Expression Profile of Interferon Regulatory Factor 1 in Chronic Hepatitis B Virus-Infected Liver Transplant Patients.

PubMed

Janfeshan, Sahar; Yaghobi, Ramin; Eidi, Akram; Karimi, Mohammad Hossein; Geramizadeh, Bita; Malekhosseini, Seyed Ali; Kafilzadeh, Farshid

2017-12-01

Hepatitis B virus, which mainly affects normal liver function, leads to severe acute and chronic hepatitis, resulting in cirrhosis and hepatocellular carcinoma, but can be safely treated after liver transplant. Evaluation of determinative biomarkers may facilitate more effective treatment of posttransplant rejection. Therefore, we investigated interferon regulatory factor 1 expression in hepatitis B virus-infected liver transplant patients with and without previous rejection compared with controls. Hepatitis B virus-infected liver recipients were divided into those with (20 patients) and without a rejection (26 patients), confirmed by pathologic analyses in those who had a rejection. In addition, a healthy control group composed of 13 individuals was included. Expression levels of interferon regulatory factor 1 were evaluated during 3 follow-ups after transplant using an in-house comparative SYBR green real-time polymerase chain reaction method. Statistical analyses were performed with SPSS software (SPSS: An IBM Company, version 16.0, IBM Corporation, Armonk, NY, USA). Modifications of interferon regulatory factor 1 gene expression levels in patient groups with and without rejection were not significant between days 1, 4, and 7 after liver transplant. Interferon regulatory factor 1 mRNA expression levels were down-regulated in patients without rejection versus patients with rejection, although not significantly at day 1 (P = .234) and day 4 (P = .302) but significantly at day 7 (P = .004) after liver transplant. Down-regulation of interferon regulatory factor 1 gene expression in hepatitis B virus patients without rejection emphasized counteraction between hepatitis B virus replication and interferon regulatory factor 1 production. On the other hand, interferon regulatory factor 1 gene overexpression in patients with rejection may result in inflammatory reactions and ischemic-reperfusion injury. Therefore, a better understanding of the association between

CisMapper: predicting regulatory interactions from transcription factor ChIP-seq data

PubMed Central

O'Connor, Timothy; Bodén, Mikael

2017-01-01

Abstract Identifying the genomic regions and regulatory factors that control the transcription of genes is an important, unsolved problem. The current method of choice predicts transcription factor (TF) binding sites using chromatin immunoprecipitation followed by sequencing (ChIP-seq), and then links the binding sites to putative target genes solely on the basis of the genomic distance between them. Evidence from chromatin conformation capture experiments shows that this approach is inadequate due to long-distance regulation via chromatin looping. We present CisMapper, which predicts the regulatory targets of a TF using the correlation between a histone mark at the TF's bound sites and the expression of each gene across a panel of tissues. Using both chromatin conformation capture and differential expression data, we show that CisMapper is more accurate at predicting the target genes of a TF than the distance-based approaches currently used, and is particularly advantageous for predicting the long-range regulatory interactions typical of tissue-specific gene expression. CisMapper also predicts which TF binding sites regulate a given gene more accurately than using genomic distance. Unlike distance-based methods, CisMapper can predict which transcription start site of a gene is regulated by a particular binding site of the TF. PMID:28204599

Factors that regulate embryonic gustatory development

PubMed Central

Krimm, Robin F

2007-01-01

Numerous molecular factors orchestrate the development of the peripheral taste system. The unique anatomy/function of the taste system makes this system ideal for understanding the mechanisms by which these factors function; yet the taste system is underutilized for this role. This review focuses on some of the many factors that are known to regulate gustatory development, and discusses a few topics where more work is needed. Some attention is given to factors that regulate epibranchial placode formation, since gustatory neurons are thought to be primarily derived from this region. Epibranchial placodes appear to arise from a pan-placodal region and a number of regulatory factors control the differentiation of individual placodes. Gustatory neuron differentiation is regulated by a series of transcription factors and perhaps bone morphongenic proteins (BMP). As neurons differentiate, they also proliferate such that their numbers exceed those in the adult, and this is followed by developmental death. Some of these cell-cycling events are regulated by neurotrophins. After gustatory neurons become post-mitotic, axon outgrowth occurs. Axons are guided by multiple chemoattractive and chemorepulsive factors, including semaphorins, to the tongue epithelium. Brain derived neurotrophic factor (BDNF), functions as a targeting factor in the final stages of axon guidance and is required for gustatory axons to find and innervate taste epithelium. Numerous factors are involved in the development of gustatory papillae including Sox-2, Sonic hedge hog and Wnt-β-catenin signaling. It is likely that just as many factors regulate taste bud differentiation; however, these factors have not yet been identified. Studies examining the molecular factors that regulate terminal field formation in the nucleus of the solitary tract are also lacking. However, it is possible that some of the factors that regulate geniculate ganglion development, outgrowth, guidance and targeting of peripheral

Inflammation, Self-Regulation, and Health: An Immunologic Model of Self-Regulatory Failure.

PubMed

Shields, Grant S; Moons, Wesley G; Slavich, George M

2017-07-01

Self-regulation is a fundamental human process that refers to multiple complex methods by which individuals pursue goals in the face of distractions. Whereas superior self-regulation predicts better academic achievement, relationship quality, financial and career success, and lifespan health, poor self-regulation increases a person's risk for negative outcomes in each of these domains and can ultimately presage early mortality. Given its centrality to understanding the human condition, a large body of research has examined cognitive, emotional, and behavioral aspects of self-regulation. In contrast, relatively little attention has been paid to specific biologic processes that may underlie self-regulation. We address this latter issue in the present review by examining the growing body of research showing that components of the immune system involved in inflammation can alter neural, cognitive, and motivational processes that lead to impaired self-regulation and poor health. Based on these findings, we propose an integrated, multilevel model that describes how inflammation may cause widespread biobehavioral alterations that promote self-regulatory failure. This immunologic model of self-regulatory failure has implications for understanding how biological and behavioral factors interact to influence self-regulation. The model also suggests new ways of reducing disease risk and enhancing human potential by targeting inflammatory processes that affect self-regulation.

The R2R3-MYB–Like Regulatory Factor EOBI, Acting Downstream of EOBII, Regulates Scent Production by Activating ODO1 and Structural Scent-Related Genes in Petunia[C][W

PubMed Central

Spitzer-Rimon, Ben; Farhi, Moran; Albo, Boaz; Cna’ani, Alon; Ben Zvi, Michal Moyal; Masci, Tania; Edelbaum, Orit; Yu, Yixun; Shklarman, Elena; Ovadis, Marianna; Vainstein, Alexander

2012-01-01

Flower scent is a highly dynamic trait, under developmental, spatial, and diurnal regulation. The mechanism governing scent production is only beginning to be unraveled. In petunia (Petunia hybrida), EMISSION OF BENZENOIDS II (EOBII) controls transcription of both the shikimate pathway-regulating MYB factor ODORANT1 (ODO1) and phenylpropanoid scent-related structural genes. A promoter-activation screen identified an R2R3-MYB–like regulatory factor of phenylpropanoid volatile biosynthesis acting downstream of EOBII, designated EOBI. EOBI silencing led to downregulation of ODO1 and numerous structural scent-related genes from both the shikimate and phenylpropanoid pathways. The ability of EOBI to directly activate ODO1, as revealed by electrophoretic mobility shift assay and yeast one-hybrid analysis, place EOBI upstream of ODO1 in regulating substrate availability for volatile biosynthesis. Interestingly, ODO1-silenced transgenic petunia flowers accumulated higher EOBI transcript levels than controls, suggesting a complex feedback loop between these regulatory factors. The accumulation pattern of EOBI transcript relative to EOBII and ODO1, and the effect of up/downregulation of EOBII on transcript levels of EOBI and ODO1, further support these factors' hierarchical relationships. The dependence of scent production on EOBI expression and its direct interaction with both regulatory and structural genes provide evidence for EOBI’s wide-ranging involvement in the production of floral volatiles. PMID:23275577

Feast/famine regulatory proteins (FFRPs): Escherichia coli Lrp, AsnC and related archaeal transcription factors.

PubMed

Yokoyama, Katsushi; Ishijima, Sanae A; Clowney, Lester; Koike, Hideaki; Aramaki, Hironori; Tanaka, Chikako; Makino, Kozo; Suzuki, Masashi

2006-01-01

Feast/famine regulatory proteins comprise a diverse family of transcription factors, which have been referred to in various individual identifications, including Escherichia coli leucine-responsive regulatory protein and asparagine synthase C gene product. A full length feast/famine regulatory protein consists of the N-terminal DNA-binding domain and the C-domain, which is involved in dimerization and further assembly, thereby producing, for example, a disc or a chromatin-like cylinder. Various ligands of the size of amino acids bind at the interface between feast/famine regulatory protein dimers, thereby altering their assembly forms. Also, the combination of feast/famine regulatory protein subunits forming the same assembly is altered. In this way, a small number of feast/famine regulatory proteins are able to regulate a large number of genes in response to various environmental changes. Because feast/famine regulatory proteins are shared by archaea and eubacteria, the genome-wide regulation by feast/famine regulatory proteins is traceable back to their common ancestor, being the prototype of highly differentiated transcription regulatory mechanisms found in organisms nowadays.

Highly accessible AU-rich regions in 3' untranslated regions are hotspots for binding of regulatory factors.

PubMed

Plass, Mireya; Rasmussen, Simon H; Krogh, Anders

2017-04-01

Post-transcriptional regulation is regarded as one of the major processes involved in the regulation of gene expression. It is mainly performed by RNA binding proteins and microRNAs, which target RNAs and typically affect their stability. Recent efforts from the scientific community have aimed at understanding post-transcriptional regulation at a global scale by using high-throughput sequencing techniques such as cross-linking and immunoprecipitation (CLIP), which facilitates identification of binding sites of these regulatory factors. However, the diversity in the experimental procedures and bioinformatics analyses has hindered the integration of multiple datasets and thus limited the development of an integrated view of post-transcriptional regulation. In this work, we have performed a comprehensive analysis of 107 CLIP datasets from 49 different RBPs in HEK293 cells to shed light on the complex interactions that govern post-transcriptional regulation. By developing a more stringent CLIP analysis pipeline we have discovered the existence of conserved regulatory AU-rich regions in the 3'UTRs where miRNAs and RBPs that regulate several processes such as polyadenylation or mRNA stability bind. Analogous to promoters, many factors have binding sites overlapping or in close proximity in these hotspots and hence the regulation of the mRNA may depend on their relative concentrations. This hypothesis is supported by RBP knockdown experiments that alter the relative concentration of RBPs in the cell. Upon AGO2 knockdown (KD), transcripts containing "free" target sites show increased expression levels compared to those containing target sites in hotspots, which suggests that target sites within hotspots are less available for miRNAs to bind. Interestingly, these hotspots appear enriched in genes with regulatory functions such as DNA binding and RNA binding. Taken together, our results suggest that hotspots are functional regulatory elements that define an extra layer of

Distinct tissue-specific transcriptional regulation revealed by gene regulatory networks in maize.

PubMed

Huang, Ji; Zheng, Juefei; Yuan, Hui; McGinnis, Karen

2018-06-07

Transcription factors (TFs) are proteins that can bind to DNA sequences and regulate gene expression. Many TFs are master regulators in cells that contribute to tissue-specific and cell-type-specific gene expression patterns in eukaryotes. Maize has been a model organism for over one hundred years, but little is known about its tissue-specific gene regulation through TFs. In this study, we used a network approach to elucidate gene regulatory networks (GRNs) in four tissues (leaf, root, SAM and seed) in maize. We utilized GENIE3, a machine-learning algorithm combined with large quantity of RNA-Seq expression data to construct four tissue-specific GRNs. Unlike some other techniques, this approach is not limited by high-quality Position Weighed Matrix (PWM), and can therefore predict GRNs for over 2000 TFs in maize. Although many TFs were expressed across multiple tissues, a multi-tiered analysis predicted tissue-specific regulatory functions for many transcription factors. Some well-studied TFs emerged within the four tissue-specific GRNs, and the GRN predictions matched expectations based upon published results for many of these examples. Our GRNs were also validated by ChIP-Seq datasets (KN1, FEA4 and O2). Key TFs were identified for each tissue and matched expectations for key regulators in each tissue, including GO enrichment and identity with known regulatory factors for that tissue. We also found functional modules in each network by clustering analysis with the MCL algorithm. By combining publicly available genome-wide expression data and network analysis, we can uncover GRNs at tissue-level resolution in maize. Since ChIP-Seq and PWMs are still limited in several model organisms, our study provides a uniform platform that can be adapted to any species with genome-wide expression data to construct GRNs. We also present a publicly available database, maize tissue-specific GRN (mGRN, https://www.bio.fsu.edu/mcginnislab/mgrn/ ), for easy querying. All source code

Innovative farmers and regulatory gatekeepers: Genetically modified crops regulation and adoption in developing countries

PubMed Central

Sinebo, Woldeyesus; Maredia, Karim

2016-01-01

ABSTRACT The regulation of genetically modified (GM) crops is a topical issue in agriculture and environment over the past 2 decades. The objective of this paper is to recount regulatory and adoption practices in some developing countries that have successfully adopted GM crops so that aspiring countries may draw useful lessons and best practices for their biosafatey regulatory regimes. The first 11 mega-GM crops growing countries each with an area of more than one million hectares in 2014 were examined. Only five out of the 11 countries had smooth and orderly adoption of these crops as per the regulatory requirement of each country. In the remaining 6 countries (all developing countries), GM crops were either introduced across borders without official authorization, released prior to regulatory approval or unapproved seeds were sold along with the approved ones in violation to the existing regulations. Rapid expansion of transgenic crops over the past 2 decades in the developing world was a result of an intense desire by farmers to adopt these crops irrespective of regulatory roadblocks. Lack of workable biosafety regulatory system and political will to support GM crops encouraged unauthorized access to GM crop varieties. In certain cases, unregulated access in turn appeared to result in the adoption of substandard or spurious technology which undermined performance and productivity. An optimal interaction among the national agricultural innovation systems, biosafety regulatory bodies, biotech companies and high level policy makers is vital in making a workable regulated progress in the adoption of GM crops. Factoring forgone opportunities to farmers to benefit from GM crops arising from overregulation into biosafety risk analysis and decision making is suggested. Building functional biosafety regulatory systems that balances the needs of farmers to access and utilize the GM technology with the regulatory imperatives to ensure adequate safety to the environment

A Regulatory Circuit Composed of a Transcription Factor, IscR, and a Regulatory RNA, RyhB, Controls Fe-S Cluster Delivery.

PubMed

Mandin, Pierre; Chareyre, Sylvia; Barras, Frédéric

2016-09-20

Fe-S clusters are cofactors conserved through all domains of life. Once assembled by dedicated ISC and/or SUF scaffolds, Fe-S clusters are conveyed to their apo-targets via A-type carrier proteins (ATCs). Escherichia coli possesses four such ATCs. ErpA is the only ATC essential under aerobiosis. Recent studies reported a possible regulation of the erpA mRNA by the small RNA (sRNA) RyhB, which controls the expression of many genes under iron starvation. Surprisingly, erpA has not been identified in recent transcriptomic analysis of the iron starvation response, thus bringing into question the actual physiological significance of the putative regulation of erpA by RyhB. Using an sRNA library, we show that among 26 sRNAs, only RyhB represses the expression of an erpA-lacZ translational fusion. We further demonstrate that this repression occurs during iron starvation. Using mutational analysis, we show that RyhB base pairs to the erpA mRNA, inducing its disappearance. In addition, IscR, the master regulator of Fe-S homeostasis, represses expression of erpA at the transcriptional level when iron is abundant, but depleting iron from the medium alleviates this repression. The conjunction of transcriptional derepression by IscR and posttranscriptional repression by RyhB under Fe-limiting conditions is best described as an incoherent regulatory circuit. This double regulation allows full expression of erpA at iron concentrations for which Fe-S biogenesis switches from the ISC to the SUF system. We further provide evidence that this regulatory circuit coordinates ATC usage to iron availability. Regulatory small RNAs (sRNAs) have emerged as major actors in the control of gene expression in the last few decades. Relatively little is known about how these regulators interact with classical transcription factors to coordinate genetic responses. We show here how an sRNA, RyhB, and a transcription factor, IscR, regulate expression of an essential gene, erpA, in the bacterium E

Regulatory coding of lymphoid lineage choice by hematopoietic transcription factors

NASA Technical Reports Server (NTRS)

Warren, Luigi A.; Rothenberg, Ellen V.

2003-01-01

During lymphopoiesis, precursor cells negotiate a complex regulatory space, defined by the levels of several competing and cross-regulating transcription factors, before arriving at stable states of commitment to the B-, T- and NK-specific developmental programs. Recent perturbation experiments provide evidence that this space has three major axes, corresponding to the PU.1 versus GATA-1 balance, the intensity of Notch signaling through the CSL pathway, and the ratio of E-box transcription factors to their Id protein antagonists.

Multilayer regulatory mechanisms control cleavage factor I proteins in filamentous fungi

PubMed Central

Rodríguez-Romero, J.; Franceschetti, M.; Bueno, E.; Sesma, A.

2015-01-01

Cleavage factor I (CFI) proteins are core components of the polyadenylation machinery that can regulate several steps of mRNA life cycle, including alternative polyadenylation, splicing, export and decay. Here, we describe the regulatory mechanisms that control two fungal CFI protein classes in Magnaporthe oryzae: Rbp35/CfI25 complex and Hrp1. Using mutational, genetic and biochemical studies we demonstrate that cellular concentration of CFI mRNAs is a limited indicator of their protein abundance. Our results suggest that several post-transcriptional mechanisms regulate Rbp35/CfI25 complex and Hrp1 in the rice blast fungus, some of which are also conserved in other ascomycetes. With respect to Rbp35, these include C-terminal processing, RGG-dependent localization and cleavage, C-terminal autoregulatory domain and regulation by an upstream open reading frame of Rbp35-dependent TOR signalling pathway. Our proteomic analyses suggest that Rbp35 regulates the levels of proteins involved in melanin and phenylpropanoids synthesis, among others. The drastic reduction of fungal CFI proteins in carbon-starved cells suggests that the pre-mRNA processing pathway is altered. Our findings uncover broad and multilayer regulatory mechanisms controlling fungal polyadenylation factors, which have profound implications in pre-mRNA maturation. This area of research offers new avenues for fungicide design by targeting fungal-specific proteins that globally affect thousands of mRNAs. PMID:25514925

Highly accessible AU-rich regions in 3’ untranslated regions are hotspots for binding of regulatory factors

PubMed Central

2017-01-01

Post-transcriptional regulation is regarded as one of the major processes involved in the regulation of gene expression. It is mainly performed by RNA binding proteins and microRNAs, which target RNAs and typically affect their stability. Recent efforts from the scientific community have aimed at understanding post-transcriptional regulation at a global scale by using high-throughput sequencing techniques such as cross-linking and immunoprecipitation (CLIP), which facilitates identification of binding sites of these regulatory factors. However, the diversity in the experimental procedures and bioinformatics analyses has hindered the integration of multiple datasets and thus limited the development of an integrated view of post-transcriptional regulation. In this work, we have performed a comprehensive analysis of 107 CLIP datasets from 49 different RBPs in HEK293 cells to shed light on the complex interactions that govern post-transcriptional regulation. By developing a more stringent CLIP analysis pipeline we have discovered the existence of conserved regulatory AU-rich regions in the 3’UTRs where miRNAs and RBPs that regulate several processes such as polyadenylation or mRNA stability bind. Analogous to promoters, many factors have binding sites overlapping or in close proximity in these hotspots and hence the regulation of the mRNA may depend on their relative concentrations. This hypothesis is supported by RBP knockdown experiments that alter the relative concentration of RBPs in the cell. Upon AGO2 knockdown (KD), transcripts containing “free” target sites show increased expression levels compared to those containing target sites in hotspots, which suggests that target sites within hotspots are less available for miRNAs to bind. Interestingly, these hotspots appear enriched in genes with regulatory functions such as DNA binding and RNA binding. Taken together, our results suggest that hotspots are functional regulatory elements that define an extra layer

GeneNetFinder2: Improved Inference of Dynamic Gene Regulatory Relations with Multiple Regulators.

