobehavior by Maternal Smoking?

ERIC Educational Resources Information Center

Stroud, Laura R.; Papandonatos, George D.; Salisbury, Amy L.; Phipps, Maureen G.; Huestis, Marilyn A.; Niaura, Raymond; Padbury, James F.; Marsit, Carmen J.; Lester, Barry M.

2016-01-01

Epigenetic regulation of the placental glucocorticoid receptor gene ("NR3C1") was investigated as a mechanism underlying links between maternal smoking during pregnancy (MSDP) and infant neurobehavior in 45 mother-infant pairs (49% MSDP-exposed; 52% minorities; ages 18-35). The Neonatal Intensive Care Unit (NICU) Network Neurobehavioral…

Rice ABERRANT PANICLE ORGANIZATION 1, encoding an F-box protein, regulates meristem fate.

PubMed

Ikeda, Kyoko; Ito, Momoyo; Nagasawa, Nobuhiro; Kyozuka, Junko; Nagato, Yasuo

2007-09-01

Inflorescence architecture is one of the most important agronomical traits. Characterization of rice aberrant panicle organization 1 (apo1) mutants revealed that APO1 positively controls spikelet number by suppressing the precocious conversion of inflorescence meristems to spikelet meristems. In addition, APO1 is associated with the regulation of the plastchron, floral organ identity, and floral determinacy. Phenotypic analyses of apo1 and floral homeotic double mutants demonstrate that APO1 positively regulates class-C floral homeotic genes, but not class-B genes. Molecular studies revealed that APO1 encodes an F-box protein, an ortholog of Arabidopsis UNUSUAL FLORAL ORGAN (UFO), which is a positive regulator of class-B genes. Overexpression of APO1 caused an increase in inflorescence branches and spikelets. As the mutant inflorescences and flowers differed considerably between apo1 and ufo, the functions of APO1 and UFO appear to have diverged during evolution.

Epigenetic mechanisms during ageing and neurogenesis as novel therapeutic avenues in human brain disorders.

PubMed

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.

Comprehensive analyses of imprinted differentially methylated regions reveal epigenetic and genetic characteristics in hepatoblastoma

PubMed Central

2013-01-01

Background Aberrant methylation at imprinted differentially methylated regions (DMRs) in human 11p15.5 has been reported in many tumors including hepatoblastoma. However, the methylation status of imprinted DMRs in imprinted loci scattered through the human genome has not been analyzed yet in any tumors. Methods The methylation statuses of 33 imprinted DMRs were analyzed in 12 hepatoblastomas and adjacent normal liver tissue by MALDI-TOF MS and pyrosequencing. Uniparental disomy (UPD) and copy number abnormalities were investigated with DNA polymorphisms. Results Among 33 DMRs analyzed, 18 showed aberrant methylation in at least 1 tumor. There was large deviation in the incidence of aberrant methylation among the DMRs. KvDMR1 and IGF2-DMR0 were the most frequently hypomethylated DMRs. INPP5Fv2-DMR and RB1-DMR were hypermethylated with high frequencies. Hypomethylation was observed at certain DMRs not only in tumors but also in a small number of adjacent histologically normal liver tissue, whereas hypermethylation was observed only in tumor samples. The methylation levels of long interspersed nuclear element-1 (LINE-1) did not show large differences between tumor tissue and normal liver controls. Chromosomal abnormalities were also found in some tumors. 11p15.5 and 20q13.3 loci showed the frequent occurrence of both genetic and epigenetic alterations. Conclusions Our analyses revealed tumor-specific aberrant hypermethylation at some imprinted DMRs in 12 hepatoblastomas with additional suggestion for the possibility of hypomethylation prior to tumor development. Some loci showed both genetic and epigenetic alterations with high frequencies. These findings will aid in understanding the development of hepatoblastoma. PMID:24373183

Comparative epigenetics: relevance to the regulation of production and health traits in cattle.

PubMed

Doherty, Rachael; O' Farrelly, Cliona; Meade, Kieran G

2014-08-01

With the development of genomic, transcriptomic and bioinformatic tools, recent advances in molecular technologies have significantly impacted bovine bioscience research and are revolutionising animal selection and breeding. Integration of epigenetic information represents yet another challenging molecular frontier. Epigenetics is the study of biochemical modifications to DNA and to histones, the proteins that provide stability to DNA. These epigenetic changes are induced by environmental stimuli; they alter gene expression and are potentially heritable. Epigenetics research holds the key to understanding how environmental factors contribute to phenotypic variation in traits of economic importance in cattle including development, nutrition, behaviour and health. In this review, we discuss the potential applications of epigenetics in bovine research, using breakthroughs in human and murine research to signpost the way. © 2014 Stichting International Foundation for Animal Genetics.

Genetic and epigenetic control of plant heat responses

PubMed Central

Liu, Junzhong; Feng, Lili; Li, Jianming; He, Zuhua

2015-01-01

Plants have evolved sophisticated genetic and epigenetic regulatory systems to respond quickly to unfavorable environmental conditions such as heat, cold, drought, and pathogen infections. In particular, heat greatly affects plant growth and development, immunity and circadian rhythm, and poses a serious threat to the global food supply. According to temperatures exposing, heat can be usually classified as warm ambient temperature (about 22–27°C), high temperature (27–30°C) and extremely high temperature (37–42°C, also known as heat stress) for the model plant Arabidopsis thaliana. The genetic mechanisms of plant responses to heat have been well studied, mainly focusing on elevated ambient temperature-mediated morphological acclimation and acceleration of flowering, modulation of circadian clock and plant immunity by high temperatures, and thermotolerance to heat stress. Recently, great progress has been achieved on epigenetic regulation of heat responses, including DNA methylation, histone modifications, histone variants, ATP-dependent chromatin remodeling, histone chaperones, small RNAs, long non-coding RNAs and other undefined epigenetic mechanisms. These epigenetic modifications regulate the expression of heat-responsive genes and function to prevent heat-related damages. This review focuses on recent progresses regarding the genetic and epigenetic control of heat responses in plants, and pays more attention to the role of the major epigenetic mechanisms in plant heat responses. Further research perspectives are also discussed. PMID:25964789

Epigenetic Library Screen Identifies Abexinostat as Novel Regulator of Adipocytic and Osteoblastic Differentiation of Human Skeletal (Mesenchymal) Stem Cells

PubMed Central

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

Epigenetic Mechanisms Regulate MHC and Antigen Processing Molecules in Human Embryonic and Induced Pluripotent Stem Cells

PubMed Central

Suárez-Álvarez, Beatriz; Rodriguez, Ramón M.; Calvanese, Vincenzo; Blanco-Gelaz, Miguel A.; Suhr, Steve T.; Ortega, Francisco; Otero, Jesus; Cibelli, Jose B.; Moore, Harry; Fraga, Mario F.; López-Larrea, Carlos

2010-01-01

Background Human embryonic stem cells (hESCs) are an attractive resource for new therapeutic approaches that involve tissue regeneration. hESCs have exhibited low immunogenicity due to low levels of Mayor Histocompatibility Complex (MHC) class-I and absence of MHC class-II expression. Nevertheless, the mechanisms regulating MHC expression in hESCs had not been explored. Methodology/Principal Findings We analyzed the expression levels of classical and non-classical MHC class-I, MHC class-II molecules, antigen-processing machinery (APM) components and NKG2D ligands (NKG2D-L) in hESCs, induced pluripotent stem cells (iPSCs) and NTera2 (NT2) teratocarcinoma cell line. Epigenetic mechanisms involved in the regulation of these genes were investigated by bisulfite sequencing and chromatin immunoprecipitation (ChIP) assays. We showed that low levels of MHC class-I molecules were associated with absent or reduced expression of the transporter associated with antigen processing 1 (TAP-1) and tapasin (TPN) components in hESCs and iPSCs, which are involved in the transport and load of peptides. Furthermore, lack of β2-microglobulin (β2m) light chain in these cells limited the expression of MHC class I trimeric molecule on the cell surface. NKG2D ligands (MICA, MICB) were observed in all pluripotent stem cells lines. Epigenetic analysis showed that H3K9me3 repressed the TPN gene in undifferentiated cells whilst HLA-B and β2m acquired the H3K4me3 modification during the differentiation to embryoid bodies (EBs). Absence of HLA-DR and HLA-G expression was regulated by DNA methylation. Conclusions/Significance Our data provide fundamental evidence for the epigenetic control of MHC in hESCs and iPSCs. Reduced MHC class I and class II expression in hESCs and iPSCs can limit their recognition by the immune response against these cells. The knowledge of these mechanisms will further allow the development of strategies to induce tolerance and improve stem cell allograft acceptance

Plant hormone signaling in flowering: An epigenetic point of view.

PubMed

Campos-Rivero, Gerardo; Osorio-Montalvo, Pedro; Sánchez-Borges, Rafael; Us-Camas, Rosa; Duarte-Aké, Fátima; De-la-Peña, Clelia

2017-07-01

Reproduction is one of the most important phases in an organism's lifecycle. In the case of angiosperm plants, flowering provides the major developmental transition from the vegetative to the reproductive stage, and requires genetic and epigenetic reprogramming to ensure the success of seed production. Flowering is regulated by a complex network of genes that integrate multiple environmental cues and endogenous signals so that flowering occurs at the right time; hormone regulation, signaling and homeostasis are very important in this process. Working alone or in combination, hormones are able to promote flowering by epigenetic regulation. Some plant hormones, such as gibberellins, jasmonic acid, abscisic acid and auxins, have important effects on chromatin compaction mediated by DNA methylation and histone posttranslational modifications, which hints at the role that epigenetic regulation may play in flowering through hormone action. miRNAs have been viewed as acting independently from DNA methylation and histone modification, ignoring their potential to interact with hormone signaling - including the signaling of auxins, gibberellins, ethylene, jasmonic acid, salicylic acid and others - to regulate flowering. Therefore, in this review we examine new findings about interactions between epigenetic mechanisms and key players in hormone signaling to coordinate flowering. Copyright © 2017 Elsevier GmbH. All rights reserved.

Concise Review: Geminin-A Tale of Two Tails: DNA Replication and Transcriptional/Epigenetic Regulation in Stem Cells.

PubMed

Patmanidi, Alexandra L; Champeris Tsaniras, Spyridon; Karamitros, Dimitris; Kyrousi, Christina; Lygerou, Zoi; Taraviras, Stavros

2017-02-01

Molecular mechanisms governing maintenance, commitment, and differentiation of stem cells are largely unexploited. Molecules involved in the regulation of multiple cellular processes are of particular importance for stem cell physiology, as they integrate different signals and coordinate cellular decisions related with self-renewal and fate determination. Geminin has emerged as a critical factor in DNA replication and stem cell differentiation in different stem cell populations. Its inhibitory interaction with Cdt1, a member of the prereplicative complex, ensures the controlled timing of DNA replication and, consequently, genomic stability in actively proliferating cells. In embryonic as well as somatic stem cells, Geminin has been shown to interact with transcription factors and epigenetic regulators to drive gene expression programs and ultimately guide cell fate decisions. An ever-growing number of studies suggests that these interactions of Geminin and proteins regulating transcription are conserved among metazoans. Interactions between Geminin and proteins modifying the epigenome, such as members of the repressive Polycomb group and the SWI/SNF proteins of the permissive Trithorax, have long been established. The complexity of these interactions, however, is only just beginning to unravel, revealing key roles on maintaining stem cell self-renewal and fate specification. In this review, we summarize current knowledge and give new perspectives for the role of Geminin on transcriptional and epigenetic regulation, alongside with its regulatory activity in DNA replication and their implication in the regulation of stem and progenitor cell biology. Stem Cells 2017;35:299-310. © 2016 AlphaMed Press.