PubMed

Han, Kyungsook; Lee, Jeonghoon

2016-01-01

A gene involved in complex regulatory interactions may have multiple regulators since gene expression in such interactions is often controlled by more than one gene. Another thing that makes gene regulatory interactions complicated is that regulatory interactions are not static, but change over time during the cell cycle. Most research so far has focused on identifying gene regulatory relations between individual genes in a particular stage of the cell cycle. In this study we developed a method for identifying dynamic gene regulations of several types from the time-series gene expression data. The method can find gene regulations with multiple regulators that work in combination or individually as well as those with single regulators. The method has been implemented as the second version of GeneNetFinder (hereafter called GeneNetFinder2) and tested on several gene expression datasets. Experimental results with gene expression data revealed the existence of genes that are not regulated by individual genes but rather by a combination of several genes. Such gene regulatory relations cannot be found by conventional methods. Our method finds such regulatory relations as well as those with multiple, independent regulators or single regulators, and represents gene regulatory relations as a dynamic network in which different gene regulatory relations are shown in different stages of the cell cycle. GeneNetFinder2 is available at http://bclab.inha.ac.kr/GeneNetFinder and will be useful for modeling dynamic gene regulations with multiple regulators.

Identification of regulatory targets for the bacterial Nus factor complex.

PubMed

Baniulyte, Gabriele; Singh, Navjot; Benoit, Courtney; Johnson, Richard; Ferguson, Robert; Paramo, Mauricio; Stringer, Anne M; Scott, Ashley; Lapierre, Pascal; Wade, Joseph T

2017-12-11

Nus factors are broadly conserved across bacterial species, and are often essential for viability. A complex of five Nus factors (NusB, NusE, NusA, NusG and SuhB) is considered to be a dedicated regulator of ribosomal RNA folding, and has been shown to prevent Rho-dependent transcription termination. Here, we identify an additional cellular function for the Nus factor complex in Escherichia coli: repression of the Nus factor-encoding gene, suhB. This repression occurs primarily by translation inhibition, followed by Rho-dependent transcription termination. Thus, the Nus factor complex can prevent or promote Rho activity depending on the gene context. Conservation of putative NusB/E binding sites upstream of Nus factor genes suggests that Nus factor autoregulation occurs in many bacterial species. Additionally, many putative NusB/E binding sites are also found upstream of other genes in diverse species, and we demonstrate Nus factor regulation of one such gene in Citrobacter koseri. We conclude that Nus factors have an evolutionarily widespread regulatory function beyond ribosomal RNA, and that they are often autoregulatory.

Coordination of meristem and boundary functions by transcription factors in the SHOOT MERISTEMLESS regulatory network.

PubMed

Scofield, Simon; Murison, Alexander; Jones, Angharad; Fozard, John; Aida, Mitsuhiro; Band, Leah R; Bennett, Malcolm; Murray, James A H

2018-04-30

The Arabidopsis homeodomain transcription factor SHOOT MERISTEMLESS (STM) is crucial for shoot apical meristem (SAM) function, yet the components and structure of the STM gene regulatory network (GRN) are largely unknown. Here, we show that transcriptional regulators are overrepresented among STM-regulated genes and, using these as GRN components in Bayesian network analysis, we infer STM GRN associations and reveal regulatory relationships between STM and factors involved in multiple aspects of SAM function. These include hormone regulation, TCP-mediated control of cell differentiation, AIL/PLT-mediated regulation of pluripotency and phyllotaxis, and specification of meristem-organ boundary zones via CUC1. We demonstrate a direct positive transcriptional feedback loop between STM and CUC1, despite their distinct expression patterns in the meristem and organ boundary, respectively. Our further finding that STM activates expression of the CUC1-targeting microRNA miR164c combined with mathematical modelling provides a potential solution for this apparent contradiction, demonstrating that these proposed regulatory interactions coupled with STM mobility could be sufficient to provide a mechanism for CUC1 localisation at the meristem-organ boundary. Our findings highlight the central role for the STM GRN in coordinating SAM functions. © 2018. Published by The Company of Biologists Ltd.

CoryneRegNet: an ontology-based data warehouse of corynebacterial transcription factors and regulatory networks.

PubMed

Baumbach, Jan; Brinkrolf, Karina; Czaja, Lisa F; Rahmann, Sven; Tauch, Andreas

2006-02-14

The application of DNA microarray technology in post-genomic analysis of bacterial genome sequences has allowed the generation of huge amounts of data related to regulatory networks. This data along with literature-derived knowledge on regulation of gene expression has opened the way for genome-wide reconstruction of transcriptional regulatory networks. These large-scale reconstructions can be converted into in silico models of bacterial cells that allow a systematic analysis of network behavior in response to changing environmental conditions. CoryneRegNet was designed to facilitate the genome-wide reconstruction of transcriptional regulatory networks of corynebacteria relevant in biotechnology and human medicine. During the import and integration process of data derived from experimental studies or literature knowledge CoryneRegNet generates links to genome annotations, to identified transcription factors and to the corresponding cis-regulatory elements. CoryneRegNet is based on a multi-layered, hierarchical and modular concept of transcriptional regulation and was implemented by using the relational database management system MySQL and an ontology-based data structure. Reconstructed regulatory networks can be visualized by using the yFiles JAVA graph library. As an application example of CoryneRegNet, we have reconstructed the global transcriptional regulation of a cellular module involved in SOS and stress response of corynebacteria. CoryneRegNet is an ontology-based data warehouse that allows a pertinent data management of regulatory interactions along with the genome-scale reconstruction of transcriptional regulatory networks. These models can further be combined with metabolic networks to build integrated models of cellular function including both metabolism and its transcriptional regulation.

DNA residence time is a regulatory factor of transcription repression

PubMed Central

Clauß, Karen; Popp, Achim P.; Schulze, Lena; Hettich, Johannes; Reisser, Matthias; Escoter Torres, Laura; Uhlenhaut, N. Henriette

2017-01-01

Abstract Transcription comprises a highly regulated sequence of intrinsically stochastic processes, resulting in bursts of transcription intermitted by quiescence. In transcription activation or repression, a transcription factor binds dynamically to DNA, with a residence time unique to each factor. Whether the DNA residence time is important in the transcription process is unclear. Here, we designed a series of transcription repressors differing in their DNA residence time by utilizing the modular DNA binding domain of transcription activator-like effectors (TALEs) and varying the number of nucleotide-recognizing repeat domains. We characterized the DNA residence times of our repressors in living cells using single molecule tracking. The residence times depended non-linearly on the number of repeat domains and differed by more than a factor of six. The factors provoked a residence time-dependent decrease in transcript level of the glucocorticoid receptor-activated gene SGK1. Down regulation of transcription was due to a lower burst frequency in the presence of long binding repressors and is in accordance with a model of competitive inhibition of endogenous activator binding. Our single molecule experiments reveal transcription factor DNA residence time as a regulatory factor controlling transcription repression and establish TALE-DNA binding domains as tools for the temporal dissection of transcription regulation. PMID:28977492

Transcription factor MITF and remodeller BRG1 define chromatin organisation at regulatory elements in melanoma cells.

PubMed

Laurette, Patrick; Strub, Thomas; Koludrovic, Dana; Keime, Céline; Le Gras, Stéphanie; Seberg, Hannah; Van Otterloo, Eric; Imrichova, Hana; Siddaway, Robert; Aerts, Stein; Cornell, Robert A; Mengus, Gabrielle; Davidson, Irwin

2015-03-24

Microphthalmia-associated transcription factor (MITF) is the master regulator of the melanocyte lineage. To understand how MITF regulates transcription, we used tandem affinity purification and mass spectrometry to define a comprehensive MITF interactome identifying novel cofactors involved in transcription, DNA replication and repair, and chromatin organisation. We show that MITF interacts with a PBAF chromatin remodelling complex comprising BRG1 and CHD7. BRG1 is essential for melanoma cell proliferation in vitro and for normal melanocyte development in vivo. MITF and SOX10 actively recruit BRG1 to a set of MITF-associated regulatory elements (MAREs) at active enhancers. Combinations of MITF, SOX10, TFAP2A, and YY1 bind between two BRG1-occupied nucleosomes thus defining both a signature of transcription factors essential for the melanocyte lineage and a specific chromatin organisation of the regulatory elements they occupy. BRG1 also regulates the dynamics of MITF genomic occupancy. MITF-BRG1 interplay thus plays an essential role in transcription regulation in melanoma.

Reconstructing genome-wide regulatory network of E. coli using transcriptome data and predicted transcription factor activities

PubMed Central

2011-01-01

Background Gene regulatory networks play essential roles in living organisms to control growth, keep internal metabolism running and respond to external environmental changes. Understanding the connections and the activity levels of regulators is important for the research of gene regulatory networks. While relevance score based algorithms that reconstruct gene regulatory networks from transcriptome data can infer genome-wide gene regulatory networks, they are unfortunately prone to false positive results. Transcription factor activities (TFAs) quantitatively reflect the ability of the transcription factor to regulate target genes. However, classic relevance score based gene regulatory network reconstruction algorithms use models do not include the TFA layer, thus missing a key regulatory element. Results This work integrates TFA prediction algorithms with relevance score based network reconstruction algorithms to reconstruct gene regulatory networks with improved accuracy over classic relevance score based algorithms. This method is called Gene expression and Transcription factor activity based Relevance Network (GTRNetwork). Different combinations of TFA prediction algorithms and relevance score functions have been applied to find the most efficient combination. When the integrated GTRNetwork method was applied to E. coli data, the reconstructed genome-wide gene regulatory network predicted 381 new regulatory links. This reconstructed gene regulatory network including the predicted new regulatory links show promising biological significances. Many of the new links are verified by known TF binding site information, and many other links can be verified from the literature and databases such as EcoCyc. The reconstructed gene regulatory network is applied to a recent transcriptome analysis of E. coli during isobutanol stress. In addition to the 16 significantly changed TFAs detected in the original paper, another 7 significantly changed TFAs have been detected by

CoryneRegNet: An ontology-based data warehouse of corynebacterial transcription factors and regulatory networks

PubMed Central

Baumbach, Jan; Brinkrolf, Karina; Czaja, Lisa F; Rahmann, Sven; Tauch, Andreas

2006-01-01

Background The application of DNA microarray technology in post-genomic analysis of bacterial genome sequences has allowed the generation of huge amounts of data related to regulatory networks. This data along with literature-derived knowledge on regulation of gene expression has opened the way for genome-wide reconstruction of transcriptional regulatory networks. These large-scale reconstructions can be converted into in silico models of bacterial cells that allow a systematic analysis of network behavior in response to changing environmental conditions. Description CoryneRegNet was designed to facilitate the genome-wide reconstruction of transcriptional regulatory networks of corynebacteria relevant in biotechnology and human medicine. During the import and integration process of data derived from experimental studies or literature knowledge CoryneRegNet generates links to genome annotations, to identified transcription factors and to the corresponding cis-regulatory elements. CoryneRegNet is based on a multi-layered, hierarchical and modular concept of transcriptional regulation and was implemented by using the relational database management system MySQL and an ontology-based data structure. Reconstructed regulatory networks can be visualized by using the yFiles JAVA graph library. As an application example of CoryneRegNet, we have reconstructed the global transcriptional regulation of a cellular module involved in SOS and stress response of corynebacteria. Conclusion CoryneRegNet is an ontology-based data warehouse that allows a pertinent data management of regulatory interactions along with the genome-scale reconstruction of transcriptional regulatory networks. These models can further be combined with metabolic networks to build integrated models of cellular function including both metabolism and its transcriptional regulation. PMID:16478536

Reconstruction and topological characterization of the sigma factor regulatory network of Mycobacterium tuberculosis

PubMed Central

Chauhan, Rinki; Ravi, Janani; Datta, Pratik; Chen, Tianlong; Schnappinger, Dirk; Bassler, Kevin E.; Balázsi, Gábor; Gennaro, Maria Laura

2016-01-01

Accessory sigma factors, which reprogram RNA polymerase to transcribe specific gene sets, activate bacterial adaptive responses to noxious environments. Here we reconstruct the complete sigma factor regulatory network of the human pathogen Mycobacterium tuberculosis by an integrated approach. The approach combines identification of direct regulatory interactions between M. tuberculosis sigma factors in an E. coli model system, validation of selected links in M. tuberculosis, and extensive literature review. The resulting network comprises 41 direct interactions among all 13 sigma factors. Analysis of network topology reveals (i) a three-tiered hierarchy initiating at master regulators, (ii) high connectivity and (iii) distinct communities containing multiple sigma factors. These topological features are likely associated with multi-layer signal processing and specialized stress responses involving multiple sigma factors. Moreover, the identification of overrepresented network motifs, such as autoregulation and coregulation of sigma and anti-sigma factor pairs, provides structural information that is relevant for studies of network dynamics. PMID:27029515

7 CFR 4284.906 - State laws, local laws, regulatory commission regulations.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 7 Agriculture 15 2013-01-01 2013-01-01 false State laws, local laws, regulatory commission...-Added Producer Grant Program General § 4284.906 State laws, local laws, regulatory commission regulations. If there are conflicts between this subpart and State or local laws or regulatory commission...

7 CFR 4284.906 - State laws, local laws, regulatory commission regulations.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 7 Agriculture 15 2014-01-01 2014-01-01 false State laws, local laws, regulatory commission...-Added Producer Grant Program General § 4284.906 State laws, local laws, regulatory commission regulations. If there are conflicts between this subpart and State or local laws or regulatory commission...

7 CFR 4284.906 - State laws, local laws, regulatory commission regulations.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 7 Agriculture 15 2012-01-01 2012-01-01 false State laws, local laws, regulatory commission...-Added Producer Grant Program General § 4284.906 State laws, local laws, regulatory commission regulations. If there are conflicts between this subpart and State or local laws or regulatory commission...

Patterns of Positive Selection of the Myogenic Regulatory Factor Gene Family in Vertebrates

PubMed Central

Zhao, Xiao; Yu, Qi; Huang, Ling; Liu, Qing-Xin

2014-01-01

The functional divergence of transcriptional factors is critical in the evolution of transcriptional regulation. However, the mechanism of functional divergence among these factors remains unclear. Here, we performed an evolutionary analysis for positive selection in members of the myogenic regulatory factor (MRF) gene family of vertebrates. We selected 153 complete vertebrate MRF nucleotide sequences from our analyses, which revealed substantial evidence of positive selection. Here, we show that sites under positive selection were more frequently detected and identified from the genes encoding the myogenic differentiation factors (MyoG and Myf6) than the genes encoding myogenic determination factors (Myf5 and MyoD). Additionally, the functional divergence within the myogenic determination factors or differentiation factors was also under positive selection pressure. The positive selection sites were more frequently detected from MyoG and MyoD than Myf6 and Myf5, respectively. Amino acid residues under positive selection were identified mainly in their transcription activation domains and on the surface of protein three-dimensional structures. These data suggest that the functional gain and divergence of myogenic regulatory factors were driven by distinct positive selection of their transcription activation domains, whereas the function of the DNA binding domains was conserved in evolution. Our study evaluated the mechanism of functional divergence of the transcriptional regulation factors within a family, whereby the functions of their transcription activation domains diverged under positive selection during evolution. PMID:24651579

Regulation of IFN regulatory factor 4 expression in human T cell leukemia virus-I-transformed T cells.

PubMed

Sharma, Sonia; Grandvaux, Nathalie; Mamane, Yael; Genin, Pierre; Azimi, Nazli; Waldmann, Thomas; Hiscott, John

2002-09-15

IFN regulatory factor (IRF)-4 is a lymphoid/myeloid-restricted member of the IRF transcription factor family that plays an essential role in the homeostasis and function of mature lymphocytes. IRF-4 expression is tightly regulated in resting primary T cells and is transiently induced at the mRNA and protein levels after activation by Ag-mimetic stimuli such as TCR cross-linking or treatment with phorbol ester and calcium ionophore (PMA/ionomycin). However, IRF-4 is constitutively upregulated in human T cell leukemia virus type I (HTLV-I) infected T cells as a direct gene target for the HTLV-I Tax oncoprotein. In this study we demonstrate that chronic IRF-4 expression in HTLV-I-infected T lymphocytes is associated with a leukemic phenotype, and we examine the mechanisms by which continuous production of IRF-4 is achieved in HTLV-I-transformed T cells. IRF-4 expression in HTLV-1-infected cells is driven through activation of the NF-kappaB and NF-AT pathways, resulting in the binding of p50, p65, and c-Rel to the kappaB1 element and p50, c-Rel, and NF-ATp to the CD28RE element within the -617 to -209 region of the IRF-4 promoter. Furthermore, mutation of either the kappaB1 or CD28RE sites blocks Tax-mediated transactivation of the human IRF-4 promoter in T cells. These experiments constitute the first detailed analysis of human IRF-4 transcriptional regulation within the context of HTLV-I infection and transformation of CD4(+) T lymphocytes.

Beyond regulatory compression: confronting the liminal spaces of health research regulation

PubMed Central

Taylor-Alexander, Samuel; Dove, Edward S.; Fletcher, Isabel; Ganguli Mitra, Agomoni; McMillan, Catriona; Laurie, Graeme

2016-01-01

ABSTRACT Biomedicine and the life sciences continuously rearrange the relationship between culture and biology. In consequence, we increasingly look for a suitable regulatory response to reduce perceived uncertainty and instability. This article examines the full implications of this ‘regulatory turn’ by drawing on the anthropological concept of liminality. We offer the term ‘regulatory compression’ to characterise the effects of extant regulatory approaches on health research practices. With its focus on transformation and the ‘in-between’, liminality allows us to see how regulatory frameworks rely on a silo-based approach to classifying and regulating research objects such that they: (1) limit the flexibility necessary in clinical and laboratory research; (2) result in the emergence of unregulated spaces that lie between the bounded regulatory spheres; and (3) curtail modes of public participation in the health research enterprise. We suggest there is a need to develop the notion of ‘processual regulation’, a novel framework that requires a temporal-spatial examination of regulatory spaces and practices as these are experienced by all actors, including the relationship of actors with the objects of regulation. PMID:28058061

An integrated approach to characterize transcription factor and microRNA regulatory networks involved in Schwann cell response to peripheral nerve injury

PubMed Central

2013-01-01

Background The regenerative response of Schwann cells after peripheral nerve injury is a critical process directly related to the pathophysiology of a number of neurodegenerative diseases. This SC injury response is dependent on an intricate gene regulatory program coordinated by a number of transcription factors and microRNAs, but the interactions among them remain largely unknown. Uncovering the transcriptional and post-transcriptional regulatory networks governing the Schwann cell injury response is a key step towards a better understanding of Schwann cell biology and may help develop novel therapies for related diseases. Performing such comprehensive network analysis requires systematic bioinformatics methods to integrate multiple genomic datasets. Results In this study we present a computational pipeline to infer transcription factor and microRNA regulatory networks. Our approach combined mRNA and microRNA expression profiling data, ChIP-Seq data of transcription factors, and computational transcription factor and microRNA target prediction. Using mRNA and microRNA expression data collected in a Schwann cell injury model, we constructed a regulatory network and studied regulatory pathways involved in Schwann cell response to injury. Furthermore, we analyzed network motifs and obtained insights on cooperative regulation of transcription factors and microRNAs in Schwann cell injury recovery. Conclusions This work demonstrates a systematic method for gene regulatory network inference that may be used to gain new information on gene regulation by transcription factors and microRNAs. PMID:23387820

A Positive Regulatory Loop between a Wnt-Regulated Non-coding RNA and ASCL2 Controls Intestinal Stem Cell Fate.

PubMed

Giakountis, Antonis; Moulos, Panagiotis; Zarkou, Vasiliki; Oikonomou, Christina; Harokopos, Vaggelis; Hatzigeorgiou, Artemis G; Reczko, Martin; Hatzis, Pantelis

2016-06-21

The canonical Wnt pathway plays a central role in stem cell maintenance, differentiation, and proliferation in the intestinal epithelium. Constitutive, aberrant activity of the TCF4/β-catenin transcriptional complex is the primary transforming factor in colorectal cancer. We identify a nuclear long non-coding RNA, termed WiNTRLINC1, as a direct target of TCF4/β-catenin in colorectal cancer cells. WiNTRLINC1 positively regulates the expression of its genomic neighbor ASCL2, a transcription factor that controls intestinal stem cell fate. WiNTRLINC1 interacts with TCF4/β-catenin to mediate the juxtaposition of its promoter with the regulatory regions of ASCL2. ASCL2, in turn, regulates WiNTRLINC1 transcriptionally, closing a feedforward regulatory loop that controls stem cell-related gene expression. This regulatory circuitry is highly amplified in colorectal cancer and correlates with increased metastatic potential and decreased patient survival. Our results uncover the interplay between non-coding RNA-mediated regulation and Wnt signaling and point to the diagnostic and therapeutic potential of WiNTRLINC1. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

Regulatory Flexibility: An Individual Differences Perspective on Coping and Emotion Regulation.