Oxidative Stress and Epigenetic Regulation in Ageing and Age-Related Diseases

PubMed Central

Cencioni, Chiara; Spallotta, Francesco; Martelli, Fabio; Valente, Sergio; Mai, Antonello; Zeiher, Andreas M.; Gaetano, Carlo

2013-01-01

Recent statistics indicate that the human population is ageing rapidly. Healthy, but also diseased, elderly people are increasing. This trend is particularly evident in Western countries, where healthier living conditions and better cures are available. To understand the process leading to age-associated alterations is, therefore, of the highest relevance for the development of new treatments for age-associated diseases, such as cancer, diabetes, Alzheimer and cardiovascular accidents. Mechanistically, it is well accepted that the accumulation of intracellular damage determined by reactive oxygen species (ROS) might orchestrate the progressive loss of control over biological homeostasis and the functional impairment typical of aged tissues. Here, we review how epigenetics takes part in the control of stress stimuli and the mechanisms of ageing physiology and physiopathology. Alteration of epigenetic enzyme activity, histone modifications and DNA-methylation is, in fact, typically associated with the ageing process. Specifically, ageing presents peculiar epigenetic markers that, taken altogether, form the still ill-defined “ageing epigenome”. The comprehension of mechanisms and pathways leading to epigenetic modifications associated with ageing may help the development of anti-ageing therapies. PMID:23989608

Environmental perception and epigenetic memory: mechanistic insight through FLC

PubMed Central

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

Epigenetic Contributions to Cognitive Aging: Disentangling Mindspan and Lifespan

ERIC Educational Resources Information Center

Spiegel, Amy M.; Sewal, Angila S.; Rapp, Peter R.

2014-01-01

Epigenetic modifications of chromatin structure provide a mechanistic interface for gene-environment interactions that impact the individualization of health trajectories across the lifespan. A growing body of research indicates that dysfunctional epigenetic regulation contributes to poor cognitive outcomes among aged populations. Here we review…

Dictating genomic destiny: Epigenetic regulation of pancreatic neuroendocrine tumours.

PubMed

Gundara, Justin S; Jamal, Karim; Kurzawinski, Tom

2018-07-05

Pancreatic neuroendocrine tumours are a diverse group of neoplasms with an increasingly well-defined genomic basis. Despite this, much of what drives this disease is still unknown and epigenetic influences represent the next tier of gene, and hence disease modifiers that are of unquestionable importance. Moreover, they are of arguably more significance than the genes themselves given their malleable nature and potential to be exploited for not only diagnosis and prognosis, but also therapy. This review summarises what is known regarding the key epigenetic modifiers of disease through the domains of diagnosis, prognosis and treatment. Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.

Pharmacokinetics and Pharmacodynamics of Curcumin in regulating anti-inflammatory and epigenetic gene expression.

PubMed

Boyanapalli, Sarandeep S S; Huang, Ying; Su, Zhengyuan; Cheng, David; Zhang, Chengyue; Guo, Yue; Rao, Rohit; Androulakis, Ioannis P; Kong, Ah-Ng

2018-06-05

Chronic inflammation is a key driver of cancer development. Nitrite levels, which are regulated by inducible nitric oxide synthase (iNOS), play a critical role in inflammation. While the anti-oxidant and anti-inflammatory effects of curcumin, a natural product present in the roots of Curcuma longa have been widely studied, the acute pharmacokinetics (PK) and pharmacodynamics (PD) of curcumin in suppressing pro-inflammatory markers and epigenetic modulators remain unclear. In this study, we evaluated the PK and PD of curcumin-induced suppression of lipopolysaccharide (LPS)-mediated inflammation in rat lymphocytes. LPS was administered intravenously either alone or with curcumin to female Sprague-Dawley rats. Plasma samples were analyzed for curcumin concentration and mRNA expression was quantified in lymphocytes. Relative gene expression of several inflammatory and epigenetic modulators was analyzed. To investigate the relationship between curcumin concentration and iNOS, TNF-α, and IL-6 gene expression, PK/PD modeling using Jusko's indirect response model (IDR) integrating transit compartments (TC) describing the delayed response was conducted. The concentration-time profile of curcumin exhibited a bi-exponential decline, which was well described by a two-compartmental pharmacokinetic model. Importantly our results demonstrate that LPS induced gene expression of pro-inflammatory markers in lymphocytes, with peak expression at approximately 3 h and curcumin suppressed the gene expression in animals administered with LPS. These effects were well captured using the IDR model and an IDR model with the transit compartments. In summary, the PK/PD modeling approach could potentially provide a robust quantitative framework for evaluating the acute anti-inflammatory and epigenetic effects of curcumin in future clinical trials. This article is protected by copyright. All rights reserved.

Epigenomics and breast cancer

PubMed Central

Lo, Pang-Kuo

2009-01-01

Breast carcinogenesis involves genetic and epigenetic alterations that cause aberrant gene function. Recent progress in the knowledge of epigenomics has had a profound impact on the understanding of mechanisms leading to breast cancer, and consequently the development of new strategies for diagnosis and treatment of breast cancer. Epigenetic regulation has been known to involve three mutually interacting events – DNA methylation, histone modifications and nucleosomal remodeling. These processes modulate chromatin structure to form euchromatin or heterochromatin, and in turn activate or silence gene expression. Alteration in expression of key genes through aberrant epigenetic regulation in breast cells can lead to initiation, promotion and maintenance of carcinogenesis, and is even implicated in the generation of drug resistance. We currently review known roles of the epigenetic machinery in the development and recurrence of breast cancer. Furthermore, we highlight the significance of epigenetic alterations as predictive biomarkers and as new targets of anticancer therapy. PMID:19072646

DNA motifs associated with aberrant CpG island methylation.

PubMed

Feltus, F Alex; Lee, Eva K; Costello, Joseph F; Plass, Christoph; Vertino, Paula M

2006-05-01

Epigenetic silencing involving the aberrant methylation of promoter region CpG islands is widely recognized as a tumor suppressor silencing mechanism in cancer. However, the molecular pathways underlying aberrant DNA methylation remain elusive. Recently we showed that, on a genome-wide level, CpG island loci differ in their intrinsic susceptibility to aberrant methylation and that this susceptibility can be predicted based on underlying sequence context. These data suggest that there are sequence/structural features that contribute to the protection from or susceptibility to aberrant methylation. Here we use motif elicitation coupled with classification techniques to identify DNA sequence motifs that selectively define methylation-prone or methylation-resistant CpG islands. Motifs common to 28 methylation-prone or 47 methylation-resistant CpG island-containing genomic fragments were determined using the MEME and MAST algorithms (). The five most discriminatory motifs derived from methylation-prone sequences were found to be associated with CpG islands in general and were nonrandomly distributed throughout the genome. In contrast, the eight most discriminatory motifs derived from the methylation-resistant CpG islands were randomly distributed throughout the genome. Interestingly, this latter group tended to associate with Alu and other repetitive sequences. Used together, the frequency of occurrence of these motifs successfully discriminated methylation-prone and methylation-resistant CpG island groups with an accuracy of 87% after 10-fold cross-validation. The motifs identified here are candidate methylation-targeting or methylation-protection DNA sequences.

Epigenetics of cartilage diseases.

PubMed

Gabay, Odile; Clouse, Kathleen A

2016-10-01

Osteoarticular diseases, such as arthritis or osteoarthritis, are multifactorial diseases with an underlying genetic etiology that are challenging to study. Genome-Wide Association studies (GWAS) have identified several genetic loci associated with these diseases. Epigenetics is a complex mechanism of chromatin and gene modulation through DNA methylation, histone deacetylation or microRNA, which might contribute to the inheritability of disease. Some of these mechanisms have been studied for decades in other diseases or as part of the aging process, where epigenetic changes seem to play an important role. With the implementation of better technological tools, such as the Illumina next generation sequencing, altered methylation of DNA has been linked to articular diseases and these mechanisms have been shown to regulate metalloprotease (MMP) expression and cartilage matrix integrity. Some miRNA have also been identified and more extensively characterized, such as delineation of the role played by miR-140 in chondrogenesis, followed by the discovery of numerous miRNA potentially involved in the epigenetic regulation of osteoarthritic disease. Histone deacetylases have long been linked to aging, particularly with respect to the Sirtuin family with Sirt1 as the major player. Because aging is the major risk factor for osteoarthritis, the involvement of Sirtuins in the etiology of osteoarthritis has been suggested and investigated. All of these fine regulations together shed new light on cartilage disease pathophysiology. We present in this short review an update of the role of these pathways in articular diseases. Copyright © 2015 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.

Epigenetic regulation of BDNF gene transcription in the consolidation of fear memory.

PubMed

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.

New insights into the epigenetics of inflammatory rheumatic diseases.

PubMed

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.

The Role of Epigenetic Regulation in Epstein-Barr Virus-Associated Gastric Cancer

PubMed Central

Nishikawa, Jun; Iizasa, Hisashi; Nakamura, Munetaka; Saito, Mari; Sasaki, Sho; Shimokuri, Kanami; Yanagihara, Masashi; Sakai, Kouhei; Suehiro, Yutaka; Yamasaki, Takahiro; Sakaida, Isao

2017-01-01

The Epstein–Barr virus (EBV) is detected in about 10% of gastric carcinoma cases throughout the world. In EBV-associated gastric carcinoma (EBVaGC), all tumor cells harbor the clonal EBV genome. The expression of latent EBV genes is strictly regulated through the methylation of EBV DNA. The methylation of viral DNA regulates the type of EBV latency, and methylation of the tumor suppressor genes is a key abnormality in EBVaGC. The methylation frequencies of several tumor suppressor genes and cell adhesion molecules are significantly higher in EBVaGC than in control cases. EBV-derived microRNAs repress translation from viral and host mRNAs. EBV regulates the expression of non-coding RNA in gastric carcinoma. With regard to the clinical application of demethylating agents against EBVaGC, we investigated the effects of decitabine against the EBVaGC cell lines. Decitabine inhibited the cell growth of EBVaGC cells. The promoter regions of p73 and Runt-related transcription factor 3(RUNX3) were demethylated, and their expression was upregulated by the treatment. We review the role of epigenetic regulation in the development and maintenance of EBVaGC and discuss the therapeutic application of DNA demethylating agents for EBVaGC. PMID:28757548

The Role of Epigenetic Regulation in Epstein-Barr Virus-Associated Gastric Cancer.