PubMed

Bonanno, George A; Burton, Charles L

2013-11-01

People respond to stressful events in different ways, depending on the event and on the regulatory strategies they choose. Coping and emotion regulation theorists have proposed dynamic models in which these two factors, the person and the situation, interact over time to inform adaptation. In practice, however, researchers have tended to assume that particular regulatory strategies are consistently beneficial or maladaptive. We label this assumption the fallacy of uniform efficacy and contrast it with findings from a number of related literatures that have suggested the emergence of a broader but as yet poorly defined construct that we refer to as regulatory flexibility. In this review, we articulate this broader construct and define both its features and limitations. Specifically, we propose a heuristic individual differences framework and review research on three sequential components of flexibility for which propensities and abilities vary: sensitivity to context, availability of a diverse repertoire of regulatory strategies, and responsiveness to feedback. We consider the methodological limitations of research on each component, review questions that future research on flexibility might address, and consider how the components might relate to each other and to broader conceptualizations about stability and change across persons and situations. © The Author(s) 2013.

Assessing efficacy and therapeutic claims in emerging indications for recombinant factor VIIa: regulatory perspectives.

PubMed

Farrugia, Albert

2006-01-01

When compared with the evidence-based, cost-effectiveness criteria underpinning most government reimbursement schemes in the social market economies, the three regulatory hurdles of safety, quality and efficacy are probably of modest impact in influencing increased usage of recombinant activated factor VII (rFVIIa; NovoSeven, Novo Nordisk, Bagsvaerd, Denmark). Nevertheless, efficacy claims must be supported if regulatory approval is to be granted for the wider range of indications that have been proposed for rFVIIa. With the refinement of clinical trial designs over the past 40 years, the randomized controlled trial (RCT) has assumed the role of gold standard, providing the highest level of evidence for therapeutic efficacy. However, it is incorrect to assume that regulatory authorities give sole credence to RCTs in assessing claims. It is noteworthy that the indications already accepted for rFVIIa by international regulatory authorities--including the treatment of inhibitors to factor VIII and factor IX, substitution for FVII deficiency, and treatment of Glanzmann's thrombasthenia--were supported not by RCTs but by studies conventionally considered to provide modest evidence levels. Therefore, the use of studies other than RCTs for the more recently proposed indications for rFVIIa in a range of conditions requiring hemostatic correction is perfectly feasible. What regulators expect are well-conducted and well-described studies adhering to principles of good clinical practice, which can be scrutinized for evidence of clinical efficacy and which are based on the initially proven principle for the drug. This paper discusses the regulatory history of rFVIIa in the major regulatory authorities and assesses the route needed to support claims being made in the mainstream literature. Recent episodes where post-market events have forced regulators to be more than usually cautious will be used as examples to suggest possible pitfalls to the extension of approved claims for

Regulation of B7.1 costimulatory molecule is mediated by the IFN regulatory factor-7 through the activation of JNK in lipopolysaccharide-stimulated human monocytic cells.

PubMed

Lim, Wilfred; Gee, Katrina; Mishra, Sasmita; Kumar, Ashok

2005-11-01

The engagement of CD28 or CTLA-4 with B7.1 provides the essential second costimulatory signal that regulates the development of immune responses, including T cell activation, differentiation, and induction of peripheral tolerance. The signaling molecules and the transcription factors involved in B7.1 regulation are poorly understood. In this study we investigated the role of MAPKs in the regulation of LPS-induced B7.1 expression in human monocytes and the promonocytic THP-1 cells. Our results show that LPS-induced B7.1 expression in monocytic cells did not involve the activation of either p38 or ERKs. Using the JNK-specific inhibitor SP600125, small interfering RNAs specific for JNK1 and JNK2, and agents such as dexamethasone that inhibit JNK activation, we determined that LPS-induced B7.1 expression was regulated by JNK MAPK in both monocytes and THP-1 cells. In addition, we identified a distinct B7.1-responsive element corresponding to the IFN regulatory factor-7 (IRF-7) binding site in the B7.1 promoter responsible for the regulation of LPS-induced B7.1 transcription. Furthermore, SP600125 and dexamethasone inhibited LPS-induced IRF-7 activity. Taken together, these results suggest that LPS-induced B7.1 transcription in human monocytic cells may be regulated by JNK-mediated activation of the IRF-7 transcription factor.

A transcription factor collective defines the HSN serotonergic neuron regulatory landscape.

PubMed

Lloret-Fernández, Carla; Maicas, Miren; Mora-Martínez, Carlos; Artacho, Alejandro; Jimeno-Martín, Ángela; Chirivella, Laura; Weinberg, Peter; Flames, Nuria

2018-03-22

Cell differentiation is controlled by individual transcription factors (TFs) that together activate a selection of enhancers in specific cell types. How these combinations of TFs identify and activate their target sequences remains poorly understood. Here, we identify the cis -regulatory transcriptional code that controls the differentiation of serotonergic HSN neurons in Caenorhabditis elegans . Activation of the HSN transcriptome is directly orchestrated by a collective of six TFs. Binding site clusters for this TF collective form a regulatory signature that is sufficient for de novo identification of HSN neuron functional enhancers. Among C. elegans neurons, the HSN transcriptome most closely resembles that of mouse serotonergic neurons. Mouse orthologs of the HSN TF collective also regulate serotonergic differentiation and can functionally substitute for their worm counterparts which suggests deep homology. Our results identify rules governing the regulatory landscape of a critically important neuronal type in two species separated by over 700 million years. © 2018, Lloret-Fernández et al.

A transcription factor collective defines the HSN serotonergic neuron regulatory landscape

PubMed Central

Artacho, Alejandro; Jimeno-Martín, Ángela; Chirivella, Laura; Weinberg, Peter

2018-01-01

Cell differentiation is controlled by individual transcription factors (TFs) that together activate a selection of enhancers in specific cell types. How these combinations of TFs identify and activate their target sequences remains poorly understood. Here, we identify the cis-regulatory transcriptional code that controls the differentiation of serotonergic HSN neurons in Caenorhabditis elegans. Activation of the HSN transcriptome is directly orchestrated by a collective of six TFs. Binding site clusters for this TF collective form a regulatory signature that is sufficient for de novo identification of HSN neuron functional enhancers. Among C. elegans neurons, the HSN transcriptome most closely resembles that of mouse serotonergic neurons. Mouse orthologs of the HSN TF collective also regulate serotonergic differentiation and can functionally substitute for their worm counterparts which suggests deep homology. Our results identify rules governing the regulatory landscape of a critically important neuronal type in two species separated by over 700 million years. PMID:29553368

MicroRNA and Transcription Factor: Key Players in Plant Regulatory Network

PubMed Central

Samad, Abdul F. A.; Sajad, Muhammad; Nazaruddin, Nazaruddin; Fauzi, Izzat A.; Murad, Abdul M. A.; Zainal, Zamri; Ismail, Ismanizan

2017-01-01

Recent achievements in plant microRNA (miRNA), a large class of small and non-coding RNAs, are very exciting. A wide array of techniques involving forward genetic, molecular cloning, bioinformatic analysis, and the latest technology, deep sequencing have greatly advanced miRNA discovery. A tiny miRNA sequence has the ability to target single/multiple mRNA targets. Most of the miRNA targets are transcription factors (TFs) which have paramount importance in regulating the plant growth and development. Various families of TFs, which have regulated a range of regulatory networks, may assist plants to grow under normal and stress environmental conditions. This present review focuses on the regulatory relationships between miRNAs and different families of TFs like; NF-Y, MYB, AP2, TCP, WRKY, NAC, GRF, and SPL. For instance NF-Y play important role during drought tolerance and flower development, MYB are involved in signal transduction and biosynthesis of secondary metabolites, AP2 regulate the floral development and nodule formation, TCP direct leaf development and growth hormones signaling. WRKY have known roles in multiple stress tolerances, NAC regulate lateral root formation, GRF are involved in root growth, flower, and seed development, and SPL regulate plant transition from juvenile to adult. We also studied the relation between miRNAs and TFs by consolidating the research findings from different plant species which will help plant scientists in understanding the mechanism of action and interaction between these regulators in the plant growth and development under normal and stress environmental conditions. PMID:28446918

MicroRNA and Transcription Factor: Key Players in Plant Regulatory Network.

PubMed

Samad, Abdul F A; Sajad, Muhammad; Nazaruddin, Nazaruddin; Fauzi, Izzat A; Murad, Abdul M A; Zainal, Zamri; Ismail, Ismanizan

2017-01-01

Recent achievements in plant microRNA (miRNA), a large class of small and non-coding RNAs, are very exciting. A wide array of techniques involving forward genetic, molecular cloning, bioinformatic analysis, and the latest technology, deep sequencing have greatly advanced miRNA discovery. A tiny miRNA sequence has the ability to target single/multiple mRNA targets. Most of the miRNA targets are transcription factors (TFs) which have paramount importance in regulating the plant growth and development. Various families of TFs, which have regulated a range of regulatory networks, may assist plants to grow under normal and stress environmental conditions. This present review focuses on the regulatory relationships between miRNAs and different families of TFs like; NF-Y, MYB, AP2, TCP, WRKY, NAC, GRF, and SPL. For instance NF-Y play important role during drought tolerance and flower development, MYB are involved in signal transduction and biosynthesis of secondary metabolites, AP2 regulate the floral development and nodule formation, TCP direct leaf development and growth hormones signaling. WRKY have known roles in multiple stress tolerances, NAC regulate lateral root formation, GRF are involved in root growth, flower, and seed development, and SPL regulate plant transition from juvenile to adult. We also studied the relation between miRNAs and TFs by consolidating the research findings from different plant species which will help plant scientists in understanding the mechanism of action and interaction between these regulators in the plant growth and development under normal and stress environmental conditions.

A systems biology model of the regulatory network in Populus leaves reveals interacting regulators and conserved regulation

PubMed Central

2011-01-01

Background Green plant leaves have always fascinated biologists as hosts for photosynthesis and providers of basic energy to many food webs. Today, comprehensive databases of gene expression data enable us to apply increasingly more advanced computational methods for reverse-engineering the regulatory network of leaves, and to begin to understand the gene interactions underlying complex emergent properties related to stress-response and development. These new systems biology methods are now also being applied to organisms such as Populus, a woody perennial tree, in order to understand the specific characteristics of these species. Results We present a systems biology model of the regulatory network of Populus leaves. The network is reverse-engineered from promoter information and expression profiles of leaf-specific genes measured over a large set of conditions related to stress and developmental. The network model incorporates interactions between regulators, such as synergistic and competitive relationships, by evaluating increasingly more complex regulatory mechanisms, and is therefore able to identify new regulators of leaf development not found by traditional genomics methods based on pair-wise expression similarity. The approach is shown to explain available gene function information and to provide robust prediction of expression levels in new data. We also use the predictive capability of the model to identify condition-specific regulation as well as conserved regulation between Populus and Arabidopsis. Conclusions We outline a computationally inferred model of the regulatory network of Populus leaves, and show how treating genes as interacting, rather than individual, entities identifies new regulators compared to traditional genomics analysis. Although systems biology models should be used with care considering the complexity of regulatory programs and the limitations of current genomics data, methods describing interactions can provide hypotheses about

Transcriptional Regulatory Network Analysis of MYB Transcription Factor Family Genes in Rice.

PubMed

Smita, Shuchi; Katiyar, Amit; Chinnusamy, Viswanathan; Pandey, Dev M; Bansal, Kailash C

2015-01-01

MYB transcription factor (TF) is one of the largest TF families and regulates defense responses to various stresses, hormone signaling as well as many metabolic and developmental processes in plants. Understanding these regulatory hierarchies of gene expression networks in response to developmental and environmental cues is a major challenge due to the complex interactions between the genetic elements. Correlation analyses are useful to unravel co-regulated gene pairs governing biological process as well as identification of new candidate hub genes in response to these complex processes. High throughput expression profiling data are highly useful for construction of co-expression networks. In the present study, we utilized transcriptome data for comprehensive regulatory network studies of MYB TFs by "top-down" and "guide-gene" approaches. More than 50% of OsMYBs were strongly correlated under 50 experimental conditions with 51 hub genes via "top-down" approach. Further, clusters were identified using Markov Clustering (MCL). To maximize the clustering performance, parameter evaluation of the MCL inflation score (I) was performed in terms of enriched GO categories by measuring F-score. Comparison of co-expressed cluster and clads analyzed from phylogenetic analysis signifies their evolutionarily conserved co-regulatory role. We utilized compendium of known interaction and biological role with Gene Ontology enrichment analysis to hypothesize function of coexpressed OsMYBs. In the other part, the transcriptional regulatory network analysis by "guide-gene" approach revealed 40 putative targets of 26 OsMYB TF hubs with high correlation value utilizing 815 microarray data. The putative targets with MYB-binding cis-elements enrichment in their promoter region, functional co-occurrence as well as nuclear localization supports our finding. Specially, enrichment of MYB binding regions involved in drought-inducibility implying their regulatory role in drought response in rice

Brucella abortus down-regulates MHC class II by the IL-6-dependent inhibition of CIITA through the downmodulation of IFN regulatory factor-1 (IRF-1).

PubMed

Velásquez, Lis N; Milillo, M Ayelén; Delpino, M Victoria; Trotta, Aldana; Fernández, Pablo; Pozner, Roberto G; Lang, Roland; Balboa, Luciana; Giambartolomei, Guillermo H; Barrionuevo, Paula

2017-03-01

Brucella abortus is an intracellular pathogen capable of surviving inside of macrophages. The success of B. abortus as a chronic pathogen relies on its ability to orchestrate different strategies to evade the adaptive CD4 + T cell responses that it elicits. Previously, we demonstrated that B. abortus inhibits the IFN-γ-induced surface expression of MHC class II (MHC-II) molecules on human monocytes, and this phenomenon correlated with a reduction in antigen presentation. However, the molecular mechanisms, whereby B. abortus is able to down-regulate the expression of MHC-II, remained to be elucidated. In this study, we demonstrated that B. abortus infection inhibits the IFN-γ-induced transcription of MHC-II, transactivator (CIITA) and MHC-II genes. Accordingly, we observed that the synthesis of MHC-II proteins was also diminished. B. abortus was not only able to reduce the expression of mature MHC-II, but it also inhibited the expression of invariant chain (Ii)-associated immature MHC-II molecules. Outer membrane protein 19 (Omp19), a prototypical B. abortus lipoprotein, diminished the expression of MHC-II and CIITA transcripts to the same extent as B. abortus infection. IL-6 contributes to these down-regulatory phenomena. In addition, B. abortus and its lipoproteins, through IL-6 secretion, induced the transcription of the negative regulators of IFN-γ signaling, suppressor of cytokine signaling (SOCS)-1 and -3, without interfering with STAT1 activation. Yet, B. abortus lipoproteins via IL-6 inhibit the expression of IFN regulatory factor 1 (IRF-1), a critical regulatory transcription factor for CIITA induction. Overall, these results indicate that B. abortus inhibits the expression of MHC-II molecules at very early points in their synthesis and in this way, may prevent recognition by T cells establishing a chronic infection. © Society for Leukocyte Biology.

[ASSESSMENT OF EXTREME FACTORS OF SHIFT WORK IN ARCTIC CONDITIONS BY WORKERS WITH DIFFERENT REGULATORY PROCESSES].

PubMed

Korneeva, Ya A; Simonova, N N

2016-01-01

A man working on a shift basis in the Arctic, every day is under the influence of various extreme factors which are inevitable for oil and gas indudtry. To adapt to shift work employees use various resources of the individual. The purpose of research is the determination of personal resources of shift workers to overcome the adverse factors of the environment in the Arctic. The study involved 191 builder of main gas pipelines, working in shifts in the Tyumen region (the length of the shift 52 days of arrival) at the age of 23 to 59 (mean age 34.9 ± 8.1) years. Methods: psychological testing, questioning, observation, descriptive statistics, discriminant step by step analysis. There was revealed the correlation between the subjective assessment of the majority of adverse climatic factors in the regulatory process "assessment of results"; production factors--regulatory processes such as flexibility, autonomy, simulation, and the general level of self-regulation; social factors are more associated with the severity of such regulatory processes, flexibility and evaluation of results.

Protein-protein interactions in the regulation of WRKY transcription factors.

PubMed

Chi, Yingjun; Yang, Yan; Zhou, Yuan; Zhou, Jie; Fan, Baofang; Yu, Jing-Quan; Chen, Zhixiang

2013-03-01

It has been almost 20 years since the first report of a WRKY transcription factor, SPF1, from sweet potato. Great progress has been made since then in establishing the diverse biological roles of WRKY transcription factors in plant growth, development, and responses to biotic and abiotic stress. Despite the functional diversity, almost all analyzed WRKY proteins recognize the TTGACC/T W-box sequences and, therefore, mechanisms other than mere recognition of the core W-box promoter elements are necessary to achieve the regulatory specificity of WRKY transcription factors. Research over the past several years has revealed that WRKY transcription factors physically interact with a wide range of proteins with roles in signaling, transcription, and chromatin remodeling. Studies of WRKY-interacting proteins have provided important insights into the regulation and mode of action of members of the important family of transcription factors. It has also emerged that the slightly varied WRKY domains and other protein motifs conserved within each of the seven WRKY subfamilies participate in protein-protein interactions and mediate complex functional interactions between WRKY proteins and between WRKY and other regulatory proteins in the modulation of important biological processes. In this review, we summarize studies of protein-protein interactions for WRKY transcription factors and discuss how the interacting partners contribute, at different levels, to the establishment of the complex regulatory and functional network of WRKY transcription factors.

[Strengthening health regulation in the Americas: regulatory authorities of regional reference].

PubMed

Ojeda, Lisette Pérez; Cristiá, Rafael Pérez

2016-05-01

Health technology regulation and quality assurance are critical to the development of national pharmaceutical policies, and implementing these actions is the responsibility of national regulatory authorities, whose level of development and maturity affect the quality, safety, and effectiveness of the products made available to the public. On the initiative of the regulatory authorities themselves, together with the Pan American Health Organization, the Region of the Americas promotes the strengthening of health regulation through an evaluation and certification process that allows for the designation of regulatory authorities of regional reference for drugs and biological products. Over the period from its implementation to the present, six authorities have been certified and one is in the process of obtaining certification. These authorities work jointly and promote dialogue and regulatory convergence, information-sharing to facilitate regulatory decision making, and regional cooperation to support the establishment of other authorities in the Region--actions having direct impact on access to effective and quality-assured health technologies. Their combined efforts have led to the recognition of this process of evaluation and certification by the World Health Organization (WHO). Among the actions resulting from the International Consultation on Regulatory Systems Strengthening, WHO recommended taking a close look at this model to assess its potential scale-up at the global level.

KH-type splicing regulatory protein is regulated by nuclear factor-κB signaling to mediate innate immunity in Caco-2 cells infected by Salmonella enteritidis.

PubMed

Nie, Yuanyang; Cao, Mei; Wu, Daoyan; Li, Ningzhe; Peng, Jingshan; Yi, Sijun; Yang, Xiaofan; Zhang, Mao; Hu, Guoku; Zhao, Jian

2018-05-04

Salmonella enteritidis infection occurs in enterogenous diseases, such as gastroenteritis and parenteral focal infection, which often involve inflammation of intestinal epithelial cells. The nuclear factor kappa B (NF-κB) pathway participates in the innate immune response to many gram-negative pathogenic bacteria and initiates inflammation in epithelial cells. KH-type splicing regulatory protein (KSRP) is a multi-domain RNA-binding protein that recruits the exosome-containing mRNA degradation complex to mRNAs coding for inflammatory response factors. However, it remains unclear whether KSRP is regulated by NF-κB signaling pathway in response to S. enteritidis infection and affects the development of inflammation. Accordingly, in this study, we investigated the role of KSRP in mediating the response to S. enteritidis in Caco-2 cells. The data revealed that S. enteritidis infection decreased KSRP expression, which was suppressed by blocking the NF-κB pathway. Additionally, S. enteritidis infection significantly increased the expression of inducible nitric oxide synthase and cyclooxygenase-2. Overexpression of KSRP reduced the expression levels of inflammatory factors in Caco-2 cells. KSRP was regulated by the NF-κB signaling pathway and participated in mediating the innate immune response to S. enteritidis infection in Caco-2 cells, and KSRP acted as a negative regulator of inflammatory gene expression.

Transcription factor clusters regulate genes in eukaryotic cells

PubMed Central

Hedlund, Erik G; Friemann, Rosmarie; Hohmann, Stefan

2017-01-01

Transcription is regulated through binding factors to gene promoters to activate or repress expression, however, the mechanisms by which factors find targets remain unclear. Using single-molecule fluorescence microscopy, we determined in vivo stoichiometry and spatiotemporal dynamics of a GFP tagged repressor, Mig1, from a paradigm signaling pathway of Saccharomyces cerevisiae. We find the repressor operates in clusters, which upon extracellular signal detection, translocate from the cytoplasm, bind to nuclear targets and turnover. Simulations of Mig1 configuration within a 3D yeast genome model combined with a promoter-specific, fluorescent translation reporter confirmed clusters are the functional unit of gene regulation. In vitro and structural analysis on reconstituted Mig1 suggests that clusters are stabilized by depletion forces between intrinsically disordered sequences. We observed similar clusters of a co-regulatory activator from a different pathway, supporting a generalized cluster model for transcription factors that reduces promoter search times through intersegment transfer while stabilizing gene expression. PMID:28841133

Integration and diversity of the regulatory network composed of Maf and CNC families of transcription factors.

PubMed

Motohashi, Hozumi; O'Connor, Tania; Katsuoka, Fumiki; Engel, James Douglas; Yamamoto, Masayuki

2002-07-10

Recent progress in the analysis of transcriptional regulation has revealed the presence of an exquisite functional network comprising the Maf and Cap 'n' collar (CNC) families of regulatory proteins, many of which have been isolated. Among Maf factors, large Maf proteins are important in the regulation of embryonic development and cell differentiation, whereas small Maf proteins serve as obligatory heterodimeric partner molecules for members of the CNC family. Both Maf homodimers and CNC-small Maf heterodimers bind to the Maf recognition element (MARE). Since the MARE contains a consensus TRE sequence recognized by AP-1, Jun and Fos family members may act to compete or interfere with the function of CNC-small Maf heterodimers. Overall then, the quantitative balance of transcription factors interacting with the MARE determines its transcriptional activity. Many putative MARE-dependent target genes such as those induced by antioxidants and oxidative stress are under concerted regulation by the CNC family member Nrf2, as clearly proven by mouse germline mutagenesis. Since these genes represent a vital aspect of the cellular defense mechanism against oxidative stress, Nrf2-null mutant mice are highly sensitive to xenobiotic and oxidative insults. Deciphering the molecular basis of the regulatory network composed of Maf and CNC families of transcription factors will undoubtedly lead to a new paradigm for the cooperative function of transcription factors.

The Adolescent Self-Regulatory Inventory: The Development and Validation of a Questionnaire of Short-Term and Long-Term Self-Regulation

ERIC Educational Resources Information Center

Moilanen, Kristin L.

2007-01-01

This manuscript presents a study in which the factor structure and validity of the Adolescent Self-Regulatory Inventory (ASRI) were examined. The ASRI is a theoretically-based questionnaire that taps two temporal aspects of self-regulation (regulation in the short- and long-term). 169 students in the 6th, 8th, and 10th grades of a small,…

Regulatory or regulating publics? The European Union's regulation of emerging health technologies and citizen participation.

PubMed

Flear, Mark L; Pickersgill, Martyn D

2013-01-01

'Citizen participation' includes various participatory techniques and is frequently viewed as an unproblematic and important social good when used as part of the regulation of the innovation and implementation of science and technology. This is perhaps especially evident in debates around 'anticipatory governance' or 'upstream engagement'. Here, we interrogate this thesis using the example of the European Union's regulation of emerging health technologies (such as nanotechnology). In this case, citizen participation in regulatory debate is concerned with innovative objects for medical application that are considered to be emergent or not yet concrete. Through synthesising insights from law, regulatory studies, critical theory, and science and technology studies, we seek to cast new light on the promises, paradoxes, and pitfalls of citizen participation as a tool or technology of regulation in itself. As such we aim to generate a new vantage point from which to view the values and sociotechnical imaginaries that are both 'designed-in' and 'designed-out' of citizen participation. In so doing, we show not only how publics (do not) regulate technologies, but also how citizens themselves are regulated through the techniques of participation.

REGULATORY OR REGULATING PUBLICS? THE EUROPEAN UNION'S REGULATION OF EMERGING HEALTH TECHNOLOGIES AND CITIZEN PARTICIPATION

PubMed Central

Flear, Mark L.; Pickersgill, Martyn D.

2013-01-01

‘Citizen participation’ includes various participatory techniques and is frequently viewed as an unproblematic and important social good when used as part of the regulation of the innovation and implementation of science and technology. This is perhaps especially evident in debates around ‘anticipatory governance’ or ‘upstream engagement’. Here, we interrogate this thesis using the example of the European Union's regulation of emerging health technologies (such as nanotechnology). In this case, citizen participation in regulatory debate is concerned with innovative objects for medical application that are considered to be emergent or not yet concrete. Through synthesising insights from law, regulatory studies, critical theory, and science and technology studies, we seek to cast new light on the promises, paradoxes, and pitfalls of citizen participation as a tool or technology of regulation in itself. As such we aim to generate a new vantage point from which to view the values and sociotechnical imaginaries that are both ‘designed-in’ and ‘designed-out’ of citizen participation. In so doing, we show not only how publics (do not) regulate technologies, but also how citizens themselves are regulated through the techniques of participation. PMID:23222171

Targeting Interferon Regulatory Factor for Cardiometabolic Diseases: Opportunities and Challenges.

PubMed

Zhang, Yaxing; Zhang, Xiao-Jing; Li, Hongliang

2017-01-01

The pathological activation of innate immune system may contribute to the development of cardiometabolic diseases. The interferon regulatory factor (IRF) family members, which are the major transcription factors in innate immune signaling, are implicated in cardiometabolic diseases. The aim of this review is to summary the current knowledge of the biological functions of IRFs in innate immune responses and immune cell development, and highlight our contemporary understanding of the functions and molecular mechanisms of IRFs in metabolic diseases, cardiovascular remodeling, and stroke. IRFs are the essential regulators of cardiometabolic diseases via immune-dependent and - independent manners. IRFs signaling is the promising target to manage the initiation and progression of cardiometabolic disorders. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Regulatory states in the developmental control of gene expression.

PubMed

Peter, Isabelle S

2017-09-01

A growing body of evidence shows that gene expression in multicellular organisms is controlled by the combinatorial function of multiple transcription factors. This indicates that not the individual transcription factors or signaling molecules, but the combination of expressed regulatory molecules, the regulatory state, should be viewed as the functional unit in gene regulation. Here, I discuss the concept of the regulatory state and its proposed role in the genome-wide control of gene expression. Recent analyses of regulatory gene expression in sea urchin embryos have been instrumental for solving the genomic control of cell fate specification in this system. Some of the approaches that were used to determine the expression of regulatory states during sea urchin embryogenesis are reviewed. Significant developmental changes in regulatory state expression leading to the distinct specification of cell fates are regulated by gene regulatory network circuits. How these regulatory state transitions are encoded in the genome is illuminated using the sea urchin endoderm-mesoderms cell fate decision circuit as an example. These observations highlight the importance of considering developmental gene regulation, and the function of individual transcription factors, in the context of regulatory states. © The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Supporting the self-regulatory resource: does conscious self-regulation incidentally prime nonconscious support processes?

PubMed

Dorris, Derek C

2009-11-01

Ego-depletion (depletion of self-regulatory strength) can impair conscious efforts at self-regulation. Research into nonconscious self-regulation has demonstrated that preconscious automaticity and implementation intentions can automatically carry out regulatory tasks during times of ego-depletion. However, preconscious automaticity can only emerge during well-practiced tasks while implementation intentions can only support tasks that have been explicitly planned. Thus, when it comes to supporting the conscious self-regulation of nonroutine and unplanned behaviour during times of ego-depletion these processes should be ineffective. However, it is argued here that because the conscious self-regulation of nonroutine and unplanned behaviour can incidentally prime the underlying mental representations those primed representations can be postconsciously re-activated to support that behaviour during times of ego-depletion. Postconscious self-regulation might, therefore, support a type of self-regulatory behaviour that has, thus far, not been associated with any form of support.

The FasX Small Regulatory RNA Negatively Regulates the Expression of Two Fibronectin-Binding Proteins in Group A Streptococcus.

PubMed

Danger, Jessica L; Makthal, Nishanth; Kumaraswami, Muthiah; Sumby, Paul

2015-12-01

The group A Streptococcus (GAS; Streptococcus pyogenes) causes more than 700 million human infections each year. The success of this pathogen can be traced in part to the extensive arsenal of virulence factors that are available for expression in temporally and spatially specific manners. To modify the expression of these virulence factors, GAS use both protein- and RNA-based regulators, with the best-characterized RNA-based regulator being the small regulatory RNA (sRNA) FasX. FasX is a 205-nucleotide sRNA that contributes to GAS virulence by enhancing the expression of the thrombolytic secreted virulence factor streptokinase and by repressing the expression of the collagen-binding cell surface pili. Here, we have expanded the FasX regulon, showing that this sRNA also negatively regulates the expression of the adhesion- and internalization-promoting, fibronectin-binding proteins PrtF1 and PrtF2. FasX posttranscriptionally regulates the expression of PrtF1/2 through a mechanism that involves base pairing to the prtF1 and prtF2 mRNAs within their 5' untranslated regions, overlapping the mRNA ribosome-binding sites. Thus, duplex formation between FasX and the prtF1 and prtF2 mRNAs blocks ribosome access, leading to an inhibition of mRNA translation. Given that FasX positively regulates the expression of the spreading factor streptokinase and negatively regulates the expression of the collagen-binding pili and of the fibronectin-binding PrtF1/2, our data are consistent with FasX functioning as a molecular switch that governs the transition of GAS between the colonization and dissemination stages of infection. More than half a million deaths each year are a consequence of infections caused by GAS. Insights into how this pathogen regulates the production of proteins during infection may facilitate the development of novel therapeutic or preventative regimens aimed at inhibiting this activity. Here, we have expanded insight into the regulatory activity of the GAS small

iTAK: A program for genome-wide prediction and classification of plant transcription factors, transcriptional regulators and protein kinases

USDA-ARS?s Scientific Manuscript database

Transcription factors (TFs) are proteins that regulate the expression of target genes by binding to specific elements in their regulatory regions. Transcriptional regulators (TRs) also regulate the expression of target genes; however, they operate indirectly via interaction with the basal transcript...

Understanding Transcription Factor Regulation by Integrating Gene Expression and DNase I Hypersensitive Sites.

PubMed

Wang, Guohua; Wang, Fang; Huang, Qian; Li, Yu; Liu, Yunlong; Wang, Yadong

2015-01-01

Transcription factors are proteins that bind to DNA sequences to regulate gene transcription. The transcription factor binding sites are short DNA sequences (5-20 bp long) specifically bound by one or more transcription factors. The identification of transcription factor binding sites and prediction of their function continue to be challenging problems in computational biology. In this study, by integrating the DNase I hypersensitive sites with known position weight matrices in the TRANSFAC database, the transcription factor binding sites in gene regulatory region are identified. Based on the global gene expression patterns in cervical cancer HeLaS3 cell and HelaS3-ifnα4h cell (interferon treatment on HeLaS3 cell for 4 hours), we present a model-based computational approach to predict a set of transcription factors that potentially cause such differential gene expression. Significantly, 6 out 10 predicted functional factors, including IRF, IRF-2, IRF-9, IRF-1 and IRF-3, ICSBP, belong to interferon regulatory factor family and upregulate the gene expression levels responding to the interferon treatment. Another factor, ISGF-3, is also a transcriptional activator induced by interferon alpha. Using the different transcription factor binding sites selected criteria, the prediction result of our model is consistent. Our model demonstrated the potential to computationally identify the functional transcription factors in gene regulation.

PlantTFDB 4.0: toward a central hub for transcription factors and regulatory interactions in plants.

PubMed

Jin, Jinpu; Tian, Feng; Yang, De-Chang; Meng, Yu-Qi; Kong, Lei; Luo, Jingchu; Gao, Ge

2017-01-04

With the goal of providing a comprehensive, high-quality resource for both plant transcription factors (TFs) and their regulatory interactions with target genes, we upgraded plant TF database PlantTFDB to version 4.0 (http://planttfdb.cbi.pku.edu.cn/). In the new version, we identified 320 370 TFs from 165 species, presenting a more comprehensive genomic TF repertoires of green plants. Besides updating the pre-existing abundant functional and evolutionary annotation for identified TFs, we generated three new types of annotation which provide more directly clues to investigate functional mechanisms underlying: (i) a set of high-quality, non-redundant TF binding motifs derived from experiments; (ii) multiple types of regulatory elements identified from high-throughput sequencing data; (iii) regulatory interactions curated from literature and inferred by combining TF binding motifs and regulatory elements. In addition, we upgraded previous TF prediction server, and set up four novel tools for regulation prediction and functional enrichment analyses. Finally, we set up a novel companion portal PlantRegMap (http://plantregmap.cbi.pku.edu.cn) for users to access the regulation resource and analysis tools conveniently. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

Regulatory focus and generalized trust: the impact of prevention-focused self-regulation on trusting others.

PubMed

Keller, Johannes; Mayo, Ruth; Greifeneder, Rainer; Pfattheicher, Stefan

2015-01-01

The current research suggests that taking self-regulatory mechanisms into account provides insights regarding individuals' responses to threats in social interactions. In general, based on the notion that a prevention-focused orientation of self-regulation is associated with a need for security and a vigilant tendency to avoid losses and other types of negative events we advocate that a prevention-focused orientation, both as a disposition as well as a situationally induced state, lowers generalized trust, thus hindering cooperation within social interactions that entail threats. Specifically, we found that the more individuals' habitual self-regulatory orientation is dominated by a prevention focus, the less likely they are to score high on a self-report measure of generalized trust (Study 1), and to express trust in a trust game paradigm as manifested in lower sums of transferred money (Studies 2 and 3). Similar findings were found when prevention focus was situationally manipulated (Study 4). Finally, one possible factor underlying the impact of prevention-focused self-regulation on generalized trust was demonstrated as individuals with a special sensitivity to negative information were significantly affected by a subtle prevention focus manipulation (versus control condition) in that they reacted with reduced trust in the trust game (Study 5). In sum, the current findings document the crucial relevance of self-regulatory orientations as conceptualized in regulatory focus theory regarding generalized trust and responses to threats within a social interaction. The theoretical and applied implications of the findings are discussed.

Uncovering transcription factor and microRNA risk regulatory pathways associated with osteoarthritis by network analysis.

PubMed

Song, Zhenhua; Zhang, Chi; He, Lingxiao; Sui, Yanfang; Lin, Xiafei; Pan, Jingjing

2018-06-12

Osteoarthritis (OA) is the most common form of joint disease. The development of inflammation have been considered to play a key role during the progression of OA. Regulatory pathways are known to play crucial roles in many pathogenic processes. Thus, deciphering these risk regulatory pathways is critical for elucidating the mechanisms underlying OA. We constructed an OA-specific regulatory network by integrating comprehensive curated transcription and post-transcriptional resource involving transcription factor (TF) and microRNA (miRNA). To deepen our understanding of underlying molecular mechanisms of OA, we developed an integrated systems approach to identify OA-specific risk regulatory pathways. In this study, we identified 89 significantly differentially expressed genes between normal and inflamed areas of OA patients. We found the OA-specific regulatory network was a standard scale-free network with small-world properties. It significant enriched many immune response-related functions including leukocyte differentiation, myeloid differentiation and T cell activation. Finally, 141 risk regulatory pathways were identified based on OA-specific regulatory network, which contains some known regulator of OA. The risk regulatory pathways may provide clues for the etiology of OA and be a potential resource for the discovery of novel OA-associated disease genes. Copyright © 2018 Elsevier Inc. All rights reserved.

Sterols regulate 3β-hydroxysterol Δ24-reductase (DHCR24) via dual sterol regulatory elements: cooperative induction of key enzymes in lipid synthesis by Sterol Regulatory Element Binding Proteins.

PubMed

Zerenturk, Eser J; Sharpe, Laura J; Brown, Andrew J

2012-10-01

3β-Hydroxysterol Δ24-reductase (DHCR24) catalyzes a final step in cholesterol synthesis, and has been ascribed diverse functions, such as being anti-apoptotic and anti-inflammatory. How this enzyme is regulated transcriptionally by sterols is currently unclear. Some studies have suggested that its expression is regulated by Sterol Regulatory Element Binding Proteins (SREBPs) while another suggests it is through the Liver X Receptor (LXR). However, these transcription factors have opposing effects on cellular sterol levels, so it is likely that one predominates. Here we establish that sterol regulation of DHCR24 occurs predominantly through SREBP-2, and identify the particular region of the DHCR24 promoter to which SREBP-2 binds. We demonstrate that sterol regulation is mediated by two sterol regulatory elements (SREs) in the promoter of the gene, assisted by two nearby NF-Y binding sites. Moreover, we present evidence that the dual SREs work cooperatively to regulate DHCR24 expression by comparison to two known SREBP target genes, the LDL receptor with one SRE, and farnesyl-diphosphate farnesyltransferase 1, with two SREs. Copyright © 2012 Elsevier B.V. All rights reserved.

Pharmacogenomics: a new clinical or regulatory paradigm? European experiences of pharmacogenomics in drug regulation and regulatory initiatives.

PubMed

Prasad, Krishna; Breckenridge, Alasdair

2011-10-01

Are regulatory agencies and processes up to speed? This is an often asked question. Recent advances in science and the improved knowledge of the human genome have a considerable influence on drug development and their impact on the regulatory aspect is also significant for several reasons, including changing stakeholder expectations and treatment paradigms. One of the challenges faced by the regulators is the need to adapt regulatory processes to accommodate the newer methodologies and techniques while ensuring that the biomarkers, tests and/or diagnostics, and the clinical trials are appropriate and fit for purpose. The change in emphasis in pharmacological treatment from a phenotype-based approach to newer methods is attractive but is it ready for universal adoption? This paper details some of the regulatory responses to the developments in this area. Crown Copyright © 2011. Published by Elsevier Ltd. All rights reserved.

Identification of trans-acting factors regulating SamDC expression in Oryza sativa

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

Basu, Supratim, E-mail: supratim_genetics@yahoo.co.in; Division of Plant Biology, Bose Institute, Kolkata; Roychoudhury, Aryadeep

2014-03-07

Highlights: • Identification of cis elements responsible for SamDC expression by in silico analysis. • qPCR analysis of SamDC expression to abiotic and biotic stress treatments. • Detection of SamDC regulators using identified cis-elements as probe by EMSA. • Southwestern Blot analysis to predict the size of the trans-acting factors. - Abstract: Abiotic stress affects the growth and productivity of crop plants; to cope with the adverse environmental conditions, plants have developed efficient defense machinery comprising of antioxidants like phenolics and flavonoids, and osmolytes like polyamines. SamDC is a key enzyme in the polyamine biosynthesis pathway in plants. In ourmore » present communication we have done in silico analysis of the promoter region of SamDC to look for the presence of different cis-regulatory elements contributing to its expression. Based on the presence of different cis-regulatory elements we completed comparative analysis of SamDC gene expression in rice lamina of IR-29 and Nonabokra by qPCR in response to the abiotic stress treatments of salinity, drought, cold and the biotic stress treatments of ABA and light. Additionally, to explore the role of the cis-regulatory elements in regulating the expression of SamDC gene in plants we comparatively analyzed the binding of rice nuclear proteins prepared from IR-29 and Nonabokra undergoing various stress treatments. The intensity of the complex formed was low and inducible in IR-29 in contrast to Nonabokra. Southwestern blot analysis helped in predicting the size of the trans-acting factors binding to these cis-elements. To our knowledge this is the first report on the comprehensive analysis of SamDC gene expression in rice and identification of the trans-acting factors regulating its expression.« less

Method to determine transcriptional regulation pathways in organisms

DOEpatents

Gardner, Timothy S.; Collins, James J.; Hayete, Boris; Faith, Jeremiah

2012-11-06

The invention relates to computer-implemented methods and systems for identifying regulatory relationships between expressed regulating polypeptides and targets of the regulatory activities of such regulating polypeptides. More specifically, the invention provides a new method for identifying regulatory dependencies between biochemical species in a cell. In particular embodiments, provided are computer-implemented methods for identifying a regulatory interaction between a transcription factor and a gene target of the transcription factor, or between a transcription factor and a set of gene targets of the transcription factor. Further provided are genome-scale methods for predicting regulatory interactions between a set of transcription factors and a corresponding set of transcriptional target substrates thereof.