PubMed

Nishikawa, Jun; Iizasa, Hisashi; Yoshiyama, Hironori; Nakamura, Munetaka; Saito, Mari; Sasaki, Sho; Shimokuri, Kanami; Yanagihara, Masashi; Sakai, Kouhei; Suehiro, Yutaka; Yamasaki, Takahiro; Sakaida, Isao

2017-07-25

The Epstein-Barr virus (EBV) is detected in about 10% of gastric carcinoma cases throughout the world. In EBV-associated gastric carcinoma (EBVaGC), all tumor cells harbor the clonal EBV genome. The expression of latent EBV genes is strictly regulated through the methylation of EBV DNA. The methylation of viral DNA regulates the type of EBV latency, and methylation of the tumor suppressor genes is a key abnormality in EBVaGC. The methylation frequencies of several tumor suppressor genes and cell adhesion molecules are significantly higher in EBVaGC than in control cases. EBV-derived microRNAs repress translation from viral and host mRNAs. EBV regulates the expression of non-coding RNA in gastric carcinoma. With regard to the clinical application of demethylating agents against EBVaGC, we investigated the effects of decitabine against the EBVaGC cell lines. Decitabine inhibited the cell growth of EBVaGC cells. The promoter regions of p73 and Runt-related transcription factor 3(RUNX3) were demethylated, and their expression was upregulated by the treatment. We review the role of epigenetic regulation in the development and maintenance of EBVaGC and discuss the therapeutic application of DNA demethylating agents for EBVaGC.

Local epigenetic reprograming induced by G-quadruplex ligands

PubMed Central

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

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.

Translational epigenetics: clinical approaches to epigenome therapeutics for cancer.

PubMed

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.

Epigenetic mechanisms: critical contributors to long-term memory formation.

PubMed

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.

Epigenetic Regulation of Inflammatory Gene Expression in Macrophages by Selenium

PubMed Central

Narayan, Vivek; Ravindra, Kodihalli C.; Liao, Chang; Kaushal, Naveen; Carlson, Bradley A.; Prabhu, K. Sandeep

2014-01-01

Acetylation of histone and non-histone proteins by histone acetyltransferases plays a pivotal role in the expression of pro-inflammatory genes. Given the importance of dietary selenium in mitigating inflammation, we hypothesized that selenium supplementation may regulate inflammatory gene expression at the epigenetic level. The effect of selenium towards histone acetylation was examined in both in vitro and in vivo models of inflammation by chromatin immunoprecipitation (ChIP) assays and immunoblotting. Our results indicated that selenium supplementation, as selenite, decreased acetylation of histone H4 at K12 and K16 in COX-2 and TNF promoters, and of the p65 subunit of the redox sensitive transcription factor NFκB in primary and immortalized macrophages. On the other hand, selenomethionine had a much weaker effect. Selenite treatment of HIV-1 infected human monocytes also significantly decreased the acetylation of H4 at K12 and K16 on the HIV-1 promoter, supporting the downregulation of proviral expression by selenium. A similar decrease in histone acetylation was also seen in the colonic extracts of mice treated with dextran sodium sulfate that correlated well with the levels of selenium in the diet. Bone marrow-derived macrophages from Trspfl/flCreLysM mice that lack expression of selenoproteins in macrophages confirmed the important role of selenoproteins in the inhibition of histone H4 acetylation. Our studies suggest that the ability of selenoproteins to skew the metabolism of arachidonic acid to contribute, in part, to their ability to inhibit histone acetylation. In summary, our studies suggest a new role for selenoproteins in the epigenetic modulation of pro-inflammatory genes. PMID:25458528

Interplay between H1 and HMGN epigenetically regulates OLIG1&2 expression and oligodendrocyte differentiation.

PubMed

Deng, Tao; Postnikov, Yuri; Zhang, Shaofei; Garrett, Lillian; Becker, Lore; Rácz, Ildikó; Hölter, Sabine M; Wurst, Wolfgang; Fuchs, Helmut; Gailus-Durner, Valerie; de Angelis, Martin Hrabe; Bustin, Michael

2017-04-07

An interplay between the nucleosome binding proteins H1 and HMGN is known to affect chromatin dynamics, but the biological significance of this interplay is still not clear. We find that during embryonic stem cell differentiation loss of HMGNs leads to down regulation of genes involved in neural differentiation, and that the transcription factor OLIG2 is a central node in the affected pathway. Loss of HMGNs affects the expression of OLIG2 as well as that of OLIG1, two transcription factors that are crucial for oligodendrocyte lineage specification and nerve myelination. Loss of HMGNs increases the chromatin binding of histone H1, thereby recruiting the histone methyltransferase EZH2 and elevating H3K27me3 levels, thus conferring a repressive epigenetic signature at Olig1&2 sites. Embryonic stem cells lacking HMGNs show reduced ability to differentiate towards the oligodendrocyte lineage, and mice lacking HMGNs show reduced oligodendrocyte count and decreased spinal cord myelination, and display related neurological phenotypes. Thus, the presence of HMGN proteins is required for proper expression of neural differentiation genes during embryonic stem cell differentiation. Specifically, we demonstrate that the dynamic interplay between HMGNs and H1 in chromatin epigenetically regulates the expression of OLIG1&2, thereby affecting oligodendrocyte development and myelination, and mouse behavior. Published by Oxford University Press on behalf of Nucleic Acids Research 2016.

Interplay between H1 and HMGN epigenetically regulates OLIG1&2 expression and oligodendrocyte differentiation

PubMed Central

Deng, Tao; Postnikov, Yuri; Zhang, Shaofei; Garrett, Lillian; Becker, Lore; Rácz, Ildikó; Hölter, Sabine M.; Wurst, Wolfgang; Fuchs, Helmut; Gailus-Durner, Valerie; de Angelis, Martin Hrabe

2017-01-01

Abstract An interplay between the nucleosome binding proteins H1 and HMGN is known to affect chromatin dynamics, but the biological significance of this interplay is still not clear. We find that during embryonic stem cell differentiation loss of HMGNs leads to down regulation of genes involved in neural differentiation, and that the transcription factor OLIG2 is a central node in the affected pathway. Loss of HMGNs affects the expression of OLIG2 as well as that of OLIG1, two transcription factors that are crucial for oligodendrocyte lineage specification and nerve myelination. Loss of HMGNs increases the chromatin binding of histone H1, thereby recruiting the histone methyltransferase EZH2 and elevating H3K27me3 levels, thus conferring a repressive epigenetic signature at Olig1&2 sites. Embryonic stem cells lacking HMGNs show reduced ability to differentiate towards the oligodendrocyte lineage, and mice lacking HMGNs show reduced oligodendrocyte count and decreased spinal cord myelination, and display related neurological phenotypes. Thus, the presence of HMGN proteins is required for proper expression of neural differentiation genes during embryonic stem cell differentiation. Specifically, we demonstrate that the dynamic interplay between HMGNs and H1 in chromatin epigenetically regulates the expression of OLIG1&2, thereby affecting oligodendrocyte development and myelination, and mouse behavior. PMID:27923998

Epigenetic Effects of Environmental Chemicals Bisphenol A and Phthalates

PubMed Central

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

Epigenetic effects of environmental chemicals bisphenol A and phthalates.

PubMed

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

Potential Role of Epigenetic Mechanism in Manganese Induced Neurotoxicity

PubMed Central

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

Epigenetics: Making your mark on DNA

NASA Astrophysics Data System (ADS)

Harada, Bryan T.; He, Chuan

2017-11-01

Understanding the biological roles of modifications to DNA, RNA and proteins is critical to revealing how cells regulate gene expression in development and disease. Two papers now present a combination of new tools and discoveries that could enable biologists and chemical biologists to better study epigenetic regulation in mammals.

Epigenetics application in the diagnosis and treatment of bladder cancer.

PubMed

Harb-de la Rosa, Alfredo; Acker, Matthew; Kumar, Raj A; Manoharan, Murugesan

2015-10-01

Bladder cancer is the sixth most common cancer in the Western world. Patients with bladder cancer require close monitoring, which may include frequent cystoscopy and urine cytology. Such monitoring results in significant health care cost. The application of epigenetics may allow for a risk adapted approach and more cost-effective method of monitoring. A number of epigenetic changes have been described for many cancer sites, including the urinary bladder. In this review, we discuss the use of epigenetics in bladder cancer and the potential diagnostic and therapeutic applications. A comprehensive search of the English medical literature was conducted in PubMed using the terms microRNA regulation, DNA methylation, histone modification and bladder cancer. The most important epigenetic changes include DNA methylation, histone modification and microRNA regulation. Both DNA hypomethylation and hypermethylation have been associated with higher rate of cancer. The association of epigenetic changes with bladder cancer has led to the research of its diagnostic and prognostic implications as well as to the development of novel drugs to target these changes with the aim of achieving a survival benefit. Recently, epigenetics has been shown to play a much greater role than previously anticipated in the initiation and propagation of many tumors. The use of epigenetics for the diagnosis and treatment of bladder cancer is an evolving and promising field. The possibility of reversing epigenetic changes may facilitate additional cancer treatment options in the future.

Epigenetics of sex determination and gonadogenesis.

PubMed

Piferrer, Francesc

2013-04-01

Epigenetics is commonly defined as the study of heritable changes in gene function that cannot be explained by changes in DNA sequence. The three major epigenetic mechanisms for gene expression regulation include DNA methylation, histone modifications, and non-coding RNAs. Epigenetic mechanisms provide organisms with the ability to integrate genomic and environmental information to modify the activity of their genes for generating a particular phenotype. During development, cells differentiate, acquire, and maintain identity through changes in gene expression. This is crucial for sex determination and differentiation, which are among the most important developmental processes for the proper functioning and perpetuation of species. This review summarizes studies showing how epigenetic regulatory mechanisms contribute to sex determination and reproductive organ formation in plants, invertebrates, and vertebrates. Further progress will be made by integrating several approaches, including genomics and Next Generation Sequencing to create epigenetic maps related to different aspects of sex determination and gonadogenesis. Epigenetics will also contribute to understand the etiology of several disorders of sexual development. It also might play a significant role in the control of reproduction in animal farm production and will aid in recognizing the environmental versus genetic influences on sex determination of sensitive species in a global change scenario. Copyright © 2013 Wiley Periodicals, Inc.

Epigenetic regulation of MdMYB1 is associated with paper bagging-induced red pigmentation of apples.