Differential Regulation of Native Estrogen Receptor-Regulatory Elements by Estradiol, Tamoxifen, and Raloxifene

PubMed Central

Levy, Nitzan; Tatomer, Dierdre; Herber, Candice B.; Zhao, Xiaoyue; Tang, Hui; Sargeant, Toby; Ball, Lonnele J.; Summers, Jonathan; Speed, Terence P.; Leitman, Dale C.

2008-01-01

Estrogen receptors (ERs) regulate gene transcription by interacting with regulatory elements. Most information regarding how ER activates genes has come from studies using a small set of target genes or simple consensus sequences such as estrogen response element, activator protein 1, and Sp1 elements. However, these elements cannot explain the differences in gene regulation patterns and clinical effects observed with estradiol (E2) and selective estrogen receptor modulators. To obtain a greater understanding of how E2 and selective estrogen receptor modulators differentially regulate genes, it is necessary to investigate their action on a more comprehensive set of native regulatory elements derived from ER target genes. Here we used chromatin immunoprecipitation-cloning and sequencing to isolate 173 regulatory elements associated with ERα. Most elements were found in the introns (38%) and regions greater than 10 kb upstream of the transcription initiation site (38%); 24% of the elements were found in the proximal promoter region (<10 kb). Only 11% of the elements contained a classical estrogen response element; 23% of the elements did not have any known response elements, including one derived from the naked cuticle homolog gene, which was associated with the recruitment of p160 coactivators. Transfection studies found that 80% of the 173 elements were regulated by E2, raloxifene, or tamoxifen with ERα or ERβ. Tamoxifen was more effective than raloxifene at activating the elements with ERα, whereas raloxifene was superior with ERβ. Our findings demonstrate that E2, tamoxifen, and raloxifene differentially regulate native ER-regulatory elements isolated by chromatin immunoprecipitation with ERα and ERβ. PMID:17962382

Characterization of the evolution of the pharmaceutical regulatory environment.

PubMed

Shafiei, Nader; Ford, James L; Morecroft, Charles W; Lisboa, Paulo J; Taylor, Mark J

2013-01-01

This paper is part of a research study that is intended to identify pharmaceutical quality risks induced by the ongoing transformation in the industry. This study establishes the current regulatory context by characterizing the development of the pharmaceutical regulatory environment. The regulatory environment is one of the most important external factors that affects a company's organization, processes, and technological strategy. This is especially the case with the pharmaceutical industry, where its products affect the quality of life of the consumers. The quantitative analysis of regulatory events since 1813 and review of the associated literature resulted in identification of six factors influencing the regulatory environment, namely public health protection, public health promotion, crisis management, harmonization, innovation, and modernization. From 1813 to the 1970s the focus of regulators was centered on crisis management and public health protection-a basic mission that has remained consistent over the years. Since the 1980s a gradual move in the regulatory environment towards a greater focus on public health promotion, international harmonization, innovation, and agency modernization may be seen. The pharmaceutical industry is currently going through changes that affect the way it performs its research, manufacturing, and regulatory activities. The impact of these changes on the approaches to quality risk management requires more understanding. The authors are engaged in research to identify elements of the changes that influence pharmaceutical quality. As quality requirements are an integral part of the pharmaceutical regulations, a comprehensive understanding of these regulations is seen as the first step. The results of this study show that (i) public health protection, public health promotion, crisis management, harmonization, innovation, and modernization are factors that affect regulations in the pharmaceutical industry; (ii) the regulators' main

Uncovering MicroRNA and Transcription Factor Mediated Regulatory Networks in Glioblastoma

PubMed Central

Sun, Jingchun; Gong, Xue; Purow, Benjamin; Zhao, Zhongming

2012-01-01

Glioblastoma multiforme (GBM) is the most common and lethal brain tumor in humans. Recent studies revealed that patterns of microRNA (miRNA) expression in GBM tissue samples are different from those in normal brain tissues, suggesting that a number of miRNAs play critical roles in the pathogenesis of GBM. However, little is yet known about which miRNAs play central roles in the pathology of GBM and their regulatory mechanisms of action. To address this issue, in this study, we systematically explored the main regulation format (feed-forward loops, FFLs) consisting of miRNAs, transcription factors (TFs) and their impacting GBM-related genes, and developed a computational approach to construct a miRNA-TF regulatory network. First, we compiled GBM-related miRNAs, GBM-related genes, and known human TFs. We then identified 1,128 3-node FFLs and 805 4-node FFLs with statistical significance. By merging these FFLs together, we constructed a comprehensive GBM-specific miRNA-TF mediated regulatory network. Then, from the network, we extracted a composite GBM-specific regulatory network. To illustrate the GBM-specific regulatory network is promising for identification of critical miRNA components, we specifically examined a Notch signaling pathway subnetwork. Our follow up topological and functional analyses of the subnetwork revealed that six miRNAs (miR-124, miR-137, miR-219-5p, miR-34a, miR-9, and miR-92b) might play important roles in GBM, including some results that are supported by previous studies. In this study, we have developed a computational framework to construct a miRNA-TF regulatory network and generated the first miRNA-TF regulatory network for GBM, providing a valuable resource for further understanding the complex regulatory mechanisms in GBM. The observation of critical miRNAs in the Notch signaling pathway, with partial verification from previous studies, demonstrates that our network-based approach is promising for the identification of new and important

The role of personal self-regulation and regulatory teaching to predict motivational-affective variables, achievement, and satisfaction: a structural model

PubMed Central

De la Fuente, Jesus; Zapata, Lucía; Martínez-Vicente, Jose M.; Sander, Paul; Cardelle-Elawar, María

2014-01-01

The present investigation examines how personal self-regulation (presage variable) and regulatory teaching (process variable of teaching) relate to learning approaches, strategies for coping with stress, and self-regulated learning (process variables of learning) and, finally, how they relate to performance and satisfaction with the learning process (product variables). The objective was to clarify the associative and predictive relations between these variables, as contextualized in two different models that use the presage-process-product paradigm (the Biggs and DEDEPRO models). A total of 1101 university students participated in the study. The design was cross-sectional and retrospective with attributional (or selection) variables, using correlations and structural analysis. The results provide consistent and significant empirical evidence for the relationships hypothesized, incorporating variables that are part of and influence the teaching–learning process in Higher Education. Findings confirm the importance of interactive relationships within the teaching–learning process, where personal self-regulation is assumed to take place in connection with regulatory teaching. Variables that are involved in the relationships validated here reinforce the idea that both personal factors and teaching and learning factors should be taken into consideration when dealing with a formal teaching–learning context at university. PMID:25964764

RNA-Sequencing Analysis Reveals a Regulatory Role for Transcription Factor Fezf2 in the Mature Motor Cortex

PubMed Central

Clare, Alison J.; Wicky, Hollie E.; Empson, Ruth M.; Hughes, Stephanie M.

2017-01-01

Forebrain embryonic zinc finger (Fezf2) encodes a transcription factor essential for the specification of layer 5 projection neurons (PNs) in the developing cerebral cortex. As with many developmental transcription factors, Fezf2 continues to be expressed into adulthood, suggesting it remains crucial to the maintenance of neuronal phenotypes. Despite the continued expression, a function has yet to be explored for Fezf2 in the PNs of the developed cortex. Here, we investigated the role of Fezf2 in mature neurons, using lentiviral-mediated delivery of a shRNA to conditionally knockdown the expression of Fezf2 in the mouse primary motor cortex (M1). RNA-sequencing analysis of Fezf2-reduced M1 revealed significant changes to the transcriptome, identifying a regulatory role for Fezf2 in the mature M1. Kyoto Encyclopedia Genes and Genomes (KEGG) pathway analyses of Fezf2-regulated genes indicated a role in neuronal signaling and plasticity, with significant enrichment of neuroactive ligand-receptor interaction, cell adhesion molecules and calcium signaling pathways. Gene Ontology analysis supported a functional role for Fezf2-regulated genes in neuronal transmission and additionally indicated an importance in the regulation of behavior. Using the mammalian phenotype ontology database, we identified a significant overrepresentation of Fezf2-regulated genes associated with specific behavior phenotypes, including associative learning, social interaction, locomotor activation and hyperactivity. These roles were distinct from that of Fezf2-regulated genes identified in development, indicating a dynamic transition in Fezf2 function. Together our findings demonstrate a regulatory role for Fezf2 in the mature brain, with Fezf2-regulated genes having functional roles in sustaining normal neuronal and behavioral phenotypes. These results support the hypothesis that developmental transcription factors are important for maintaining neuron transcriptomes and that disruption of their

Regulation of cell fate determination by single-repeat R3 MYB transcription factors in Arabidopsis

PubMed Central

Wang, Shucai; Chen, Jin-Gui

2014-01-01

MYB transcription factors regulate multiple aspects of plant growth and development. Among the large family of MYB transcription factors, single-repeat R3 MYBs are characterized by their short sequence (<120 amino acids) consisting largely of the single MYB DNA-binding repeat. In the model plant Arabidopsis, R3 MYBs mediate lateral inhibition during epidermal patterning and are best characterized for their regulatory roles in trichome and root hair development. R3 MYBs act as negative regulators for trichome formation but as positive regulators for root hair development. In this article, we provide a comprehensive review on the role of R3 MYBs in the regulation of cell type specification in the model plant Arabidopsis. PMID:24782874

An apple NAC transcription factor negatively regulates cold tolerance via CBF-dependent pathway.

PubMed

An, Jian-Ping; Li, Rui; Qu, Feng-Jia; You, Chun-Xiang; Wang, Xiao-Fei; Hao, Yu-Jin

2018-02-01

Cold stress is an adverse stimulus that affects plant growth and development, and the C-repeat binding factor (CBF) cold-regulatory cascade has been regarded as a master regulator in the plant response to cold stress. Here, we showed that a NAC transcription factor modulated low-temperature tolerance. MdNAC029/MdNAP, an apple NAC gene was isolated and its role in regulating cold tolerance was investigated. MdNAC029 was responsive to low-temperature treatment, and over-expression of MdNAC029 reduced cold tolerance in apple calli and Arabidopsis. Furthermore, EMSA assays and transient expression assays demonstrated that MdNAC029 directly repressed the expression of MdCBF1 and MdCBF4 by binding to their promoters. Taken together, our data suggest that MdNAC029 functions as a negative regulator in regulating plant cold tolerance in a CBF-dependent manner, providing a deeper understanding of NAC transcription-factor-mediated cold tolerance. Copyright © 2017 Elsevier GmbH. All rights reserved.

Identification of a cis-Regulatory Element Involved in Phytochrome Down-Regulated Expression of the Pea Small GTPase Gene pra21

PubMed Central

Inaba, Takehito; Nagano, Yukio; Sakakibara, Toshihiro; Sasaki, Yukiko

1999-01-01

The pra2 gene encodes a pea (Pisum sativum) small GTPase belonging to the YPT/rab family, and its expression is down-regulated by light, mediated by phytochrome. We have isolated and characterized a genomic clone of this gene and constructed a fusion DNA of its 5′-upstream region in front of the gene for firefly luciferase. Using this construct in a transient assay, we determined a pra2 cis-regulatory region sufficient to direct the light down-regulation of the luciferase reporter gene. Both 5′- and internal deletion analyses revealed that the 93-bp sequence between −734 and −642 from the transcriptional start site was important for phytochrome down-regulation. Gain-of-function analysis showed that this 93-bp region could confer light down-regulation when fused to the cauliflower mosaic virus 35S promoter. Furthermore, linker-scanning analysis showed that a 12-bp sequence within the 93-bp region mediated phytochrome down-regulation. Gel-retardation analysis showed the presence of a nuclear factor that was specifically bound to the 12-bp sequence in vitro. These results indicate that this element is a cis-regulatory element involved in phytochrome down-regulated expression. PMID:10364400

Childcare Regulations: Regulatory Enforcement in Ireland. What Happens When the Inspector Calls?

ERIC Educational Resources Information Center

Moloney, Mary

2016-01-01

Childcare regulations ensure children's rights to Early Childhood Care and Education settings that protect them from harm and promote their healthy development. To ensure that settings comply, power is vested with regulatory bodies that are tasked with enforcing regulations. Using a qualitative methodology, 43 interviews were undertaken with Early…

Petri Net computational modelling of Langerhans cell Interferon Regulatory Factor Network predicts their role in T cell activation.

PubMed

Polak, Marta E; Ung, Chuin Ying; Masapust, Joanna; Freeman, Tom C; Ardern-Jones, Michael R

2017-04-06

Langerhans cells (LCs) are able to orchestrate adaptive immune responses in the skin by interpreting the microenvironmental context in which they encounter foreign substances, but the regulatory basis for this has not been established. Utilising systems immunology approaches combining in silico modelling of a reconstructed gene regulatory network (GRN) with in vitro validation of the predictions, we sought to determine the mechanisms of regulation of immune responses in human primary LCs. The key role of Interferon regulatory factors (IRFs) as controllers of the human Langerhans cell response to epidermal cytokines was revealed by whole transcriptome analysis. Applying Boolean logic we assembled a Petri net-based model of the IRF-GRN which provides molecular pathway predictions for the induction of different transcriptional programmes in LCs. In silico simulations performed after model parameterisation with transcription factor expression values predicted that human LC activation of antigen-specific CD8 T cells would be differentially regulated by epidermal cytokine induction of specific IRF-controlled pathways. This was confirmed by in vitro measurement of IFN-γ production by activated T cells. As a proof of concept, this approach shows that stochastic modelling of a specific immune networks renders transcriptome data valuable for the prediction of functional outcomes of immune responses.

Diversification of transcription factor-DNA interactions and the evolution of gene regulatory networks.

PubMed

Rogers, Julia M; Bulyk, Martha L

2018-04-25

Sequence-specific transcription factors (TFs) bind short DNA sequences in the genome to regulate the expression of target genes. In the last decade, numerous technical advances have enabled the determination of the DNA-binding specificities of many of these factors. Large-scale screens of many TFs enabled the creation of databases of TF DNA-binding specificities, typically represented as position weight matrices (PWMs). Although great progress has been made in determining and predicting binding specificities systematically, there are still many surprises to be found when studying a particular TF's interactions with DNA in detail. Paralogous TFs' binding specificities can differ in subtle ways, in a manner that is not immediately apparent from looking at their PWMs. These differences affect gene regulatory outputs and enable TFs to rewire transcriptional networks over evolutionary time. This review discusses recent observations made in the study of TF-DNA interactions that highlight the importance of continued in-depth analysis of TF-DNA interactions and their inherent complexity. This article is categorized under: Biological Mechanisms > Regulatory Biology. © 2018 Wiley Periodicals, Inc.

Arabidopsis TRANSPARENT TESTA GLABRA2 is directly regulated by R2R3 MYB transcription factors and is involved in regulation of GLABRA2 transcription in epidermal differentiation.

PubMed

Ishida, Tetsuya; Hattori, Sayoko; Sano, Ryosuke; Inoue, Kayoko; Shirano, Yumiko; Hayashi, Hiroaki; Shibata, Daisuke; Sato, Shusei; Kato, Tomohiko; Tabata, Satoshi; Okada, Kiyotaka; Wada, Takuji

2007-08-01

Arabidopsis thaliana TRANSPARENT TESTA GLABRA2 (TTG2) encodes a WRKY transcription factor and is expressed in young leaves, trichomes, seed coats, and root hairless cells. An examination of several trichome and root hair mutants indicates that MYB and bHLH genes regulate TTG2 expression. Two MYB binding sites in the TTG2 5' regulatory region act as cis regulatory elements and as direct targets of R2R3 MYB transcription factors such as WEREWOLF, GLABRA1, and TRANSPARENT TESTA2. Mutations in TTG2 cause phenotypic defects in trichome development and seed color pigmentation. Transgenic plants expressing a chimeric repressor version of the TTG2 protein (TTG2:SRDX) showed defects in trichome formation, anthocyanin accumulation, seed color pigmentation, and differentiation of root hairless cells. GLABRA2 (GL2) expression was markedly reduced in roots of ProTTG2:TTG2:SRDX transgenic plants, suggesting that TTG2 is involved in the regulation of GL2 expression, although GL2 expression in the ttg2 mutant was similar to that in the wild type. Our analysis suggests a new step in a regulatory cascade of epidermal differentiation, in which complexes containing R2R3 MYB and bHLH transcription factors regulate the expression of TTG2, which then regulates GL2 expression with complexes containing R2R3 MYB and bHLH in the differentiation of trichomes and root hairless cells.

Evolution of context dependent regulation by expansion of feast/famine regulatory proteins.

PubMed

Plaisier, Christopher L; Lo, Fang-Yin; Ashworth, Justin; Brooks, Aaron N; Beer, Karlyn D; Kaur, Amardeep; Pan, Min; Reiss, David J; Facciotti, Marc T; Baliga, Nitin S

2014-11-14

Expansion of transcription factors is believed to have played a crucial role in evolution of all organisms by enabling them to deal with dynamic environments and colonize new environments. We investigated how the expansion of the Feast/Famine Regulatory Protein (FFRP) or Lrp-like proteins into an eight-member family in Halobacterium salinarum NRC-1 has aided in niche-adaptation of this archaeon to a complex and dynamically changing hypersaline environment. We mapped genome-wide binding locations for all eight FFRPs, investigated their preference for binding different effector molecules, and identified the contexts in which they act by analyzing transcriptional responses across 35 growth conditions that mimic different environmental and nutritional conditions this organism is likely to encounter in the wild. Integrative analysis of these data constructed an FFRP regulatory network with conditionally active states that reveal how interrelated variations in DNA-binding domains, effector-molecule preferences, and binding sites in target gene promoters have tuned the functions of each FFRP to the environments in which they act. We demonstrate how conditional regulation of similar genes by two FFRPs, AsnC (an activator) and VNG1237C (a repressor), have striking environment-specific fitness consequences for oxidative stress management and growth, respectively. This study provides a systems perspective into the evolutionary process by which gene duplication within a transcription factor family contributes to environment-specific adaptation of an organism.

Evolution of Osteocrin as an activity-regulated factor in the primate brain

PubMed Central

Ataman, Bulent; Boulting, Gabriella L.; Harmin, David A.; Yang, Marty G.; Baker-Salisbury, Mollie; Yap, Ee-Lynn; Malik, Athar N.; Mei, Kevin; Rubin, Alex A.; Spiegel, Ivo; Durresi, Ershela; Sharma, Nikhil; Hu, Linda S.; Pletikos, Mihovil; Griffith, Eric C.; Partlow, Jennifer N.; Stevens, Christine R.; Adli, Mazhar; Chahrour, Maria; Sestan, Nenad; Walsh, Christopher A.; Berezovskii, Vladimir K.; Livingstone, Margaret S.; Greenberg, Michael E.

2017-01-01

Sensory stimuli drive the maturation and function of the mammalian nervous system in part through the activation of gene expression networks that regulate synapse development and plasticity. These networks have primarily been studied in mice, and it is not known whether there are species- or clade-specific activity-regulated genes that control features of brain development and function. Here we use transcriptional profiling of human fetal brain cultures to identify an activity-dependent secreted factor, Osteocrin (OSTN), that is induced by membrane depolarization of human but not mouse neurons. We find that OSTN has been repurposed in primates through the evolutionary acquisition of DNA regulatory elements that bind the activity-regulated transcription factor MEF2. In addition, we demonstrate that OSTN is expressed in primate neocortex and restricts activity-dependent dendritic growth in human neurons. These findings suggest that, in response to sensory input, OSTN regulates features of neuronal structure and function that are unique to primates. PMID:27830782

Developing self-regulation for dietary temptations: intervention effects on physical, self-regulatory and psychological outcomes.

PubMed

McKee, Heather C; Ntoumanis, Nikos

2014-12-01

We aimed to investigate whether a self-regulatory skills intervention can improve weight loss-related outcomes. Fifty-five participants (M BMI = 32.60 ± 4.86) were randomized into self-regulation training and advice groups and received two training workshops and weekly practice tasks. The self-regulation training group was trained to use six self-regulatory skills: Delayed gratification, thought control, goal setting, self-monitoring, mindfulness, and coping. The advice group received dietary and physical activity advice for weight loss. Physical, self-regulatory, and psychological measures were taken at baseline, end of intervention (week 8) and at follow-up (week 12). Using intention-to-treat analysis, weight, waist circumference, body fat and body mass index (BMI) were significantly reduced at follow-up for both groups. There were significant increases in all six self-regulatory skills and the psychological measures of self-efficacy, self-regulatory success, and physical self-worth for both groups. Results indicate that self-regulatory skills training might be as effective as dietary and physical activity advice in terms of weight loss and related outcomes.