PubMed

Bai, Songling; Tuan, Pham Anh; Saito, Takanori; Honda, Chikako; Hatsuyama, Yoshimichi; Ito, Akiko; Moriguchi, Takaya

2016-09-01

Paper-bagging treatment can transform non-transcribed MdMYB1 - 2 and MdMYB1 - 3 alleles into transcribed alleles through epigenetic regulations, resulting in the red pigmentation of a normally non-red apple cultivar 'Mutsu.' Anthocyanin biosynthesis in apples is regulated by MdMYB1/A/10, an R2R3-Type MYB gene. 'Mutsu,' a triploid apple cultivar harboring non-transcribed MdMYB1-2 and MdMYB1-3 alleles, retains green skin color under field conditions. However, it can show red/pink pigmentation under natural or artificial ultraviolet-B (UV-B) light exposure after paper-bagging and bag removal treatment. In the present study, we found that in 'Mutsu,' paper bagging-induced red pigmentation was due to the activation of non-transcribed MdMYB1-2/-3 alleles, which triggered the expression of downstream anthocyanin biosynthesis genes in a UV-B-dependent manner. By monitoring the epigenetic changes during UV-B-induced pigmentation, no significant differences in DNA methylation and histone modifications in the 5' upstream region of MdMYB1-2/-3 were recorded between the UV-B-treated fruit skin (red) and the fruit skin treated only by white light (green). In contrast, bag treatment lowered the DNA methylation in this region of MdMYB1-2/-3 alleles. Similarly, higher levels of histone H3 acetylation and trimethylation of H3 tail at lysine 4, and lower level of trimethylation of H3 tail at lysine 27 were observed in the 5' upstream region of MdMYB1-2/-3 in the skin of the fruit immediately after bag removal. These results suggest that bagging treatment can induce epigenetic changes, facilitating the binding of trans factor(s) to MdMYB1-2/-3 alleles, resulting in the activation of these MYBs after bag removal.

Epigenetics: The origins and evolution of a fashionable topic.

PubMed

Deichmann, Ute

2016-08-01

The term "epigenetics" was introduced in 1942 by embryologist Conrad Waddington, who, relating it to the 17th century concept of "epigenesis", defined it as the complex of developmental processes between the genotype and phenotype. While in the years that followed, these processes - in particular gene regulation - were tackled, not in the frame of epigenetics but of genetics, research labelled "epigenetics" rose strongly only in the 21st century. Then it consisted of research on chromatin modifications, i.e. chemical modifications of DNA or histone proteins around DNA that do not change the base sequence. This rise was accompanied by far-reaching claims, such as that epigenetics provides a mechanism for "Lamarckian" inheritance. This article highlights the origin of epigenetics, the major phases of epigenetic research, and the changes in the meaning of the term. It also calls into question some of the far-reaching claims that have accompanied the recent rise of epigenetics. Copyright © 2016 Elsevier Inc. All rights reserved.

Extinction of aversive memories associated with morphine withdrawal requires ERK-mediated epigenetic regulation of brain-derived neurotrophic factor transcription in the rat ventromedial prefrontal cortex.

PubMed

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.

Epigenetics and environmental exposures.

PubMed

Stein, Richard A

2012-01-01

It is becoming increasingly apparent that genetic factors are inadequate to fully explain many processes that shape development and disease. For example, monozygotic twin pairs, despite sharing identical DNA sequences, are often discordant for many traits and diseases, indicating that the same genotype can give rise to distinct phenotypes. This points towards the involvement of additional factors that cannot be explained solely by the sequence of the genome. Epigenetic modifications, defined as heritable changes that do not alter the nucleotide sequence, emerge as key factors that regulate chromatin structure and gene expression and, together with genetic factors, provide the mechanistic basis to understand the biological effects of various classes of environmental exposures. Epigenetic mechanisms explain the ability of certain chemical compounds to initiate biological perturbations that can lead to malignancy, despite being weak mutagens or lacking mutagenic activity altogether-a view that challenges old beliefs and opens new avenues in public health. The field of epigenetics also explains the causal link between certain infectious diseases and cancer, a relationship that was first observed over a century ago and was initially discounted, then fell into oblivion and more recently re-emerged as an important concept in biology. A key feature that distinguishes epigenetic modifications from genetic changes is their reversible nature. This provides exciting prophylactic and therapeutic perspectives, some of which already materialised with the approval of the first drugs that modulate the epigenetic machinery, reinforcing the idea that our genes are not our destiny.

Epigenetic understanding of gene-environment interactions in psychiatric disorders: a new concept of clinical genetics

PubMed Central

2012-01-01

Epigenetics is a mechanism that regulates gene expression independently of the underlying DNA sequence, relying instead on the chemical modification of DNA and histone proteins. Although environmental and genetic factors were thought to be independently associated with disorders, several recent lines of evidence suggest that epigenetics bridges these two factors. Epigenetic gene regulation is essential for normal development, thus defects in epigenetics cause various rare congenital diseases. Because epigenetics is a reversible system that can be affected by various environmental factors, such as drugs, nutrition, and mental stress, the epigenetic disorders also include common diseases induced by environmental factors. In this review, we discuss the nature of epigenetic disorders, particularly psychiatric disorders, on the basis of recent findings: 1) susceptibility of the conditions to environmental factors, 2) treatment by taking advantage of their reversible nature, and 3) transgenerational inheritance of epigenetic changes, that is, acquired adaptive epigenetic changes that are passed on to offspring. These recently discovered aspects of epigenetics provide a new concept of clinical genetics. PMID:22414323

[Genetic and epigenetic news in gerontology].

PubMed

Baranov, V S; Glotov, O S; Baranova, E V

2014-01-01

The overview represents the recent most conspicuous findings in aging studies. It includes new data on the whole genome association studies (GWAS) in big cohort of centenaries, recently found mutation protecting from Alzheimer disease, discovery of hypothalamus as a command center of human aging, very important data on the negative effect of common antioxidants in the treatment of lung cancer as well as new data concerning antiaging and anticancer effects of common drugs such as rapamycine and metformin. Substantial part of the review is devoted to the epigenetic problems of senescence and feasible impact of basic epigenetic mechanisms (methylation of DNA and histone proteins, DNA heterochromatization) in regulation of gene expression, long-term genome reprogramming during early childhood, and transgeneration transmission of epigenetic traits. The necessity of transition from molecular studies of dormant human genome (anatomy of human genome) to genome in action (dynamic genome) and thus with special emphasis to epigenetic medicine is stressed.

Cancer Chemoprevention by Traditional Chinese Herbal Medicine and Dietary Phytochemicals: Targeting Nrf2-Mediated Oxidative Stress/Anti-Inflammatory Responses, Epigenetics, and Cancer Stem Cells

PubMed Central

Hun Lee, Jong; Shu, Limin; Fuentes, Francisco; Su, Zheng-Yuan; Tony Kong, Ah-Ng

2013-01-01

Excessive oxidative stress induced by reactive oxygen species (ROS), reactive nitrogen species (RNS), and reactive metabolites of carcinogens alters cellular homeostasis, leading to genetic/epigenetic changes, genomic instability, neoplastic transformation, and cancer initiation/progression. As a protective mechanism against oxidative stress, antioxidant/detoxifying enzymes reduce these reactive species and protect normal cells from endo-/exogenous oxidative damage. The transcription factor nuclear factor-erythroid 2 p45 (NF-E2)-related factor 2 (Nrf2), a master regulator of the antioxidative stress response, plays a critical role in the expression of many cytoprotective enzymes, including NAD(P)H:quinine oxidoreductase (NQO1), heme oxygenase-1 (HO-1), UDP-glucuronosyltransferase (UGT), and glutathione S-transferase (GST). Recent studies demonstrated that many dietary phytochemicals derived from various vegetables, fruits, spices, and herbal medicines induce Nrf2-mediated antioxidant/detoxifying enzymes, restore aberrant epigenetic alterations, and eliminate cancer stem cells (CSCs). The Nrf2-mediated antioxidant response prevents many age-related diseases, including cancer. Owing to their fundamental contribution to carcinogenesis, epigenetic modifications and CSCs are novel targets of dietary phytochemicals and traditional Chinese herbal medicine (TCHM). In this review, we summarize cancer chemoprevention by dietary phytochemicals, including TCHM, which have great potential as a safer and more effective strategy for preventing cancer. PMID:24716158

Cancer chemoprevention by traditional chinese herbal medicine and dietary phytochemicals: targeting nrf2-mediated oxidative stress/anti-inflammatory responses, epigenetics, and cancer stem cells.

PubMed

Hun Lee, Jong; Shu, Limin; Fuentes, Francisco; Su, Zheng-Yuan; Tony Kong, Ah-Ng

2013-01-01

Excessive oxidative stress induced by reactive oxygen species (ROS), reactive nitrogen species (RNS), and reactive metabolites of carcinogens alters cellular homeostasis, leading to genetic/epigenetic changes, genomic instability, neoplastic transformation, and cancer initiation/progression. As a protective mechanism against oxidative stress, antioxidant/detoxifying enzymes reduce these reactive species and protect normal cells from endo-/exogenous oxidative damage. The transcription factor nuclear factor-erythroid 2 p45 (NF-E2)-related factor 2 (Nrf2), a master regulator of the antioxidative stress response, plays a critical role in the expression of many cytoprotective enzymes, including quinine oxidoreductase (NQO1), heme oxygenase-1 (HO-1), UDP-glucuronosyltransferase (UGT), and glutathione S-transferase (GST). Recent studies demonstrated that many dietary phytochemicals derived from various vegetables, fruits, spices, and herbal medicines induce Nrf2-mediated antioxidant/detoxifying enzymes, restore aberrant epigenetic alterations, and eliminate cancer stem cells (CSCs). The Nrf2-mediated antioxidant response prevents many age-related diseases, including cancer. Owing to their fundamental contribution to carcinogenesis, epigenetic modifications and CSCs are novel targets of dietary phytochemicals and traditional Chinese herbal medicine (TCHM). In this review, we summarize cancer chemoprevention by dietary phytochemicals, including TCHM, which have great potential as a safer and more effective strategy for preventing cancer.

The Epigenetics of Adult (Somatic) Stem Cells

PubMed Central

Eilertsen, Kenneth J.; Floyd, Z. Elizabeth; Gimble, Jeffrey M.

2009-01-01

While genetic studies have provided a wealth of information about health and disease, there is a growing awareness that individual characteristics are also determined by factors other than genetic sequences. These “epigenetic” changes broadly encompass the influence of the environment on gene regulation and expression and in a more narrow sense, describe the mechanisms controlling DNA methylation, histone modification and genetic imprinting. In this review, we focus on the epigenetic mechanisms that regulate adult (somatic) stem cell differentiation, beginning with the metabolic pathways and factors regulating chromatin structure and DNA methylation and the molecular biological tools that are currently available to study these processes. The role of these epigenetic mechanisms in manipulating adult stem cells is followed by a discussion of the challenges and opportunities facing this emerging field. PMID:18540823

Genetics and epigenetics of aging and longevity

PubMed Central

Moskalev, Alexey A; Aliper, Alexander M; Smit-McBride, Zeljka; Buzdin, Anton; Zhavoronkov, Alex

2014-01-01

Evolutionary theories of aging predict the existence of certain genes that provide selective advantage early in life with adverse effect on lifespan later in life (antagonistic pleiotropy theory) or longevity insurance genes (disposable soma theory). Indeed, the study of human and animal genetics is gradually identifying new genes that increase lifespan when overexpressed or mutated: gerontogenes. Furthermore, genetic and epigenetic mechanisms are being identified that have a positive effect on longevity. The gerontogenes are classified as lifespan regulators, mediators, effectors, housekeeping genes, genes involved in mitochondrial function, and genes regulating cellular senescence and apoptosis. In this review we demonstrate that the majority of the genes as well as genetic and epigenetic mechanisms that are involved in regulation of longevity are highly interconnected and related to stress response. PMID:24603410

Epigenetics, microbiota, and intraocular inflammation: New paradigms of immune regulation in the eye.

PubMed

Wen, Xiaofeng; Hu, Xiao; Miao, Li; Ge, Xiaofei; Deng, Yuhua; Bible, Paul W; Wei, Lai

2018-05-01

Sight threatening immune responses that damage the eye characterize intraocular inflammatory diseases. These diseases including uveitis and age-related macular degeneration are worryingly common and quality of life shattering. Genetic studies in past decades significantly advanced our understanding of the etiology of these devastating diseases. Unfortunately, patient genetics alone failed to adequately explain disease origin, susceptibility, and progression. Non-genetic factors such as the epigenetic regulation of ocular diseases and the environmental factors triggering intraocular inflammation offer new insight into intraocular inflammatory disorders. Importantly, mounting evidence is signaling that dysbiosis of human microbiota leads to rapid epigenomic reprograming of host cells and results in the onset of many diseases. In this review, we discuss how epigenetic mechanisms and microbiota may cooperate to initiate and perpetuate ocular inflammation. Lastly, we propose that the discovery of intraocular microbiota presents a significant shift in thought affecting current approaches to the diagnosis, treatment, and prevention of intraocular inflammatory diseases such as uveitis and age-related macular degeneration. The geographical and genetic background difference in both disease presentation and genetic association of intraocular inflammatory diseases may be due to the variation of intraocular microbiota. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

Polycyclic aromatic hydrocarbons, tobacco smoke, and epigenetic remodeling in asthma

PubMed Central

Klingbeil, E. C.; Hew, K. M.; Nygaard, U. C.; Nadeau, K. C.

2014-01-01

Environmental determinants including aerosolized pollutants such as polycyclic aromatic hydrocarbons (PAHs) and tobacco smoke have been associated with exacerbation and increased incidence of asthma. The influence of aerosolized pollutants on the development of immune dysfunction in asthmatics has been suggested to be mediated through epigenetic remodeling. Genome accessibility and transcription are regulated primarily through DNA methylation, histone modification, and microRNA transcript silencing. Epigenetic remodeling has been shown in studies to be associated with Th2 polarization and associated cytokine and chemokine regulation in the development of asthma. This review will present evidence for the contribution of the aerosolized pollutants PAH and environmental tobacco smoke to epigenetic remodeling in asthma. PMID:24760221

Epigenetic game theory: How to compute the epigenetic control of maternal-to-zygotic transition

NASA Astrophysics Data System (ADS)

Wang, Qian; Gosik, Kirk; Xing, Sujuan; Jiang, Libo; Sun, Lidan; Chinchilli, Vernon M.; Wu, Rongling

2017-03-01

Epigenetic reprogramming is thought to play a critical role in maintaining the normal development of embryos. How the methylation state of paternal and maternal genomes regulates embryogenesis depends on the interaction and coordination of the gametes of two sexes. While there is abundant research in exploring the epigenetic interactions of sperms and oocytes, a knowledge gap exists in the mechanistic quantitation of these interactions and their impact on embryo development. This review aims at formulating a modeling framework to address this gap through the integration and synthesis of evolutionary game theory and the latest discoveries of the epigenetic control of embryo development by next-generation sequencing. This framework, named epigenetic game theory or epiGame, views embryogenesis as an ecological system in which two highly distinct and specialized gametes coordinate through either cooperation or competition, or both, to maximize the fitness of embryos under Darwinian selection. By implementing a system of ordinary differential equations, epiGame quantifies the pattern and relative magnitude of the methylation effects on embryogenesis by the mechanisms of cooperation and competition. epiGame may gain new insight into reproductive biology and can be potentially applied to design personalized medicines for genetic disorder intervention.

Impact of physical activity and doping on epigenetic gene regulation.

PubMed

Schwarzenbach, Heidi

2011-10-01

To achieve success in sports, many athletes consume doping substances, such as anabolic androgenic steroids and growth hormones, and ignore the negative influence of these drugs on their health. Apart from the unethical aspect of doping in sports, it is essential to consider the tremendous risk it represents to their physical condition. The abuse of pharmaceuticals which improve athletic performance may alter the expression of specific genes involved in muscle and bone metabolism by epigenetic mechanisms, such as DNA methylation and histone modifications. Moreover, excessive and relentless training to increase the muscle mass, may also have an influence on the health of the athletes. This stress releases neurotransmitters and growth factors, and may affect the expression of endogenous genes by DNA methylation, too. This paper focuses on the relationship between epigenetic mechanisms and sports, highlights the potential consequences of abuse of doping drugs on gene expression, and describes methods to molecularly detect epigenetic changes of gene markers reflecting the physiological or metabolic effects of doping agents. Copyright © 2011 John Wiley & Sons, Ltd.

An assessment of molecular pathways of obesity susceptible to nutrient, toxicant and genetically induced epigenetic perturbation

PubMed Central

Xue, Jing; Ideraabdullah, Folami Y.

2015-01-01

In recent years, the etiology of human disease has greatly improved with the inclusion of epigenetic mechanisms, in particular as a common link between environment and disease. However, for most diseases we lack a detailed interpretation of the epigenetic regulatory pathways perturbed by environment and causal mechanisms. Here, we focus on recent findings elucidating nutrient-related epigenetic changes linked to obesity. We highlight studies demonstrating that obesity is a complex disease linked to disruption of epigenetically regulated metabolic pathways in the brain, adipose tissue and liver. These pathways regulate (1) homeostatic and hedonic eating behaviors (2) adipocyte differentiation and fat accumulation, and (3) energy expenditure. By compiling these data we illustrate that obesity-related phenotypes are repeatedly linked to disruption of critical epigenetic mechanisms that regulate of key metabolic genes. These data are supported by genetic mutation of key epigenetic regulators and many of the diet induced epigenetic mechanisms of obesity are also perturbed by exposure to environmental toxicants. Identifying similarly perturbed epigenetic mechanisms in multiple experimental models of obesity strengthens the translational applications of these findings. We also discuss many of the ongoing challenges to understanding the role of environmentally-induced epigenetic pathways in obesity and suggest future studies to elucidate these roles. This assessment illustrates our current understanding of molecular pathways of obesity that are susceptible to environmental perturbation via epigenetic mechanisms. Thus, it lays the groundwork for dissecting the complex interactions between diet, genes, and toxicants that contribute to obesity and obesity-related phenotypes. PMID:27012616

Epigenetic Alterations in Human Papillomavirus-Associated Cancers

PubMed Central

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

Hotspots of aberrant enhancer activity punctuate the colorectal cancer epigenome

PubMed Central

Cohen, Andrea J.; Saiakhova, Alina; Corradin, Olivia; Luppino, Jennifer M.; Lovrenert, Katreya; Bartels, Cynthia F.; Morrow, James J.; Mack, Stephen C.; Dhillon, Gursimran; Beard, Lydia; Myeroff, Lois; Kalady, Matthew F.; Willis, Joseph; Bradner, James E.; Keri, Ruth A.; Berger, Nathan A.; Pruett-Miller, Shondra M.; Markowitz, Sanford D.; Scacheri, Peter C.

2017-01-01

In addition to mutations in genes, aberrant enhancer element activity at non-coding regions of the genome is a key driver of tumorigenesis. Here, we perform epigenomic enhancer profiling of a cohort of more than forty genetically diverse human colorectal cancer (CRC) specimens. Using normal colonic crypt epithelium as a comparator, we identify enhancers with recurrently gained or lost activity across CRC specimens. Of the enhancers highly recurrently activated in CRC, most are constituents of super enhancers, are occupied by AP-1 and cohesin complex members, and originate from primed chromatin. Many activate known oncogenes, and CRC growth can be mitigated through pharmacologic inhibition or genome editing of these loci. Nearly half of all GWAS CRC risk loci co-localize to recurrently activated enhancers. These findings indicate that the CRC epigenome is defined by highly recurrent epigenetic alterations at enhancers which activate a common, aberrant transcriptional programme critical for CRC growth and survival. PMID:28169291

Epigenetics: relevance and implications for public health.

PubMed

Rozek, Laura S; Dolinoy, Dana C; Sartor, Maureen A; Omenn, Gilbert S

2014-01-01

Improved understanding of the multilayer regulation of the human genome has led to a greater appreciation of environmental, nutritional, and epigenetic risk factors for human disease. Chromatin remodeling, histone tail modifications, and DNA methylation are dynamic epigenetic changes responsive to external stimuli. Careful interpretation can provide insights for actionable public health through collaboration between population and basic scientists and through integration of multiple data sources. We review key findings in environmental epigenetics both in human population studies and in animal models, and discuss the implications of these results for risk assessment and public health protection. To ultimately succeed in identifying epigenetic mechanisms leading to complex phenotypes and disease, researchers must integrate the various animal models, human clinical approaches, and human population approaches while paying attention to life-stage sensitivity, to generate effective prescriptions for human health evaluation and disease prevention.

Epigenetic Mechanisms in Learned Fear: Implications for PTSD

PubMed Central

Zovkic, Iva B; Sweatt, J David

2013-01-01

One of the most exciting discoveries in the learning and memory field in the past two decades is the observation that active regulation of gene expression is necessary for experience to trigger lasting functional and behavioral change, in a wide variety of species, including humans. Thus, as opposed to the traditional view of ‘nature' (genes) being separate from ‘nurture' (environment and experience), it is now clear that experience actively drives alterations in central nervous system (CNS) gene expression in an ongoing fashion, and that the resulting transcriptional changes are necessary for experience to trigger altered long-term behavior. In parallel over the past decade, epigenetic mechanisms, including regulation of chromatin structure and DNA methylation, have been shown to be potent regulators of gene transcription in the CNS. In this review, we describe data supporting the hypothesis that epigenetic molecular mechanisms, especially DNA methylation and demethylation, drive long-term behavioral change through active regulation of gene transcription in the CNS. Specifically, we propose that epigenetic molecular mechanisms underlie the formation and stabilization of context- and cue-triggered fear conditioning based in the hippocampus and amygdala, a conclusion reached in a wide variety of studies using laboratory animals. Given the relevance of cued and contextual fear conditioning to post-traumatic stress, by extension we propose that these mechanisms may contribute to post-traumatic stress disorder (PTSD) in humans. Moreover, we speculate that epigenetically based pharmacotherapy may provide a new avenue of drug treatment for PTSD-related cognitive and behavioral function. PMID:22692566

An in silico pipeline to filter the Toxoplasma gondii proteome for proteins that could traffic to the host cell nucleus and influence host cell epigenetic regulation.

PubMed

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.