Arabidopsis TRANSPARENT TESTA GLABRA2 Is Directly Regulated by R2R3 MYB Transcription Factors and Is Involved in Regulation of GLABRA2 Transcription in Epidermal Differentiation[W

PubMed Central

Ishida, Tetsuya; Hattori, Sayoko; Sano, Ryosuke; Inoue, Kayoko; Shirano, Yumiko; Hayashi, Hiroaki; Shibata, Daisuke; Sato, Shusei; Kato, Tomohiko; Tabata, Satoshi; Okada, Kiyotaka; Wada, Takuji

2007-01-01

Arabidopsis thaliana TRANSPARENT TESTA GLABRA2 (TTG2) encodes a WRKY transcription factor and is expressed in young leaves, trichomes, seed coats, and root hairless cells. An examination of several trichome and root hair mutants indicates that MYB and bHLH genes regulate TTG2 expression. Two MYB binding sites in the TTG2 5′ regulatory region act as cis regulatory elements and as direct targets of R2R3 MYB transcription factors such as WEREWOLF, GLABRA1, and TRANSPARENT TESTA2. Mutations in TTG2 cause phenotypic defects in trichome development and seed color pigmentation. Transgenic plants expressing a chimeric repressor version of the TTG2 protein (TTG2:SRDX) showed defects in trichome formation, anthocyanin accumulation, seed color pigmentation, and differentiation of root hairless cells. GLABRA2 (GL2) expression was markedly reduced in roots of ProTTG2:TTG2:SRDX transgenic plants, suggesting that TTG2 is involved in the regulation of GL2 expression, although GL2 expression in the ttg2 mutant was similar to that in the wild type. Our analysis suggests a new step in a regulatory cascade of epidermal differentiation, in which complexes containing R2R3 MYB and bHLH transcription factors regulate the expression of TTG2, which then regulates GL2 expression with complexes containing R2R3 MYB and bHLH in the differentiation of trichomes and root hairless cells. PMID:17766401

Epstein-Barr Virus Latent Membrane Protein 1 Regulates the Function of Interferon Regulatory Factor 7 by Inducing Its Sumoylation

PubMed Central

Bentz, Gretchen L.; Shackelford, Julia

2012-01-01

Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) induces multiple signal transduction pathways during latent EBV infection via its C-terminal activating region 1 (CTAR1), CTAR2, and the less-studied CTAR3. One mechanism by which LMP1 regulates cellular activation is through the induction of protein posttranslational modifications, including phosphorylation and ubiquitination. We recently documented that LMP1 induces a third major protein modification by physically interacting with the SUMO-conjugating enzyme Ubc9 through CTAR3 and inducing the sumoylation of cellular proteins in latently infected cells. We have now identified a specific target of LMP1-induced sumoylation, interferon regulatory factor 7 (IRF7). We hypothesize that during EBV latency, LMP1 induces the sumoylation of IRF7, limiting its transcriptional activity and modulating the activation of innate immune responses. Our data show that endogenously sumoylated IRF7 is detected in latently infected EBV lymphoblastoid cell lines. LMP1 expression coincided with increased sumoylation of IRF7 in a CTAR3-dependent manner. Additional experiments show that LMP1 CTAR3-induced sumoylation regulates the expression and function of IRF7 by decreasing its turnover, increasing its nuclear retention, decreasing its DNA binding, and limiting its transcriptional activation. Finally, we identified that IRF7 is sumoylated at lysine 452. These data demonstrate that LMP1 CTAR3 does in fact function in intracellular signaling, leading to biologic effects. We propose that CTAR3 is an important signaling region of LMP1 that regulates protein function by sumoylation. We have shown specifically that LMP1 CTAR3, in cooperation with CTAR2, can limit the ability of IRF7 to induce innate immune responses by inducing the sumoylation of IRF7. PMID:22951831

Effector Regulatory T Cell Differentiation and Immune Homeostasis Depend on the Transcription Factor Myb.

PubMed

Dias, Sheila; D'Amico, Angela; Cretney, Erika; Liao, Yang; Tellier, Julie; Bruggeman, Christine; Almeida, Francisca F; Leahy, Jamie; Belz, Gabrielle T; Smyth, Gordon K; Shi, Wei; Nutt, Stephen L

2017-01-17

FoxP3-expressing regulatory T (Treg) cells are essential for maintaining immune homeostasis. Activated Treg cells undergo further differentiation into an effector state that highly expresses genes critical for Treg cell function, although how this process is coordinated on a transcriptional level is poorly understood. Here, we demonstrate that mice lacking the transcription factor Myb in Treg cells succumbed to a multi-organ inflammatory disease. Myb was specifically expressed in, and required for the differentiation of, thymus-derived effector Treg cells. The combination of transcriptome and genomic footprint analyses revealed that Myb directly regulated a large proportion of the gene expression specific to effector Treg cells, identifying Myb as a critical component of the gene regulatory network controlling effector Treg cell differentiation and function. Copyright © 2017 Elsevier Inc. All rights reserved.

Reconstructing directed gene regulatory network by only gene expression data.

PubMed

Zhang, Lu; Feng, Xi Kang; Ng, Yen Kaow; Li, Shuai Cheng

2016-08-18

Accurately identifying gene regulatory network is an important task in understanding in vivo biological activities. The inference of such networks is often accomplished through the use of gene expression data. Many methods have been developed to evaluate gene expression dependencies between transcription factor and its target genes, and some methods also eliminate transitive interactions. The regulatory (or edge) direction is undetermined if the target gene is also a transcription factor. Some methods predict the regulatory directions in the gene regulatory networks by locating the eQTL single nucleotide polymorphism, or by observing the gene expression changes when knocking out/down the candidate transcript factors; regrettably, these additional data are usually unavailable, especially for the samples deriving from human tissues. In this study, we propose the Context Based Dependency Network (CBDN), a method that is able to infer gene regulatory networks with the regulatory directions from gene expression data only. To determine the regulatory direction, CBDN computes the influence of source to target by evaluating the magnitude changes of expression dependencies between the target gene and the others with conditioning on the source gene. CBDN extends the data processing inequality by involving the dependency direction to distinguish between direct and transitive relationship between genes. We also define two types of important regulators which can influence a majority of the genes in the network directly or indirectly. CBDN can detect both of these two types of important regulators by averaging the influence functions of candidate regulator to the other genes. In our experiments with simulated and real data, even with the regulatory direction taken into account, CBDN outperforms the state-of-the-art approaches for inferring gene regulatory network. CBDN identifies the important regulators in the predicted network: 1. TYROBP influences a batch of genes that are

Identification of Neurodegenerative Factors Using Translatome-Regulatory Network Analysis

PubMed Central

Brichta, Lars; Shin, William; Jackson-Lewis, Vernice; Blesa, Javier; Yap, Ee-Lynn; Walker, Zachary; Zhang, Jack; Roussarie, Jean-Pierre; Alvarez, Mariano J.; Califano, Andrea; Przedborski, Serge; Greengard, Paul

2016-01-01

For degenerative disorders of the central nervous system, the major obstacle to therapeutic advancement has been the challenge of identifying the key molecular mechanisms underlying neuronal loss. We developed a combinatorial approach including translational profiling and brain regulatory network analysis to search for key determinants of neuronal survival or death. Following the generation of transgenic mice for cell type-specific profiling of midbrain dopaminergic neurons, we established and compared translatome libraries reflecting the molecular signature of these cells at baseline or under degenerative stress. Analysis of these libraries by interrogating a context-specific brain regulatory network led to the identification of a repertoire of intrinsic upstream regulators that drive the dopaminergic stress response. The altered activity of these regulators was not associated with changes in their expression levels. This strategy can be generalized for the elucidation of novel molecular determinants involved in the degeneration of other classes of neurons. PMID:26214373

MAGIA2: from miRNA and genes expression data integrative analysis to microRNA–transcription factor mixed regulatory circuits (2012 update)

PubMed Central

Bisognin, Andrea; Sales, Gabriele; Coppe, Alessandro; Bortoluzzi, Stefania; Romualdi, Chiara

2012-01-01

MAGIA2 (http://gencomp.bio.unipd.it/magia2) is an update, extension and evolution of the MAGIA web tool. It is dedicated to the integrated analysis of in silico target prediction, microRNA (miRNA) and gene expression data for the reconstruction of post-transcriptional regulatory networks. miRNAs are fundamental post-transcriptional regulators of several key biological and pathological processes. As miRNAs act prevalently through target degradation, their expression profiles are expected to be inversely correlated to those of the target genes. Low specificity of target prediction algorithms makes integration approaches an interesting solution for target prediction refinement. MAGIA2 performs this integrative approach supporting different association measures, multiple organisms and almost all target predictions algorithms. Nevertheless, miRNAs activity should be viewed as part of a more complex scenario where regulatory elements and their interactors generate a highly connected network and where gene expression profiles are the result of different levels of regulation. The updated MAGIA2 tries to dissect this complexity by reconstructing mixed regulatory circuits involving either miRNA or transcription factor (TF) as regulators. Two types of circuits are identified: (i) a TF that regulates both a miRNA and its target and (ii) a miRNA that regulates both a TF and its target. PMID:22618880

PLOD2 regulated by transcription factor FOXA1 promotes metastasis in NSCLC

PubMed Central

Du, Hongzhi; Chen, Yulong; Hou, Xiaoying; Huang, Yue; Wei, Xiaohui; Yu, Xiaowen; Feng, Shuyun; Wu, Yao; Zhan, Meixiao; Shi, Xin; Lin, Sensen; Lu, Ligong; Yuan, Shengtao; Sun, Li

2017-01-01

In multiple types of tumors, fibrotic collagen is regarded as the 'highway' for cancer cell migration, which is mainly modified by lysyl hydroxylase 2 (PLOD2). The previous findings have demonstrated that the expression of PLOD2 was regulated by multiple factors, including HIF-1α, TGF-β and microRNA-26a/b. Although PLOD2 was confirmed to be related to poor prognosis in lung adenocarcinoma, the regulatory mechanism and function of PLOD2 in human lung adenocarcinoma is poorly understood. On the other hand, upregulation or hyperactivation of epidermal growth factor receptor is considered as a prognostic marker in many cancers, especially in non-small-cell lung cancer (NSCLC). In this study, we found that PLOD2 was elevated in NSCLC specimens and positively links to NSCLC poor prognosis. Gain- and loss-of-function studies and orthotopic implantation metastasis model pinpointed that PLOD2 promotes NSCLC metastasis directly by enhancing migration and indirectly by inducing collagen reorganization. In addition, we revealed that PLOD2 was regulated by PI3K/AKT-FOXA1 axis. The transcription factor FOXA1 directly bound to the PLOD2 promoter, and turned on PLOD2 transcription. In summary, our findings revealed a regulatory mechanism of NSCLC metastasis through EGFR-PI3K/AKT-FOXA1-PLOD2 pathway, and provided PLOD2 as a therapeutic target for NSCLC treatment. PMID:29072684

A novel processing system of sterol regulatory element-binding protein-1c regulated by polyunsaturated fatty acid.

PubMed

Nakakuki, Masanori; Kawano, Hiroyuki; Notsu, Tatsuto; Imada, Kazunori; Mizuguchi, Kiyoshi; Shimano, Hitoshi

2014-05-01

The proteolytic cascade is the key step in transactivation of sterol regulatory element-binding proteins (SREBPs), a transcriptional factor of lipid synthesis. Proteolysis of SREBP-2 is strictly regulated by sterols, but that of SREBP-1c was not strongly sterol-regulated, but inhibited by polyunsaturated fatty acids (PUFAs). In this study, the proteolytic processing of SREBP-1 and -2 was examined by transfection studies of cDNA-encoding mutants in which all the known cleavage sites were disrupted. In cultured cells, sterol-regulated SREBP-2 processing was completely eliminated by mutation of cleavage sites. In contrast, the corresponding SREBP-1c mutants as well as wild type exhibited large amounts of cleaved products in the nuclear extracts from culture cells and murine liver in vivo. The nuclear form of the mutant SREBP-1c was induced by delipidated condition and suppressed by eicosapentaenoic acid, an n-3 PUFA, but not by sterols. This novel processing mechanism was affected by neither SREBP cleavage-activating protein (SCAP) nor insulin-induced gene (Insig)-1, unlike SREBP-2, but abolished by a serine protease inhibitor. Through analysis of deletion mutant, a site-2 protease recognition sequence (DRSR) was identified to be involved in this novel processing. These findings suggest that SREBP-1c cleavage could be subjected to a novel PUFA-regulated cleavage system in addition to the sterol-regulatory SCAP/Insig system.

Ikkepsilon regulates viral-induced interferon regulatory factor-3 activation via a redox-sensitive pathway

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

Indukuri, Hemalatha; Castro, Shawn M.; Liao, S.-M.

2006-09-15

Respiratory syncytial virus (RSV)-induced chemokine gene expression occurs through the activation of a subset of transcription factors, including Interferon Regulatory Factor (IRF)-3. In this study, we have investigated the signaling pathway leading to RSV-induced IRF-3 activation and whether it is mediated by intracellular reactive oxygen species (ROS) generation. Our results show that RSV infection induces expression and catalytic activity of IKK{epsilon}, a noncanonical IKK-like kinase. Expression of a kinase-inactive IKK{epsilon} blocks RSV-induced IRF-3 serine phosphorylation, nuclear translocation and DNA-binding, leading to inhibition of RANTES gene transcription, mRNA expression and protein synthesis. Treatment of alveolar epithelial cells with antioxidants or withmore » NAD(P)H oxidase inhibitors abrogates RSV-induced chemokine secretion, IRF-3 phosphorylation and IKK{epsilon} induction, indicating that ROS generation plays a fundamental role in the signaling pathway leading to IRF-3 activation, therefore, identifying a novel molecular target for the development of strategies aimed to modify the inflammatory response associated with RSV infection of the lung.« less

Genome-wide identification of Hfq-regulated small RNAs in the fire blight pathogen Erwinia amylovora discovered small RNAs with virulence regulatory function.

PubMed

Zeng, Quan; Sundin, George W

2014-05-31

Erwinia amylovora is a phytopathogenic bacterium and causal agent of fire blight disease in apples and pears. Although many virulence factors have been characterized, the coordination of expression of these virulence factors in E. amylovora is still not clear. Regulatory small RNAs (sRNAs) are important post-transcriptional regulatory components in bacteria. A large number of sRNAs require the RNA chaperone Hfq for both stability and functional activation. In E. amylovora, Hfq was identified as a major regulator of virulence and various virulence traits. However, information is still lacking about Hfq-dependent sRNAs on a genome scale, including the virulence regulatory functions of these sRNAs in E. amylovora. Using both an RNA-seq analysis and a Rho-independent terminator search, 40 candidate Hfq-dependent sRNAs were identified in E. amylovora. The expression and sizes of 12 sRNAs and the sequence boundaries of seven sRNAs were confirmed by Northern blot and 5' RACE assay respectively. Sequence conservation analysis identified sRNAs conserved only in the Erwinia genus as well as E. amylovora species-specific sRNAs. In addition, a dynamic re-patterning of expression of Hfq-dependent sRNAs was observed at 6 and 12 hours after induction in Hrp-inducing minimal medium. Furthermore, sRNAs that control virulence traits were characterized, among which ArcZ positively controls the type III secretion system (T3SS), amylovoran exopolysaccahride production, biofilm formation, and motility, and negatively modulates attachment while RmaA (Hrs6) and OmrAB both negatively regulate amylovoran production and positively regulate motility. This study has significantly enhanced our understanding of the Hfq-dependent sRNAs in E. amylovora at the genome level. The identification of multiple virulence-regulating sRNAs also suggests that post-transcriptional regulation by sRNAs may play a role in the deployment of virulence factors needed during varying stages of pathogenesis during

Identifying significant genetic regulatory networks in the prostate cancer from microarray data based on transcription factor analysis and conditional independency.

PubMed

Yeh, Hsiang-Yuan; Cheng, Shih-Wu; Lin, Yu-Chun; Yeh, Cheng-Yu; Lin, Shih-Fang; Soo, Von-Wun

2009-12-21

Prostate cancer is a world wide leading cancer and it is characterized by its aggressive metastasis. According to the clinical heterogeneity, prostate cancer displays different stages and grades related to the aggressive metastasis disease. Although numerous studies used microarray analysis and traditional clustering method to identify the individual genes during the disease processes, the important gene regulations remain unclear. We present a computational method for inferring genetic regulatory networks from micorarray data automatically with transcription factor analysis and conditional independence testing to explore the potential significant gene regulatory networks that are correlated with cancer, tumor grade and stage in the prostate cancer. To deal with missing values in microarray data, we used a K-nearest-neighbors (KNN) algorithm to determine the precise expression values. We applied web services technology to wrap the bioinformatics toolkits and databases to automatically extract the promoter regions of DNA sequences and predicted the transcription factors that regulate the gene expressions. We adopt the microarray datasets consists of 62 primary tumors, 41 normal prostate tissues from Stanford Microarray Database (SMD) as a target dataset to evaluate our method. The predicted results showed that the possible biomarker genes related to cancer and denoted the androgen functions and processes may be in the development of the prostate cancer and promote the cell death in cell cycle. Our predicted results showed that sub-networks of genes SREBF1, STAT6 and PBX1 are strongly related to a high extent while ETS transcription factors ELK1, JUN and EGR2 are related to a low extent. Gene SLC22A3 may explain clinically the differentiation associated with the high grade cancer compared with low grade cancer. Enhancer of Zeste Homolg 2 (EZH2) regulated by RUNX1 and STAT3 is correlated to the pathological stage. We provide a computational framework to reconstruct

Identifying significant genetic regulatory networks in the prostate cancer from microarray data based on transcription factor analysis and conditional independency

PubMed Central

2009-01-01

Background Prostate cancer is a world wide leading cancer and it is characterized by its aggressive metastasis. According to the clinical heterogeneity, prostate cancer displays different stages and grades related to the aggressive metastasis disease. Although numerous studies used microarray analysis and traditional clustering method to identify the individual genes during the disease processes, the important gene regulations remain unclear. We present a computational method for inferring genetic regulatory networks from micorarray data automatically with transcription factor analysis and conditional independence testing to explore the potential significant gene regulatory networks that are correlated with cancer, tumor grade and stage in the prostate cancer. Results To deal with missing values in microarray data, we used a K-nearest-neighbors (KNN) algorithm to determine the precise expression values. We applied web services technology to wrap the bioinformatics toolkits and databases to automatically extract the promoter regions of DNA sequences and predicted the transcription factors that regulate the gene expressions. We adopt the microarray datasets consists of 62 primary tumors, 41 normal prostate tissues from Stanford Microarray Database (SMD) as a target dataset to evaluate our method. The predicted results showed that the possible biomarker genes related to cancer and denoted the androgen functions and processes may be in the development of the prostate cancer and promote the cell death in cell cycle. Our predicted results showed that sub-networks of genes SREBF1, STAT6 and PBX1 are strongly related to a high extent while ETS transcription factors ELK1, JUN and EGR2 are related to a low extent. Gene SLC22A3 may explain clinically the differentiation associated with the high grade cancer compared with low grade cancer. Enhancer of Zeste Homolg 2 (EZH2) regulated by RUNX1 and STAT3 is correlated to the pathological stage. Conclusions We provide a

Cis-regulatory signatures of orthologous stress-associated bZIP transcription factors from rice, sorghum and Arabidopsis based on phylogenetic footprints

PubMed Central

2012-01-01

Background The potential contribution of upstream sequence variation to the unique features of orthologous genes is just beginning to be unraveled. A core subset of stress-associated bZIP transcription factors from rice (Oryza sativa) formed ten clusters of orthologous groups (COG) with genes from the monocot sorghum (Sorghum bicolor) and dicot Arabidopsis (Arabidopsis thaliana). The total cis-regulatory information content of each stress-associated COG was examined by phylogenetic footprinting to reveal ortholog-specific, lineage-specific and species-specific conservation patterns. Results The most apparent pattern observed was the occurrence of spatially conserved ‘core modules’ among the COGs but not among paralogs. These core modules are comprised of various combinations of two to four putative transcription factor binding site (TFBS) classes associated with either developmental or stress-related functions. Outside the core modules are specific stress (ABA, oxidative, abiotic, biotic) or organ-associated signals, which may be functioning as ‘regulatory fine-tuners’ and further define lineage-specific and species-specific cis-regulatory signatures. Orthologous monocot and dicot promoters have distinct TFBS classes involved in disease and oxidative-regulated expression, while the orthologous rice and sorghum promoters have distinct combinations of root-specific signals, a pattern that is not particularly conserved in Arabidopsis. Conclusions Patterns of cis-regulatory conservation imply that each ortholog has distinct signatures, further suggesting that they are potentially unique in a regulatory context despite the presumed conservation of broad biological function during speciation. Based on the observed patterns of conservation, we postulate that core modules are likely primary determinants of basal developmental programming, which may be integrated with and further elaborated by additional intrinsic or extrinsic signals in conjunction with lineage

l-Arginine-Dependent Epigenetic Regulation of Interleukin-10, but Not Transforming Growth Factor-β, Production by Neonatal Regulatory T Lymphocytes

PubMed Central

Yu, Hong-Ren; Tsai, Ching-Chang; Chang, Ling-Sai; Huang, Hsin-Chun; Cheng, Hsin-Hsin; Wang, Jiu-Yao; Sheen, Jiunn-Ming; Kuo, Ho-Chang; Hsieh, Kai-Sheng; Huang, Ying-Hsien; Yang, Kuender D.; Hsu, Te-Yao

2017-01-01

A growing number of diseases in humans, including trauma, certain cancers, and infection, are known to be associated with l-arginine deficiency. In addition, l-arginine must be supplemented by diet during pregnancy to aid fetal development. In conditions of l-arginine depletion, T cell proliferation is impaired. We have previously shown that neonatal blood has lower l-arginine levels than adult blood, which is associated with poor neonatal lymphocyte proliferation, and that l-arginine enhances neonatal lymphocyte proliferation through an interleukin (IL)-2-independent pathway. In this study, we have further investigated how exogenous l-arginine enhances neonatal regulatory T-cells (Tregs) function in relation to IL-10 production under epigenetic regulation. Results showed that cord blood mononuclear cells (CBMCs) produced higher levels of IL-10 than adult peripheral blood mononuclear cells (PBMCs) by phytohemagglutinin stimulation but not by anti-CD3/anti-CD28 stimulation. Addition of exogenous l-arginine had no effect on transforming growth factor-β production by PBMCs or CBMCs, but enhanced IL-10 production by neonatal CD4+CD25+FoxP3+ Tregs. Further studies showed that IL-10 promoter DNA hypomethylation, rather than histone modification, corresponded to the l-arginine-induced increase in IL-10 production by neonatal CD4+ T cells. These results suggest that l-arginine modulates neonatal Tregs through the regulation of IL-10 promoter DNA methylation. l-arginine supplementation may correct the Treg function in newborns with l-arginine deficiency. PMID:28487700

Genomic analysis reveals a tight link between transcription factor dynamics and regulatory network architecture.