Epigenetic alterations induced by genotoxic occupational and environmental human chemical carcinogens: A systematic literature review

PubMed Central

Chappell, Grace; Pogribny, Igor P.; Guyton, Kathryn Z.; Rusyn, Ivan

2016-01-01

Accumulating evidence suggests that epigenetic alterations play an important role in chemically-induced carcinogenesis. Although the epigenome and genome may be equally important in carcinogenicity, the genotoxicity of chemical agents and exposure-related transcriptomic responses have been more thoroughly studied and characterized. To better understand the evidence for epigenetic alterations of human carcinogens, and the potential association with genotoxic endpoints, we conducted a systematic review of published studies of genotoxic carcinogens that reported epigenetic endpoints. Specifically, we searched for publications reporting epigenetic effects for the 28 agents and occupations included in Monograph Volume 100F of the International Agency for the Research on Cancer (IARC) that were classified as “carcinogenic to humans” (Group 1) with strong evidence of genotoxic mechanisms of carcinogenesis. We identified a total of 158 studies that evaluated epigenetic alterations for 12 of these 28 carcinogenic agents and occupations (1,3-butadiene, 4-aminobiphenyl, aflatoxins, benzene, benzidine, benzo[a]pyrene, coke production, formaldehyde, occupational exposure as a painter, sulfur mustard, and vinyl chloride). Aberrant DNA methylation was most commonly studied, followed by altered expression of non-coding RNAs and histone changes (totaling 85, 59 and 25 studies, respectively). For 3 carcinogens (aflatoxins, benzene and benzo[a]pyrene), 10 or more studies reported epigenetic effects. However, epigenetic studies were sparse for the remaining 9 carcinogens; for 4 agents, only 1 or 2 published reports were identified. While further research is needed to better identify carcinogenesis-associated epigenetic perturbations for many potential carcinogens, published reports on specific epigenetic endpoints can be systematically identified and increasingly incorporated in cancer hazard assessments. PMID:27234561

Epigenetic alterations induced by genotoxic occupational and environmental human chemical carcinogens: A systematic literature review.

PubMed

Chappell, Grace; Pogribny, Igor P; Guyton, Kathryn Z; Rusyn, Ivan

2016-01-01

Accumulating evidence suggests that epigenetic alterations play an important role in chemically-induced carcinogenesis. Although the epigenome and genome may be equally important in carcinogenicity, the genotoxicity of chemical agents and exposure-related transcriptomic responses have been more thoroughly studied and characterized. To better understand the evidence for epigenetic alterations of human carcinogens, and the potential association with genotoxic endpoints, we conducted a systematic review of published studies of genotoxic carcinogens that reported epigenetic endpoints. Specifically, we searched for publications reporting epigenetic effects for the 28 agents and occupations included in Monograph Volume 100F of the International Agency for the Research on Cancer (IARC) that were classified as "carcinogenic to humans" (Group 1) with strong evidence of genotoxic mechanisms of carcinogenesis. We identified a total of 158 studies that evaluated epigenetic alterations for 12 of these 28 carcinogenic agents and occupations (1,3-butadiene, 4-aminobiphenyl, aflatoxins, benzene, benzidine, benzo[a]pyrene, coke production, formaldehyde, occupational exposure as a painter, sulfur mustard, and vinyl chloride). Aberrant DNA methylation was most commonly studied, followed by altered expression of non-coding RNAs and histone changes (totaling 85, 59 and 25 studies, respectively). For 3 carcinogens (aflatoxins, benzene and benzo[a]pyrene), 10 or more studies reported epigenetic effects. However, epigenetic studies were sparse for the remaining 9 carcinogens; for 4 agents, only 1 or 2 published reports were identified. While further research is needed to better identify carcinogenesis-associated epigenetic perturbations for many potential carcinogens, published reports on specific epigenetic endpoints can be systematically identified and increasingly incorporated in cancer hazard assessments. Copyright © 2016 Elsevier B.V. All rights reserved.

AIM1 and LINE-1 Epigenetic Aberrations In Tumor and Serum Relate to Melanoma Progression and Disease Outcome

PubMed Central

Hoshimoto, Sojun; Kuo, Christine; Chong, Kelly; Takeshima, Ling; Takei, Yoshiki; Li, Michelle; Huang, Sharon; Sim, Myung-Shin; Morton, Donald L.; Hoon, Dave S.B.

2012-01-01

Aberrations in the methylation status of non-coding genomic repeat DNA sequences and specific gene promoter region are important epigenetic events in melanoma progression. Promoter methylation status in LINE-1 and Absent in melanoma-1(AIM1;6q21) associated with melanoma progression and disease outcome was assessed. LINE-1 and AIM1 methylation status was assessed in paraffin-embedded archival tissues(PEAT)(n=133) and melanoma patients’ serum(n=56). LINE-1 U-Index(hypomethylation) and AIM1 were analyzed in microdissected melanoma PEAT sections. The LINE-1 U-Index of melanoma(n=100) was significantly higher than that of normal skin(n=14) and nevi(n=12)(P=0.0004). LINE-1 U-Index level was elevated with increasing AJCC stage(P<0.0001). AIM1 promoter hypermethylation was found in higher frequency(P=0.005) in metastatic melanoma(65%) than in primary melanomas(38%). When analyzed, high LINE-1 U-Index and/or AIM1 methylation in melanomas were associated with disease-free survival(DFS) and overall survival(OS) in Stage I/II patients (P=0.017, 0.027; respectively). In multivariate analysis, melanoma AIM1 methylation status was a significant prognostic factor of OS(P=0.032). Furthermore, serum unmethylated LINE-1 was at higher levels in both stage III(n=20) and stage IV(n=36) patients compared to healthy donors(n=14)(P=0.022). Circulating methylated AIM1 was detected in patients’ serum and was predictive of OS in Stage IV patients (P=0.009). LINE-1 hypomethylation and AIM1 hypermethylation have prognostic utility in both melanoma patients’ tumors and serum. PMID:22402438

Krebs cycle dysfunction shapes epigenetic landscape of chromatin: novel insights into mitochondrial regulation of aging process.

PubMed

Salminen, Antero; Kaarniranta, Kai; Hiltunen, Mikko; Kauppinen, Anu

2014-07-01

Although there is a substantial literature that mitochondria have a crucial role in the aging process, the mechanism has remained elusive. The role of reactive oxygen species, mitochondrial DNA injuries, and a decline in mitochondrial quality control has been proposed. Emerging studies have demonstrated that Krebs cycle intermediates, 2-oxoglutarate (also known as α-ketoglutarate), succinate and fumarate, can regulate the level of DNA and histone methylation. Moreover, citrate, also a Krebs cycle metabolite, can enhance histone acetylation. Genome-wide screening studies have revealed that the aging process is linked to significant epigenetic changes in the chromatin landscape, e.g. global demethylation of DNA and histones and increase in histone acetylation. Interestingly, recent studies have revealed that the demethylases of DNA (TET1-3) and histone lysines (KDM2-7) are members of 2-oxoglutarate-dependent dioxygenases (2-OGDO). The 2-OGDO enzymes are activated by oxygen, iron and the major Krebs cycle intermediate, 2-oxoglutarate, whereas they are inhibited by succinate and fumarate. Considering the endosymbiont origin of mitochondria, it is not surprising that Krebs cycle metabolites can control the gene expression of host cell by modifying the epigenetic landscape of chromatin. It seems that age-related disturbances in mitochondrial metabolism can induce epigenetic reprogramming, which promotes the appearance of senescent phenotype and degenerative diseases. Copyright © 2014 Elsevier Inc. All rights reserved.

Epigenetic dysregulation of interleukin 8 (CXCL8) hypersecretion in cystic fibrosis airway epithelial cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Poghosyan, Anna, E-mail: pannagos@yahoo.com; Patel, Jamie K.; Clifford, Rachel L.

Airway epithelial cells in cystic fibrosis (CF) overexpress Interleukin 8 (CXCL8) through poorly defined mechanisms. CXCL8 transcription is dependent on coordinated binding of CCAAT/enhancer binding protein (C/EBP)β, nuclear factor (NF)-κB, and activator protein (AP)-1 to the promoter. Here we show abnormal epigenetic regulation is responsible for CXCL8 overexpression in CF cells. Under basal conditions CF cells had increased bromodomain (Brd)3 and Brd4 recruitment and enhanced NF-κB and C/EBPβ binding to the CXCL8 promoter compared to non-CF cells due to trimethylation of histone H3 at lysine 4 (H3K4me3) and DNA hypomethylation at CpG6. IL-1β increased NF-κB, C/EBPβ and Brd4 binding. Furthermore, inhibitors ofmore » bromodomain and extra-terminal domain family (BET) proteins reduced CXCL8 production in CF cells suggesting a therapeutic target for the BET pathway. -- Highlights: •A regulatory mechanism of CXCL8 transcriptional control in CF airways is proposed. •There was an increased binding of NF-κB and C/EBPβ transcription factors. •There was enhanced recruitment of BET proteins to the CXCL8 promoter. •Epigenetic modifications are responsible for the aberrant CXCL8 transcription.« less

Transgenerational epigenetic effects on animal behaviour.

PubMed

Jensen, Per

2013-12-01

Over the last decade a shift in paradigm has occurred with respect to the interaction between environment and genes. It is now clear that animal genomes are regulated to a large extent as a result of input from environmental events and experiences, which cause short- and long-term modifications in epigenetic markings of DNA and histones. In this review, the evidence that such epigenetic modifications can affect the behaviour of animals is explored, and whether such acquired behaviour alterations can transfer across generation borders. First, the mechanisms by which experiences cause epigenetic modifications are examined. This includes, for example, methylation of cytosine in CpG positions and acetylation of histones, and studies showing that this can be modified by early experiences. Secondly, the evidence that specific modifications in the epigenome can be the cause of behaviour variation is reviewed. Thirdly, the extent to which this phenotypically active epigenetic variants can be inherited either through the germline or through reoccurring environmental conditions is examined. A particularly interesting observation is that epigenetic modifications are often linked to stress, and may possibly be mediated by steroid effects. Finally, the idea that transgenerationally stable epigenetic variants may serve as substrates for natural selection is explored, and it is speculated that they may even predispose for directed, non-random mutations. Copyright © 2013 Elsevier Ltd. All rights reserved.

Epigenetic modification and inheritance in sexual reversal of fish.

PubMed

Shao, Changwei; Li, Qiye; Chen, Songlin; Zhang, Pei; Lian, Jinmin; Hu, Qiaomu; Sun, Bing; Jin, Lijun; Liu, Shanshan; Wang, Zongji; Zhao, Hongmei; Jin, Zonghui; Liang, Zhuo; Li, Yangzhen; Zheng, Qiumei; Zhang, Yong; Wang, Jun; Zhang, Guojie

2014-04-01

Environmental sex determination (ESD) occurs in divergent, phylogenetically unrelated taxa, and in some species, co-occurs with genetic sex determination (GSD) mechanisms. Although epigenetic regulation in response to environmental effects has long been proposed to be associated with ESD, a systemic analysis on epigenetic regulation of ESD is still lacking. Using half-smooth tongue sole (Cynoglossus semilaevis) as a model-a marine fish that has both ZW chromosomal GSD and temperature-dependent ESD-we investigated the role of DNA methylation in transition from GSD to ESD. Comparative analysis of the gonadal DNA methylomes of pseudomale, female, and normal male fish revealed that genes in the sex determination pathways are the major targets of substantial methylation modification during sexual reversal. Methylation modification in pseudomales is globally inherited in their ZW offspring, which can naturally develop into pseudomales without temperature incubation. Transcriptome analysis revealed that dosage compensation occurs in a restricted, methylated cytosine enriched Z chromosomal region in pseudomale testes, achieving equal expression level in normal male testes. In contrast, female-specific W chromosomal genes are suppressed in pseudomales by methylation regulation. We conclude that epigenetic regulation plays multiple crucial roles in sexual reversal of tongue sole fish. We also offer the first clues on the mechanisms behind gene dosage balancing in an organism that undergoes sexual reversal. Finally, we suggest a causal link between the bias sex chromosome assortment in the offspring of a pseudomale family and the transgenerational epigenetic inheritance of sexual reversal in tongue sole fish.

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.

“Curcumin, the King of Spices”: Epigenetic Regulatory Mechanisms in the Prevention of Cancer, Neurological, and Inflammatory Diseases

PubMed Central

Boyanapalli, Sarandeep S. S.

2015-01-01

Curcumin (diferuloylmethane), a polyphenolic compound, is a component of Curcuma longa, commonly known as turmeric. It is a well-known anti-inflammatory, anti-oxidative, and anti-lipidemic agent and has recently been shown to modulate several diseases via epigenetic regulation. Many recent studies have demonstrated the role of epigenetic inactivation of pivotal genes that regulate human pathologies, such as neurocognitive disorders, inflammation, obesity, and cancers. Epigenetic changes involve changes in DNA methylation, histone modifications, or altered microRNA expression patterns which are known to be interconnected and play a key role in tumor progression and failure of conventional chemotherapy. The majority of epigenetic changes are influenced by lifestyle and diets. In this regard, dietary phytochemicals as dietary supplements have emerged as a promising source that are able to reverse these epigenetic alterations, to actively regulate gene expression and molecular targets that are known to promote tumorigenesis, and also to prevent age-related diseases through epigenetic modifications. There have been several studies which reported the role of curcumin as an epigenetic regulator in neurological disorders, inflammation, and in diabetes apart from cancers. The epigenetic regulatory roles of curcumin include (1) inhibition of DNA methyltransferases (DNMTs), which has been well defined from the recent studies on its function as a DNA hypomethylating agent; (2) regulation of histone modifications via regulation of histone acetyltransferases (HATs) and histone deacetylases (HDACs); and (3) regulation of micro RNAs (miRNA). This review summarizes the current knowledge on the effect of curcumin in the treatment and/or prevention of inflammation, neurodegenerative diseases, and cancers by regulating histone deacetylases, histone acetyltransferases, and DNA methyltransferases. PMID:26457241

Regulation of RNA-binding proteins affinity to export receptors enables the nuclear basket proteins to distinguish and retain aberrant mRNAs

PubMed Central

Soheilypour, M.; Mofrad, M. R. K.

2016-01-01

Export of messenger ribonucleic acids (mRNAs) into the cytoplasm is a fundamental step in gene regulation processes, which is meticulously quality controlled by highly efficient mechanisms in eukaryotic cells. Yet, it remains unclear how the aberrant mRNAs are recognized and retained inside the nucleus. Using a new modelling approach for complex systems, namely the agent-based modelling (ABM) approach, we develop a minimal model of the mRNA quality control (QC) mechanism. Our results demonstrate that regulation of the affinity of RNA-binding proteins (RBPs) to export receptors along with the weak interaction between the nuclear basket protein (Mlp1 or Tpr) and RBPs are the minimum requirements to distinguish and retain aberrant mRNAs. Our results show that the affinity between Tpr and RBPs is optimized to maximize the retention of aberrant mRNAs. In addition, we demonstrate how the length of mRNA affects the QC process. Since longer mRNAs spend more time in the nuclear basket to form a compact conformation and initiate their export, nuclear basket proteins could more easily capture and retain them inside the nucleus. PMID:27805000

Regulation of RNA-binding proteins affinity to export receptors enables the nuclear basket proteins to distinguish and retain aberrant mRNAs.

PubMed

Soheilypour, M; Mofrad, M R K

2016-11-02

Export of messenger ribonucleic acids (mRNAs) into the cytoplasm is a fundamental step in gene regulation processes, which is meticulously quality controlled by highly efficient mechanisms in eukaryotic cells. Yet, it remains unclear how the aberrant mRNAs are recognized and retained inside the nucleus. Using a new modelling approach for complex systems, namely the agent-based modelling (ABM) approach, we develop a minimal model of the mRNA quality control (QC) mechanism. Our results demonstrate that regulation of the affinity of RNA-binding proteins (RBPs) to export receptors along with the weak interaction between the nuclear basket protein (Mlp1 or Tpr) and RBPs are the minimum requirements to distinguish and retain aberrant mRNAs. Our results show that the affinity between Tpr and RBPs is optimized to maximize the retention of aberrant mRNAs. In addition, we demonstrate how the length of mRNA affects the QC process. Since longer mRNAs spend more time in the nuclear basket to form a compact conformation and initiate their export, nuclear basket proteins could more easily capture and retain them inside the nucleus.

Epigenetics of Huntington's Disease.

PubMed

Bassi, Silvia; Tripathi, Takshashila; Monziani, Alan; Di Leva, Francesca; Biagioli, Marta

2017-01-01

Huntington's disease (HD) is a genetic, fatal autosomal dominant neurodegenerative disorder typically occurring in midlife with symptoms ranging from chorea, to dementia, to personality disturbances (Philos Trans R Soc Lond Ser B Biol Sci 354:957-961, 1999). HD is inherited in a dominant fashion, and the underlying mutation in all cases is a CAG trinucleotide repeat expansion within exon 1 of the HD gene (Cell 72:971-983, 1993). The expanded CAG repeat, translated into a lengthened glutamine tract at the amino terminus of the huntingtin protein, affects its structural properties and functional activities. The effects are pleiotropic, as huntingtin is broadly expressed in different cellular compartments (i.e., cytosol, nucleus, mitochondria) as well as in all cell types of the body at all developmental stages, such that HD pathogenesis likely starts at conception and is a lifelong process (Front Neurosci 9:509, 2015). The rate-limiting mechanism(s) of neurodegeneration in HD still remains elusive: many different processes are commonly disrupted in HD cell lines and animal models, as well as in HD patient cells (Eur J Neurosci 27:2803-2820, 2008); however, epigenetic-chromatin deregulation, as determined by the analysis of DNA methylation, histone modifications, and noncoding RNAs, has now become a prevailing feature. Thus, the overarching goal of this chapter is to discuss the current status of the literature, reviewing how an aberrant epigenetic landscape can contribute to altered gene expression and neuronal dysfunction in HD.

Uhrf1 controls the self-renewal versus differentiation of hematopoietic stem cells by epigenetically regulating the cell-division modes

PubMed Central

Zhao, Jingyao; Chen, Xufeng; Song, Guangrong; Zhang, Jiali; Liu, Haifeng; Liu, Xiaolong

2017-01-01

Hematopoietic stem cells (HSCs) are able to both self-renew and differentiate. However, how individual HSC makes the decision between self-renewal and differentiation remains largely unknown. Here we report that ablation of the key epigenetic regulator Uhrf1 in the hematopoietic system depletes the HSC pool, leading to hematopoietic failure and lethality. Uhrf1-deficient HSCs display normal survival and proliferation, yet undergo erythroid-biased differentiation at the expense of self-renewal capacity. Notably, Uhrf1 is required for the establishment of DNA methylation patterns of erythroid-specific genes during HSC division. The expression of these genes is enhanced in the absence of Uhrf1, which disrupts the HSC-division modes by promoting the symmetric differentiation and suppressing the symmetric self-renewal. Moreover, overexpression of one of the up-regulated genes, Gata1, in HSCs is sufficient to phenocopy Uhrf1-deficient HSCs, which show impaired HSC symmetric self-renewal and increased differentiation commitment. Taken together, our findings suggest that Uhrf1 controls the self-renewal versus differentiation of HSC through epigenetically regulating the cell-division modes, thus providing unique insights into the relationship among Uhrf1-mediated DNA methylation, cell-division mode, and HSC fate decision. PMID:27956603

The genetics of insomnia--evidence for epigenetic mechanisms?

PubMed

Palagini, Laura; Biber, Knut; Riemann, Dieter

2014-06-01

Sleep is a complex physiological process and still remains one of the great mysteries of science. Over the past 10 y, genetic research has provided a new avenue to address the regulation and function of sleep. Gene loci that contribute quantitatively to sleep characteristics and variability have already been identified. However, up to now, a genetic basis has been established only for a few sleep disorders. Little is yet known about the genetic background of insomnia, one of the most common sleep disorders. According to the conceptualisation of the 3P model of insomnia, predisposing, precipitating and perpetuating factors contribute to the development and maintenance of insomnia. Growing evidence from studies of predisposing factors suggests a certain degree of heritability for insomnia and for a reactivity of sleep patterns to stressful events, explaining the emergence of insomnia in response to stressful life events. While a genetic susceptibility may modulate the impact of stress on the brain, this finding does not provide us with a complete understanding of the capacity of stress to produce long-lasting perturbations of brain and behaviour. Epigenetic gene-environment interactions have been identified just recently and may provide a more complex understanding of the genetic control of sleep and its disorders. It was recently hypothesised that stress-response-related brain plasticity might be epigenetically controlled and, moreover, several epigenetic mechanisms have been assumed to be involved in the regulation of sleep. Hence, it might be postulated that insomnia may be influenced by an epigenetic control process of both sleep mechanisms and stress-response-related gene-environment interactions having an impact on brain plasticity. This paper reviews the evidence for the genetic basis of insomnia and recent theories about epigenetic mechanisms involved in both sleep regulation and brain-stress response, leading to the hypothesis of an involvement of epigenetic

Mitochondria, Energetics, Epigenetics, and Cellular Responses to Stress

PubMed Central

McAllister, Kimberly; Worth, Leroy; Haugen, Astrid C.; Meyer, Joel N.; Domann, Frederick E.; Van Houten, Bennett; Mostoslavsky, Raul; Bultman, Scott J.; Baccarelli, Andrea A.; Begley, Thomas J.; Sobol, Robert W.; Hirschey, Matthew D.; Ideker, Trey; Santos, Janine H.; Copeland, William C.; Tice, Raymond R.; Balshaw, David M.; Tyson, Frederick L.