PubMed

Jothi, Raja; Balaji, S; Wuster, Arthur; Grochow, Joshua A; Gsponer, Jörg; Przytycka, Teresa M; Aravind, L; Babu, M Madan

2009-01-01

Although several studies have provided important insights into the general principles of biological networks, the link between network organization and the genome-scale dynamics of the underlying entities (genes, mRNAs, and proteins) and its role in systems behavior remain unclear. Here we show that transcription factor (TF) dynamics and regulatory network organization are tightly linked. By classifying TFs in the yeast regulatory network into three hierarchical layers (top, core, and bottom) and integrating diverse genome-scale datasets, we find that the TFs have static and dynamic properties that are similar within a layer and different across layers. At the protein level, the top-layer TFs are relatively abundant, long-lived, and noisy compared with the core- and bottom-layer TFs. Although variability in expression of top-layer TFs might confer a selective advantage, as this permits at least some members in a clonal cell population to initiate a response to changing conditions, tight regulation of the core- and bottom-layer TFs may minimize noise propagation and ensure fidelity in regulation. We propose that the interplay between network organization and TF dynamics could permit differential utilization of the same underlying network by distinct members of a clonal cell population.

Integrated regulatory network reveals novel candidate regulators in the development of negative energy balance in cattle.

PubMed

Mozduri, Z; Bakhtiarizadeh, M R; Salehi, A

2018-06-01

Negative energy balance (NEB) is an altered metabolic state in modern high-yielding dairy cows. This metabolic state occurs in the early postpartum period when energy demands for milk production and maintenance exceed that of energy intake. Negative energy balance or poor adaptation to this metabolic state has important effects on the liver and can lead to metabolic disorders and reduced fertility. The roles of regulatory factors, including transcription factors (TFs) and micro RNAs (miRNAs) have often been separately studied for evaluating of NEB. However, adaptive response to NEB is controlled by complex gene networks and still not fully understood. In this study, we aimed to discover the integrated gene regulatory networks involved in NEB development in liver tissue. We downloaded data sets including mRNA and miRNA expression profiles related to three and four cows with severe and moderate NEB, respectively. Our method integrated two independent types of information: module inference network by TFs, miRNAs and mRNA expression profiles (RNA-seq data) and computational target predictions. In total, 176 modules were predicted by using gene expression data and 64 miRNAs and 63 TFs were assigned to these modules. By using our integrated computational approach, we identified 13 TF-module and 19 miRNA-module interactions. Most of these modules were associated with liver metabolic processes as well as immune and stress responses, which might play crucial roles in NEB development. Literature survey results also showed that several regulators and gene targets have already been characterized as important factors in liver metabolic processes. These results provided novel insights into regulatory mechanisms at the TF and miRNA levels during NEB. In addition, the method described in this study seems to be applicable to construct integrated regulatory networks for different diseases or disorders.

A Csr-type regulatory system, including small non-coding RNAs, regulates the global virulence regulator RovA of Yersinia pseudotuberculosis through RovM.

PubMed

Heroven, Ann Kathrin; Böhme, Katja; Rohde, Manfred; Dersch, Petra

2008-06-01

The MarR-type regulator RovA controls expression of virulence genes of Yersinia pseudotuberculosis in response to environmental signals. Using a genetic strategy to discover components that influence rovA expression, we identified new regulatory factors with homology to components of the carbon storage regulator system (Csr). We showed that overexpression of a CsrB- or a CsrC-type RNA activates rovA, whereas a CsrA-like protein represses RovA synthesis. We further demonstrate that influence of the Csr system on rovA is indirect and occurs through control of the LysR regulator RovM, which inhibits rovA transcription. The CsrA protein had also a major influence on the motility of Yersinia, which was independent of RovM. The CsrB and CsrC RNAs are differentially expressed in Yersinia. CsrC is highly induced in complex but not in minimal media, indicating that medium-dependent rovM expression is mediated through CsrC. CsrB synthesis is generally very low. However, overexpression of the response regulator UvrY was found to activate CsrB production, which in turn represses CsrC synthesis independent of the growth medium. In summary, the post-transcriptional Csr-type components were shown to be key regulators in the co-ordinated environmental control of physiological processes and virulence factors, which are crucial for the initiation of Yersinia infections.

Evolution of context dependent regulation by expansion of feast/famine regulatory proteins

DOE PAGES

Plaisier, Christopher L.; Lo, Fang -Yin; Ashworth, Justin; ...

2014-11-14

Expansion of transcription factors is believed to have played a crucial role in evolution of all organisms by enabling them to deal with dynamic environments and colonize new environments. We investigated how the expansion of the Feast/Famine Regulatory Protein (FFRP) or Lrp-like proteins into an eight-member family in Halobacterium salinarum NRC-1 has aided in niche-adaptation of this archaeon to a complex and dynamically changing hypersaline environment. We mapped genome-wide binding locations for all eight FFRPs, investigated their preference for binding different effector molecules, and identified the contexts in which they act by analyzing transcriptional responses across 35 growth conditions thatmore » mimic different environmental and nutritional conditions this organism is likely to encounter in the wild. Integrative analysis of these data constructed an FFRP regulatory network with conditionally active states that reveal how interrelated variations in DNA-binding domains, effector-molecule preferences, and binding sites in target gene promoters have tuned the functions of each FFRP to the environments in which they act. We demonstrate how conditional regulation of similar genes by two FFRPs, AsnC (an activator) and VNG1237C (a repressor), have striking environment-specific fitness consequences for oxidative stress management and growth, respectively. This study provides a systems perspective into the evolutionary process by which gene duplication within a transcription factor family contributes to environment-specific adaptation of an organism.« less

Global transcriptional regulatory network for Escherichia coli robustly connects gene expression to transcription factor activities

PubMed Central

Fang, Xin; Sastry, Anand; Mih, Nathan; Kim, Donghyuk; Tan, Justin; Lloyd, Colton J.; Gao, Ye; Yang, Laurence; Palsson, Bernhard O.

2017-01-01

Transcriptional regulatory networks (TRNs) have been studied intensely for >25 y. Yet, even for the Escherichia coli TRN—probably the best characterized TRN—several questions remain. Here, we address three questions: (i) How complete is our knowledge of the E. coli TRN; (ii) how well can we predict gene expression using this TRN; and (iii) how robust is our understanding of the TRN? First, we reconstructed a high-confidence TRN (hiTRN) consisting of 147 transcription factors (TFs) regulating 1,538 transcription units (TUs) encoding 1,764 genes. The 3,797 high-confidence regulatory interactions were collected from published, validated chromatin immunoprecipitation (ChIP) data and RegulonDB. For 21 different TF knockouts, up to 63% of the differentially expressed genes in the hiTRN were traced to the knocked-out TF through regulatory cascades. Second, we trained supervised machine learning algorithms to predict the expression of 1,364 TUs given TF activities using 441 samples. The algorithms accurately predicted condition-specific expression for 86% (1,174 of 1,364) of the TUs, while 193 TUs (14%) were predicted better than random TRNs. Third, we identified 10 regulatory modules whose definitions were robust against changes to the TRN or expression compendium. Using surrogate variable analysis, we also identified three unmodeled factors that systematically influenced gene expression. Our computational workflow comprehensively characterizes the predictive capabilities and systems-level functions of an organism’s TRN from disparate data types. PMID:28874552

A mammary cell-specific enhancer in mouse mammary tumor virus DNA is composed of multiple regulatory elements including binding sites for CTF/NFI and a novel transcription factor, mammary cell-activating factor.

PubMed Central

Mink, S; Härtig, E; Jennewein, P; Doppler, W; Cato, A C

1992-01-01

Mouse mammary tumor virus (MMTV) is a milk-transmitted retrovirus involved in the neoplastic transformation of mouse mammary gland cells. The expression of this virus is regulated by mammary cell type-specific factors, steroid hormones, and polypeptide growth factors. Sequences for mammary cell-specific expression are located in an enhancer element in the extreme 5' end of the long terminal repeat region of this virus. This enhancer, when cloned in front of the herpes simplex thymidine kinase promoter, endows the promoter with mammary cell-specific response. Using functional and DNA-protein-binding studies with constructs mutated in the MMTV long terminal repeat enhancer, we have identified two main regulatory elements necessary for the mammary cell-specific response. These elements consist of binding sites for a transcription factor in the family of CTF/NFI proteins and the transcription factor mammary cell-activating factor (MAF) that recognizes the sequence G Pu Pu G C/G A A G G/T. Combinations of CTF/NFI- and MAF-binding sites or multiple copies of either one of these binding sites but not solitary binding sites mediate mammary cell-specific expression. The functional activities of these two regulatory elements are enhanced by another factor that binds to the core sequence ACAAAG. Interdigitated binding sites for CTF/NFI, MAF, and/or the ACAAAG factor are also found in the 5' upstream regions of genes encoding whey milk proteins from different species. These findings suggest that mammary cell-specific regulation is achieved by a concerted action of factors binding to multiple regulatory sites. Images PMID:1328867

Establishing a Framework for the Ad/Abaxial Regulatory Network of Arabidopsis: Ascertaining Targets of Class III HOMEODOMAIN LEUCINE ZIPPER and KANADI Regulation[W

PubMed Central

Reinhart, Brenda J.; Liu, Tie; Newell, Nicole R.; Magnani, Enrico; Huang, Tengbo; Kerstetter, Randall; Michaels, Scott; Barton, M. Kathryn

2013-01-01

The broadly conserved Class III HOMEODOMAIN LEUCINE ZIPPER (HD-ZIPIII) and KANADI transcription factors have opposing and transformational effects on polarity and growth in all tissues and stages of the plant's life. To obtain a comprehensive understanding of how these factors work, we have identified transcripts that change in response to induced HD-ZIPIII or KANADI function. Additional criteria used to identify high-confidence targets among this set were presence of an adjacent HD-ZIPIII binding site, expression enriched within a subdomain of the shoot apical meristem, mutant phenotype showing defect in polar leaf and/or meristem development, physical interaction between target gene product and HD-ZIPIII protein, opposite regulation by HD-ZIPIII and KANADI, and evolutionary conservation of the regulator–target relationship. We find that HD-ZIPIII and KANADI regulate tissue-specific transcription factors involved in subsidiary developmental decisions, nearly all major hormone pathways, and new actors (such as INDETERMINATE DOMAIN4) in the ad/abaxial regulatory network. Multiple feedback loops regulating HD-ZIPIII and KANADI are identified, as are mechanisms through which HD-ZIPIII and KANADI oppose each other. This work lays the foundation needed to understand the components, structure, and workings of the ad/abaxial regulatory network directing basic plant growth and development. PMID:24076978

Autophagy Regulatory Network - a systems-level bioinformatics resource for studying the mechanism and regulation of autophagy.

PubMed

Türei, Dénes; Földvári-Nagy, László; Fazekas, Dávid; Módos, Dezső; Kubisch, János; Kadlecsik, Tamás; Demeter, Amanda; Lenti, Katalin; Csermely, Péter; Vellai, Tibor; Korcsmáros, Tamás

2015-01-01

Autophagy is a complex cellular process having multiple roles, depending on tissue, physiological, or pathological conditions. Major post-translational regulators of autophagy are well known, however, they have not yet been collected comprehensively. The precise and context-dependent regulation of autophagy necessitates additional regulators, including transcriptional and post-transcriptional components that are listed in various datasets. Prompted by the lack of systems-level autophagy-related information, we manually collected the literature and integrated external resources to gain a high coverage autophagy database. We developed an online resource, Autophagy Regulatory Network (ARN; http://autophagy-regulation.org), to provide an integrated and systems-level database for autophagy research. ARN contains manually curated, imported, and predicted interactions of autophagy components (1,485 proteins with 4,013 interactions) in humans. We listed 413 transcription factors and 386 miRNAs that could regulate autophagy components or their protein regulators. We also connected the above-mentioned autophagy components and regulators with signaling pathways from the SignaLink 2 resource. The user-friendly website of ARN allows researchers without computational background to search, browse, and download the database. The database can be downloaded in SQL, CSV, BioPAX, SBML, PSI-MI, and in a Cytoscape CYS file formats. ARN has the potential to facilitate the experimental validation of novel autophagy components and regulators. In addition, ARN helps the investigation of transcription factors, miRNAs and signaling pathways implicated in the control of the autophagic pathway. The list of such known and predicted regulators could be important in pharmacological attempts against cancer and neurodegenerative diseases.

Identification of the transcription factor ZEB1 as a central component of the adipogenic gene regulatory network

PubMed Central

Gubelmann, Carine; Schwalie, Petra C; Raghav, Sunil K; Röder, Eva; Delessa, Tenagne; Kiehlmann, Elke; Waszak, Sebastian M; Corsinotti, Andrea; Udin, Gilles; Holcombe, Wiebke; Rudofsky, Gottfried; Trono, Didier; Wolfrum, Christian; Deplancke, Bart

2014-01-01

Adipose tissue is a key determinant of whole body metabolism and energy homeostasis. Unraveling the regulatory mechanisms underlying adipogenesis is therefore highly relevant from a biomedical perspective. Our current understanding of fat cell differentiation is centered on the transcriptional cascades driven by the C/EBP protein family and the master regulator PPARγ. To elucidate further components of the adipogenic gene regulatory network, we performed a large-scale transcription factor (TF) screen overexpressing 734 TFs in mouse pre-adipocytes and probed their effect on differentiation. We identified 22 novel pro-adipogenic TFs and characterized the top ranking TF, ZEB1, as being essential for adipogenesis both in vitro and in vivo. Moreover, its expression levels correlate with fat cell differentiation potential in humans. Genomic profiling further revealed that this TF directly targets and controls the expression of most early and late adipogenic regulators, identifying ZEB1 as a central transcriptional component of fat cell differentiation. DOI: http://dx.doi.org/10.7554/eLife.03346.001 PMID:25163748

Regulation of Cell Fate Determination by Single-Repeat R3 MYB Transcription Factors in Arabidopsis

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

Wang, Shucai; Chen, Jay

2014-01-01

MYB transcription factors regulate multiple aspects of plant growth and development. Among the large family of MYB transcription factors, single-repeat R3 MYB are characterized by their short sequence (<120 amino acids) consisting largely of the single MYB DNA-binding repeat. In the model plant Arabidopsis, R3 MYBs mediate lateral inhibition during epidermal patterning and are best characterized for their regulatory roles in trichome and root hair development. R3 MYBs act as negative regulators for trichome formation but as positive regulators for root hair development. In this article, we provide a comprehensive review on the role of R3 MYBs in the regulationmore » of cell type specification in the model plant Arabidopsis.« less

SmARTest regulation? Comparing the regulatory structures for ART in the UK and Australia.

PubMed

Petersen, Kerry; Johnson, Martin H

2007-08-01

Assisted reproductive technologies are regulated in both the UK and Australia, thereby curtailing both reproductive and professional autonomy. Different regulatory models have developed in each jurisdiction, despite the similar legal, scientific and cultural histories of the two jurisdictions. In the UK the regulatory structures are under review, largely in the absence of empirical research on the costs and benefits of regulation. The regulatory structures in each jurisdiction are compared and some key differences identified. The UK regulatory structure governing assisted reproductive technologies is currently simpler, more accountable and more transparent than that in Australia. On the other hand, despite administrative and legislative restrictions (particularly in Victoria), the medical scientists and clinicians in Australia generally have more control than their British counterparts over the technical aspects of their work in the provision of IVF and other treatment services, and to a lesser extent in embryo research. Recent proposals appear to move the UK regulatory structure towards a less accountable and less transparent model, but with no evident increase in reproductive or professional autonomy. It is suggested that this change is not in the interests of patients, doctors and the public, and a different model is outlined for devolution of both authority and accountability to the professions.

Differential regulation of the androgen receptor by protein phosphatase regulatory subunits

PubMed Central

Grey, James; Jones, Dominic; Wilson, Laura; Nakjang, Sirintra; Clayton, Jake; Temperley, Richard; Clark, Emma; Gaughan, Luke; Robson, Craig

2018-01-01

The Androgen Receptor (AR) is a key molecule in the development, maintenance and progression of prostate cancer (PC). However, the relationship between the AR and co-regulatory proteins that facilitate AR activity in castrate resistant settings remain understudied. Here we show that protein phosphatase 1 regulatory subunits, identified from a phosphatase RNAi screen, direct PP1 catalytic subunits to a varied yet significant response in AR function. As such, we have characterised the PP1β holoenzyme, myosin phosphatase (MLCP), as a novel ligand independent regulator of the AR. Sustained MLCP activity through down-regulation of the MLCP inhibitory subunit, PPP1R14C, results in impaired AR nuclear translocation, protein stability and transcriptional activity in distinct models of PC progression, culminating in restoration of a non-malignant prostate genotype. Phenotypically, a marked reduction in cell proliferation and migration, characterised by G1 cell cycle arrest is observed, confirming PP1 holoenzyme disruption as a novel treatment approach in PC. PMID:29423094

Integrated Module and Gene-Specific Regulatory Inference Implicates Upstream Signaling Networks

PubMed Central

Roy, Sushmita; Lagree, Stephen; Hou, Zhonggang; Thomson, James A.; Stewart, Ron; Gasch, Audrey P.

2013-01-01

Regulatory networks that control gene expression are important in diverse biological contexts including stress response and development. Each gene's regulatory program is determined by module-level regulation (e.g. co-regulation via the same signaling system), as well as gene-specific determinants that can fine-tune expression. We present a novel approach, Modular regulatory network learning with per gene information (MERLIN), that infers regulatory programs for individual genes while probabilistically constraining these programs to reveal module-level organization of regulatory networks. Using edge-, regulator- and module-based comparisons of simulated networks of known ground truth, we find MERLIN reconstructs regulatory programs of individual genes as well or better than existing approaches of network reconstruction, while additionally identifying modular organization of the regulatory networks. We use MERLIN to dissect global transcriptional behavior in two biological contexts: yeast stress response and human embryonic stem cell differentiation. Regulatory modules inferred by MERLIN capture co-regulatory relationships between signaling proteins and downstream transcription factors thereby revealing the upstream signaling systems controlling transcriptional responses. The inferred networks are enriched for regulators with genetic or physical interactions, supporting the inference, and identify modules of functionally related genes bound by the same transcriptional regulators. Our method combines the strengths of per-gene and per-module methods to reveal new insights into transcriptional regulation in stress and development. PMID:24146602

Regulatory Snapshots: integrative mining of regulatory modules from expression time series and regulatory networks.