2014-01-01

Background: Cells respond to environmental stressors through several key pathways, including response to reactive oxygen species (ROS), nutrient and ATP sensing, DNA damage response (DDR), and epigenetic alterations. Mitochondria play a central role in these pathways not only through energetics and ATP production but also through metabolites generated in the tricarboxylic acid cycle, as well as mitochondria–nuclear signaling related to mitochondria morphology, biogenesis, fission/fusion, mitophagy, apoptosis, and epigenetic regulation. Objectives: We investigated the concept of bidirectional interactions between mitochondria and cellular pathways in response to environmental stress with a focus on epigenetic regulation, and we examined DNA repair and DDR pathways as examples of biological processes that respond to exogenous insults through changes in homeostasis and altered mitochondrial function. Methods: The National Institute of Environmental Health Sciences sponsored the Workshop on Mitochondria, Energetics, Epigenetics, Environment, and DNA Damage Response on 25–26 March 2013. Here, we summarize key points and ideas emerging from this meeting. Discussion: A more comprehensive understanding of signaling mechanisms (cross-talk) between the mitochondria and nucleus is central to elucidating the integration of mitochondrial functions with other cellular response pathways in modulating the effects of environmental agents. Recent studies have highlighted the importance of mitochondrial functions in epigenetic regulation and DDR with environmental stress. Development and application of novel technologies, enhanced experimental models, and a systems-type research approach will help to discern how environmentally induced mitochondrial dysfunction affects key mechanistic pathways. Conclusions: Understanding mitochondria–cell signaling will provide insight into individual responses to environmental hazards, improving prediction of hazard and susceptibility to

Aberrant DNA methylation at genes associated with a stem cell-like phenotype in cholangiocarcinoma tumours

PubMed Central

Dai, Wei; Siddiq, Afshan; Walley, Andrew J; Limpaiboon, Temduang; Brown, Robert

2013-01-01

Genetic abnormalities of cholangiocarcinoma have been widely studied; however, epigenomic changes related to cholangiocarcinogenesis have been less well characterised. We have profiled the DNA methylomes of 28 primary cholangiocarcinoma and six matched adjacent normal tissues using Infinium’s HumanMethylation27 BeadChips with the aim of identifying gene sets aberrantly epigenetically regulated in this tumour type. Using a linear model for microarray data we identified 1610 differentially methylated autosomal CpG sites with 809 CpG sites (representing 603 genes) being hypermethylated and 801 CpG sites (representing 712 genes) being hypomethylated in cholangiocarcinoma versus adjacent normal tissues (false discovery rate ≤ 0.05). Gene ontology and gene set enrichment analyses identified gene sets significantly associated with hypermethylation at linked CpG sites in cholangiocarcinoma including homeobox genes and target genes of PRC2, EED, SUZ12 and histone H3 trimethylation at lysine 27. We confirmed frequent hypermethylation at the homeobox genes HOXA9 and HOXD9 by bisulfite pyrosequencing in a larger cohort of cholangiocarcinoma (n = 102). Our findings indicate a key role for hypermethylation of multiple CpG sites at genes associated with a stem cell-like phenotype as a common molecular aberration in cholangiocarcinoma. These data have implications for cholangiocarcinogenesis, as well as possible novel treatment options using histone methyltransferase inhibitors. PMID:24089088

Rice epigenomics and epigenetics: challenges and opportunities.

PubMed

Chen, Xiangsong; Zhou, Dao-Xiu

2013-05-01

During recent years rice genome-wide epigenomic information such as DNA methylation and histone modifications, which are important for genome activity has been accumulated. The function of a number of rice epigenetic regulators has been studied, many of which are found to be involved in a diverse range of developmental and stress-responsive pathways. Analysis of epigenetic variations among different rice varieties indicates that epigenetic modification may lead to inheritable phenotypic variation. Characterizing phenotypic consequences of rice epigenomic variations and the underlining chromatin mechanism and identifying epialleles related to important agronomic traits may provide novel strategies to enhance agronomically favorable traits and grain productivity in rice. Copyright © 2013 Elsevier Ltd. All rights reserved.

Multi-step aberrant CpG island hyper-methylation is associated with the progression of adult T-cell leukemia/lymphoma.

PubMed

Sato, Hiaki; Oka, Takashi; Shinnou, Yoko; Kondo, Takami; Washio, Kana; Takano, Masayuki; Takata, Katsuyoshi; Morito, Toshiaki; Huang, Xingang; Tamura, Maiko; Kitamura, Yuta; Ohara, Nobuya; Ouchida, Mamoru; Ohshima, Koichi; Shimizu, Kenji; Tanimoto, Mitsune; Takahashi, Kiyoshi; Matsuoka, Masao; Utsunomiya, Atae; Yoshino, Tadashi

2010-01-01

Aberrant CpG island methylation contributes to the pathogenesis of various malignancies. However, little is known about the association of epigenetic abnormalities with multistep tumorigenic events in adult T cell leukemia/lymphoma (ATLL). To determine whether epigenetic abnormalities induce the progression of ATLL, we analyzed the methylation profiles of the SHP1, p15, p16, p73, HCAD, DAPK, hMLH-1, and MGMT genes by methylation specific PCR assay in 65 cases with ATLL patients. The number of CpG island methylated genes increased with disease progression and aberrant hypermethylation in specific genes was detected even in HTLV-1 carriers and correlated with progression to ATLL. The CpG island methylator phenotype (CIMP) was observed most frequently in lymphoma type ATLL and was also closely associated with the progression and crisis of ATLL. The high number of methylated genes and increase of CIMP incidence were shown to be unfavorable prognostic factors and correlated with a shorter overall survival by Kaplan-Meyer analysis. The present findings strongly suggest that the multistep accumulation of aberrant CpG methylation in specific target genes and the presence of CIMP are deeply involved in the crisis, progression, and prognosis of ATLL, as well as indicate the value of CpG methylation and CIMP for new diagnostic and prognostic biomarkers.

Multi-Step Aberrant CpG Island Hyper-Methylation Is Associated with the Progression of Adult T–Cell Leukemia/Lymphoma

PubMed Central

Sato, Hiaki; Oka, Takashi; Shinnou, Yoko; Kondo, Takami; Washio, Kana; Takano, Masayuki; Takata, Katsuyoshi; Morito, Toshiaki; Huang, Xingang; Tamura, Maiko; Kitamura, Yuta; Ohara, Nobuya; Ouchida, Mamoru; Ohshima, Koichi; Shimizu, Kenji; Tanimoto, Mitsune; Takahashi, Kiyoshi; Matsuoka, Masao; Utsunomiya, Atae; Yoshino, Tadashi

2010-01-01

Aberrant CpG island methylation contributes to the pathogenesis of various malignancies. However, little is known about the association of epigenetic abnormalities with multistep tumorigenic events in adult T cell leukemia/lymphoma (ATLL). To determine whether epigenetic abnormalities induce the progression of ATLL, we analyzed the methylation profiles of the SHP1, p15, p16, p73, HCAD, DAPK, hMLH-1, and MGMT genes by methylation specific PCR assay in 65 cases with ATLL patients. The number of CpG island methylated genes increased with disease progression and aberrant hypermethylation in specific genes was detected even in HTLV-1 carriers and correlated with progression to ATLL. The CpG island methylator phenotype (CIMP) was observed most frequently in lymphoma type ATLL and was also closely associated with the progression and crisis of ATLL. The high number of methylated genes and increase of CIMP incidence were shown to be unfavorable prognostic factors and correlated with a shorter overall survival by Kaplan-Meyer analysis. The present findings strongly suggest that the multistep accumulation of aberrant CpG methylation in specific target genes and the presence of CIMP are deeply involved in the crisis, progression, and prognosis of ATLL, as well as indicate the value of CpG methylation and CIMP for new diagnostic and prognostic biomarkers. PMID:20019193

HEMD: an integrated tool of human epigenetic enzymes and chemical modulators for therapeutics.

PubMed

Huang, Zhimin; Jiang, Haiming; Liu, Xinyi; Chen, Yingyi; Wong, Jiemin; Wang, Qi; Huang, Wenkang; Shi, Ting; Zhang, Jian

2012-01-01

Epigenetic mechanisms mainly include DNA methylation, post-translational modifications of histones, chromatin remodeling and non-coding RNAs. All of these processes are mediated and controlled by enzymes. Abnormalities of the enzymes are involved in a variety of complex human diseases. Recently, potent natural or synthetic chemicals are utilized to establish the quantitative contributions of epigenetic regulation through the enzymes and provide novel insight for developing new therapeutics. However, the development of more specific and effective epigenetic therapeutics requires a more complete understanding of the chemical epigenomic landscape. Here, we present a human epigenetic enzyme and modulator database (HEMD), the database which provides a central resource for the display, search, and analysis of the structure, function, and related annotation for human epigenetic enzymes and chemical modulators focused on epigenetic therapeutics. Currently, HEMD contains 269 epigenetic enzymes and 4377 modulators in three categories (activators, inhibitors, and regulators). Enzymes are annotated with detailed description of epigenetic mechanisms, catalytic processes, and related diseases, and chemical modulators with binding sites, pharmacological effect, and therapeutic uses. Integrating the information of epigenetic enzymes in HEMD should allow for the prediction of conserved features for proteins and could potentially classify them as ideal targets for experimental validation. In addition, modulators curated in HEMD can be used to investigate potent epigenetic targets for the query compound and also help chemists to implement structural modifications for the design of novel epigenetic drugs. HEMD could be a platform and a starting point for biologists and medicinal chemists for furthering research on epigenetic therapeutics. HEMD is freely available at http://mdl.shsmu.edu.cn/HEMD/.

Genome-wide placental DNA methylation analysis of severely growth-discordant monochorionic twins reveals novel epigenetic targets for intrauterine growth restriction.

PubMed

Roifman, Maian; Choufani, Sanaa; Turinsky, Andrei L; Drewlo, Sascha; Keating, Sarah; Brudno, Michael; Kingdom, John; Weksberg, Rosanna

2016-01-01

Intrauterine growth restriction (IUGR), which refers to reduced fetal growth in the context of placental insufficiency, is etiologically heterogeneous. IUGR is associated not only with perinatal morbidity and mortality but also with adult-onset disorders, such as cardiovascular disease and diabetes, posing a major health burden. Placental epigenetic dysregulation has been proposed as one mechanism that causes IUGR; however, the spectrum of epigenetic pathophysiological mechanisms leading to IUGR remains to be elucidated. Monozygotic monochorionic twins are particularly affected by IUGR, in the setting of severe discordant growth. Because monozygotic twins have the same genotype at conception and a shared maternal environment, they provide an ideal model system for studying epigenetic dysregulation of the placenta. We compared genome-wide placental DNA methylation patterns of severely growth-discordant twins to identify novel candidate genes for IUGR. Snap-frozen placental samples for eight severely growth-discordant monozygotic monochorionic twin pairs were obtained at delivery from each twin. A high-resolution DNA methylation array platform was used to identify methylation differences between IUGR and normal twins. Our analysis revealed differentially methylated regions in the promoters of eight genes: DECR1, ZNF300, DNAJA4, CCL28, LEPR, HSPA1A/L, GSTO1, and GNE. The largest methylation differences between the two groups were in the promoters of DECR1 and ZNF300. The significance of these group differences was independently validated by bisulfite pyrosequencing, implicating aberrations in fatty acid beta oxidation and transcriptional regulation, respectively. Further analysis of the array data identified methylation changes most prominently affecting the Wnt and cadherin pathways in the IUGR cohort. Our results suggest that IUGR in monozygotic twins is associated with impairments in lipid metabolism and transcriptional regulation as well as cadherin and Wnt