PubMed

Gonçalves, Joana P; Aires, Ricardo S; Francisco, Alexandre P; Madeira, Sara C

2012-01-01

Explaining regulatory mechanisms is crucial to understand complex cellular responses leading to system perturbations. Some strategies reverse engineer regulatory interactions from experimental data, while others identify functional regulatory units (modules) under the assumption that biological systems yield a modular organization. Most modular studies focus on network structure and static properties, ignoring that gene regulation is largely driven by stimulus-response behavior. Expression time series are key to gain insight into dynamics, but have been insufficiently explored by current methods, which often (1) apply generic algorithms unsuited for expression analysis over time, due to inability to maintain the chronology of events or incorporate time dependency; (2) ignore local patterns, abundant in most interesting cases of transcriptional activity; (3) neglect physical binding or lack automatic association of regulators, focusing mainly on expression patterns; or (4) limit the discovery to a predefined number of modules. We propose Regulatory Snapshots, an integrative mining approach to identify regulatory modules over time by combining transcriptional control with response, while overcoming the above challenges. Temporal biclustering is first used to reveal transcriptional modules composed of genes showing coherent expression profiles over time. Personalized ranking is then applied to prioritize prominent regulators targeting the modules at each time point using a network of documented regulatory associations and the expression data. Custom graphics are finally depicted to expose the regulatory activity in a module at consecutive time points (snapshots). Regulatory Snapshots successfully unraveled modules underlying yeast response to heat shock and human epithelial-to-mesenchymal transition, based on regulations documented in the YEASTRACT and JASPAR databases, respectively, and available expression data. Regulatory players involved in functionally enriched

Regulatory Snapshots: Integrative Mining of Regulatory Modules from Expression Time Series and Regulatory Networks

PubMed Central

Gonçalves, Joana P.; Aires, Ricardo S.; Francisco, Alexandre P.; Madeira, Sara C.

2012-01-01

Explaining regulatory mechanisms is crucial to understand complex cellular responses leading to system perturbations. Some strategies reverse engineer regulatory interactions from experimental data, while others identify functional regulatory units (modules) under the assumption that biological systems yield a modular organization. Most modular studies focus on network structure and static properties, ignoring that gene regulation is largely driven by stimulus-response behavior. Expression time series are key to gain insight into dynamics, but have been insufficiently explored by current methods, which often (1) apply generic algorithms unsuited for expression analysis over time, due to inability to maintain the chronology of events or incorporate time dependency; (2) ignore local patterns, abundant in most interesting cases of transcriptional activity; (3) neglect physical binding or lack automatic association of regulators, focusing mainly on expression patterns; or (4) limit the discovery to a predefined number of modules. We propose Regulatory Snapshots, an integrative mining approach to identify regulatory modules over time by combining transcriptional control with response, while overcoming the above challenges. Temporal biclustering is first used to reveal transcriptional modules composed of genes showing coherent expression profiles over time. Personalized ranking is then applied to prioritize prominent regulators targeting the modules at each time point using a network of documented regulatory associations and the expression data. Custom graphics are finally depicted to expose the regulatory activity in a module at consecutive time points (snapshots). Regulatory Snapshots successfully unraveled modules underlying yeast response to heat shock and human epithelial-to-mesenchymal transition, based on regulations documented in the YEASTRACT and JASPAR databases, respectively, and available expression data. Regulatory players involved in functionally enriched

Metabolic and molecular analyses of white mutant Vaccinium berries show down-regulation of MYBPA1-type R2R3 MYB regulatory factor.

PubMed

Primetta, Anja K; Karppinen, Katja; Riihinen, Kaisu R; Jaakola, Laura

2015-09-01

MYBPA1-type R2R3 MYB transcription factor shows down-regulation in white mutant berries of Vaccinium uliginosum deficient in anthocyanins but not proanthocyanidins suggesting a role in the regulation of anthocyanin biosynthesis. Berries of the genus Vaccinium are among the best natural sources of flavonoids. In this study, the expression of structural and regulatory flavonoid biosynthetic genes and the accumulation of flavonoids in white mutant and blue-colored wild-type bog bilberry (V. uliginosum) fruits were measured at different stages of berry development. In contrast to high contents of anthocyanins in ripe blue-colored berries, only traces were detected by HPLC-ESI-MS in ripe white mutant berries. However, similar profile and high levels of flavonol glycosides and proanthocyanidins were quantified in both ripe white and ripe wild-type berries. Analysis with qRT-PCR showed strong down-regulation of structural genes chalcone synthase (VuCHS), dihydroflavonol 4-reductase (VuDFR) and anthocyanidin synthase (VuANS) as well as MYBPA1-type transcription factor VuMYBPA1 in white berries during ripening compared to wild-type berries. The profiles of transcript accumulation of chalcone isomerase (VuCHI), anthocyanidin reductase (VuANR), leucoanthocyanidin reductase (VuLAR) and flavonoid 3'5' hydroxylase (VuF3'5'H) were more similar between the white and the wild-type berries during fruit development, while expression of UDP-glucose: flavonoid 3-O-glucosyltransferase (VuUFGT) showed similar trend but fourfold lower level in white mutant. VuMYBPA1, the R2R3 MYB family member, is a homologue of VmMYB2 of V. myrtillus and VcMYBPA1 of V. corymbosum and belongs to MYBPA1-type MYB family which members are shown in some species to be related with proanthocyanidin biosynthesis in fruits. Our results combined with earlier data of the role of VmMYB2 in white mutant berries of V. myrtillus suggest that the regulation of anthocyanin biosynthesis in Vaccinium species could differ

Roles for Arabidopsis CAMTA transcription factors in cold-regulated gene expression and freezing tolerance.

PubMed

Doherty, Colleen J; Van Buskirk, Heather A; Myers, Susan J; Thomashow, Michael F

2009-03-01

The Arabidopsis thaliana CBF cold response pathway plays a central role in cold acclimation. It is characterized by rapid cold induction of genes encoding the CBF1-3 transcription factors, followed by expression of the CBF gene regulon, which imparts freezing tolerance. Our goal was to further the understanding of the cis-acting elements and trans-acting factors involved in expression of CBF2. We identified seven conserved DNA motifs (CM), CM1 to 7, that are present in the promoters of CBF2 and another rapidly cold-induced gene encoding a transcription factor, ZAT12. The results presented indicate that in the CBF2 promoter, CM4 and CM6 have negative regulatory activity and that CM2 has both negative and positive activity. A Myc binding site in the CBF2 promoter was also found to have positive regulatory effects. Moreover, our results indicate that members of the calmodulin binding transcription activator (CAMTA) family of transcription factors bind to the CM2 motif, that CAMTA3 is a positive regulator of CBF2 expression, and that double camta1 camta3 mutant plants are impaired in freezing tolerance. These results establish a role for CAMTA proteins in cold acclimation and provide a possible point of integrating low-temperature calcium and calmodulin signaling with cold-regulated gene expression.

Decoding the regulatory landscape of melanoma reveals TEADS as regulators of the invasive cell state

PubMed Central

Verfaillie, Annelien; Imrichova, Hana; Atak, Zeynep Kalender; Dewaele, Michael; Rambow, Florian; Hulselmans, Gert; Christiaens, Valerie; Svetlichnyy, Dmitry; Luciani, Flavie; Van den Mooter, Laura; Claerhout, Sofie; Fiers, Mark; Journe, Fabrice; Ghanem, Ghanem-Elias; Herrmann, Carl; Halder, Georg; Marine, Jean-Christophe; Aerts, Stein

2015-01-01

Transcriptional reprogramming of proliferative melanoma cells into a phenotypically distinct invasive cell subpopulation is a critical event at the origin of metastatic spreading. Here we generate transcriptome, open chromatin and histone modification maps of melanoma cultures; and integrate this data with existing transcriptome and DNA methylation profiles from tumour biopsies to gain insight into the mechanisms underlying this key reprogramming event. This shows thousands of genomic regulatory regions underlying the proliferative and invasive states, identifying SOX10/MITF and AP-1/TEAD as regulators, respectively. Knockdown of TEADs shows a previously unrecognized role in the invasive gene network and establishes a causative link between these transcription factors, cell invasion and sensitivity to MAPK inhibitors. Using regulatory landscapes and in silico analysis, we show that transcriptional reprogramming underlies the distinct cellular states present in melanoma. Furthermore, it reveals an essential role for the TEADs, linking it to clinically relevant mechanisms such as invasion and resistance. PMID:25865119

Intracellular concentrations of 65 species of transcription factors with known regulatory functions in Escherichia coli.

PubMed

Ishihama, Akira; Kori, Ayako; Koshio, Etsuko; Yamada, Kayoko; Maeda, Hiroto; Shimada, Tomohiro; Makinoshima, Hideki; Iwata, Akira; Fujita, Nobuyuki

2014-08-01

The expression pattern of the Escherichia coli genome is controlled in part by regulating the utilization of a limited number of RNA polymerases among a total of its approximately 4,600 genes. The distribution pattern of RNA polymerase changes from modulation of two types of protein-protein interactions: the interaction of core RNA polymerase with seven species of the sigma subunit for differential promoter recognition and the interaction of RNA polymerase holoenzyme with about 300 different species of transcription factors (TFs) with regulatory functions. We have been involved in the systematic search for the target promoters recognized by each sigma factor and each TF using the newly developed Genomic SELEX system. In parallel, we developed the promoter-specific (PS)-TF screening system for identification of the whole set of TFs involved in regulation of each promoter. Understanding the regulation of genome transcription also requires knowing the intracellular concentrations of the sigma subunits and TFs under various growth conditions. This report describes the intracellular levels of 65 species of TF with known function in E. coli K-12 W3110 at various phases of cell growth and at various temperatures. The list of intracellular concentrations of the sigma factors and TFs provides a community resource for understanding the transcription regulation of E. coli under various stressful conditions in nature. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

E3 Ubiquitin Ligase VHL Regulates Hypoxia-Inducible Factor-1α to Maintain Regulatory T Cell Stability and Suppressive Capacity.

PubMed

Lee, Jee H; Elly, Chris; Park, Yoon; Liu, Yun-Cai

2015-06-16

Foxp3(+) regulatory T (Treg) cells play a critical role in immune homeostasis; however, the mechanisms to maintain their function remain unclear. Here, we report that the E3 ubiquitin ligase VHL is essential for Treg cell function. Mice with Foxp3-restricted VHL deletion displayed massive inflammation associated with excessive Treg cell interferon-γ (IFN-γ) production. VHL-deficient Treg cells failed to prevent colitis induction, but converted into Th1-like effector T cells. VHL intrinsically orchestrated such conversion under both steady and inflammatory conditions followed by Foxp3 downregulation, which was reversed by IFN-γ deficiency. Augmented hypoxia-inducible factor 1α (HIF-1α)-induced glycolytic reprogramming was required for IFN-γ production. Furthermore, HIF-1α bound directly to the Ifng promoter. HIF-1α knockdown or knockout could reverse the increased IFN-γ by VHL-deficient Treg cells and restore their suppressive function in vivo. These findings indicate that regulation of HIF-1α pathway by VHL is crucial to maintain the stability and suppressive function of Foxp3(+) T cells. Copyright © 2015 Elsevier Inc. All rights reserved.

Exploring the factors influencing clinical students' self-regulated learning.

PubMed

Berkhout, Joris J; Helmich, Esther; Teunissen, Pim W; van den Berg, Joost W; van der Vleuten, Cees P M; Jaarsma, A Debbie C

2015-06-01

The importance of self-regulated learning (SRL) has been broadly recognised by medical education institutions and regulatory bodies. Supporting the development of SRL skills has proven difficult because self-regulation is a complex interactive process and we know relatively little about the factors influencing this process in real practice settings. The aim of our study was therefore to identify factors that support or hamper medical students' SRL in a clinical context. We conducted a constructivist grounded theory study using semi-structured interviews with 17 medical students from two universities enrolled in clerkships. Participants were purposively sampled to ensure variety in age, gender, experience and current clerkship. The Day Reconstruction Method was used to help participants remember their activities of the previous day. The interviews were transcribed verbatim and analysed iteratively using constant comparison and open, axial and interpretive coding. Self-regulated learning by students in the clinical environment was influenced by the specific goals perceived by students, the autonomy they experienced, the learning opportunities they were given or created themselves, and the anticipated outcomes of an activity. All of these factors were affected by personal, contextual and social attributes. Self-regulated learning of medical students in the clinical environment is different for every individual. The factors influencing this process are affected by personal, social and contextual attributes. Some of these are similar to those known from previous research in classroom settings, but others are unique to the clinical environment and include the facilities available, the role of patients, and social relationships pertaining to peers and other hospital staff. To better support students' SRL, we believe it is important to increase students' metacognitive awareness and to offer students more tailored learning opportunities. © 2015 John Wiley & Sons Ltd.

Casein kinase 1 regulates sterol regulatory element-binding protein (SREBP) to control sterol homeostasis.

PubMed

Brookheart, Rita T; Lee, Chih-Yung S; Espenshade, Peter J

2014-01-31

Sterol homeostasis is tightly controlled by the sterol regulatory element-binding protein (SREBP) transcription factor that is highly conserved from fungi to mammals. In fission yeast, SREBP functions in an oxygen-sensing pathway to promote adaptation to decreased oxygen supply that limits oxygen-dependent sterol synthesis. Low oxygen stimulates proteolytic cleavage of the SREBP homolog Sre1, generating the active transcription factor Sre1N that drives expression of sterol biosynthetic enzymes. In addition, low oxygen increases the stability and DNA binding activity of Sre1N. To identify additional signals controlling Sre1 activity, we conducted a genetic overexpression screen. Here, we describe our isolation and characterization of the casein kinase 1 family member Hhp2 as a novel regulator of Sre1N. Deletion of Hhp2 increases Sre1N protein stability and ergosterol levels in the presence of oxygen. Hhp2-dependent Sre1N degradation by the proteasome requires Hhp2 kinase activity, and Hhp2 binds and phosphorylates Sre1N at specific residues. Our results describe a role for casein kinase 1 as a direct regulator of sterol homeostasis. Given the role of mammalian Hhp2 homologs, casein kinase 1δ and 1ε, in regulation of the circadian clock, these findings may provide a mechanism for coordinating circadian rhythm and lipid metabolism.

Regulation of acrosomal exocytosis. II. The zona pellucida-induced acrosome reaction of bovine spermatozoa is controlled by extrinsic positive regulatory elements.

PubMed

Florman, H M; First, N L

1988-08-01

The effects of accessory sex gland secretions on the zona pellucida-induced acrosome reaction of bovine spermatozoa were investigated. Soluble extracts of zonae pellucidae initiated exocytosis in ejaculated spermatozoa. This process had an ED50 of 20 ng/microliter zona pellucida protein and saturated at 50 ng/microliter (Florman and First, 1988. Dev. Biol. 128, 453-463). In epididymal sperm this dose-response relationship was shifted toward greater agonist concentrations by at least a factor of 10(3). Reconstitution of high potency agonist response was achieved in vitro by incubation of epididymal sperm with bovine seminal plasma. Reconstitution was dependent on the seminal plasma protein concentration. The ED50 of this process was 62 micrograms protein/10(8) sperm and saturation was observed with 124 micrograms protein/10(8) sperm. Agonist responses in reconstituted epididymal sperm and in ejaculated sperm were indistinguishable with regard to dependence on the zona pellucida protein concentration and the kinetics of induced acrosome reactions. Kinetic studies suggest that reconstitution is due to adsorption of regulatory factors from seminal plasma. In addition to the positive regulatory elements responsible for reconstituting activity, seminal plasma also contains negative regulatory elements which inhibit agonist response. These negative factors are inactivated during sperm capacitation, permitting the expression of positive regulators. Acting together, these regulatory elements could coordinate high affinity agonist response with the availability of eggs in vivo.

Regulatory RNAs in Bacillus subtilis: a Gram-Positive Perspective on Bacterial RNA-Mediated Regulation of Gene Expression.

PubMed

Mars, Ruben A T; Nicolas, Pierre; Denham, Emma L; van Dijl, Jan Maarten

2016-12-01

Bacteria can employ widely diverse RNA molecules to regulate their gene expression. Such molecules include trans-acting small regulatory RNAs, antisense RNAs, and a variety of transcriptional attenuation mechanisms in the 5' untranslated region. Thus far, most regulatory RNA research has focused on Gram-negative bacteria, such as Escherichia coli and Salmonella. Hence, there is uncertainty about whether the resulting insights can be extrapolated directly to other bacteria, such as the Gram-positive soil bacterium Bacillus subtilis. A recent study identified 1,583 putative regulatory RNAs in B. subtilis, whose expression was assessed across 104 conditions. Here, we review the current understanding of RNA-based regulation in B. subtilis, and we categorize the newly identified putative regulatory RNAs on the basis of their conservation in other bacilli and the stability of their predicted secondary structures. Our present evaluation of the publicly available data indicates that RNA-mediated gene regulation in B. subtilis mostly involves elements at the 5' ends of mRNA molecules. These can include 5' secondary structure elements and metabolite-, tRNA-, or protein-binding sites. Importantly, sense-independent segments are identified as the most conserved and structured potential regulatory RNAs in B. subtilis. Altogether, the present survey provides many leads for the identification of new regulatory RNA functions in B. subtilis. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Regulatory RNAs in Bacillus subtilis: a Gram-Positive Perspective on Bacterial RNA-Mediated Regulation of Gene Expression

PubMed Central

Mars, Ruben A. T.; Nicolas, Pierre; Denham, Emma L.

2016-01-01

SUMMARY Bacteria can employ widely diverse RNA molecules to regulate their gene expression. Such molecules include trans-acting small regulatory RNAs, antisense RNAs, and a variety of transcriptional attenuation mechanisms in the 5′ untranslated region. Thus far, most regulatory RNA research has focused on Gram-negative bacteria, such as Escherichia coli and Salmonella. Hence, there is uncertainty about whether the resulting insights can be extrapolated directly to other bacteria, such as the Gram-positive soil bacterium Bacillus subtilis. A recent study identified 1,583 putative regulatory RNAs in B. subtilis, whose expression was assessed across 104 conditions. Here, we review the current understanding of RNA-based regulation in B. subtilis, and we categorize the newly identified putative regulatory RNAs on the basis of their conservation in other bacilli and the stability of their predicted secondary structures. Our present evaluation of the publicly available data indicates that RNA-mediated gene regulation in B. subtilis mostly involves elements at the 5′ ends of mRNA molecules. These can include 5′ secondary structure elements and metabolite-, tRNA-, or protein-binding sites. Importantly, sense-independent segments are identified as the most conserved and structured potential regulatory RNAs in B. subtilis. Altogether, the present survey provides many leads for the identification of new regulatory RNA functions in B. subtilis. PMID:27784798

Genome-Scale Architecture of Small Molecule Regulatory Networks and the Fundamental Trade-Off between Regulation and Enzymatic Activity

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

Reznik, Ed; Christodoulou, Dimitris; Goldford, Joshua E.

Metabolic flux is in part regulated by endogenous small molecules that modulate the catalytic activity of an enzyme, e.g., allosteric inhibition. In contrast to transcriptional regulation of enzymes, technical limitations have hindered the production of a genome-scale atlas of small molecule-enzyme regulatory interactions. Here, we develop a framework leveraging the vast, but fragmented, biochemical literature to reconstruct and analyze the small molecule regulatory network (SMRN) of the model organism Escherichia coli, including the primary metabolite regulators and enzyme targets. Using metabolic control analysis, we prove a fundamental trade-off between regulation and enzymatic activity, and we combine it with metabolomic measurementsmore » and the SMRN to make inferences on the sensitivity of enzymes to their regulators. By generalizing the analysis to other organisms, we identify highly conserved regulatory interactions across evolutionarily divergent species, further emphasizing a critical role for small molecule interactions in the maintenance of metabolic homeostasis.« less

Genome-Scale Architecture of Small Molecule Regulatory Networks and the Fundamental Trade-Off between Regulation and Enzymatic Activity

DOE PAGES

Reznik, Ed; Christodoulou, Dimitris; Goldford, Joshua E.; ...

2017-09-12

Metabolic flux is in part regulated by endogenous small molecules that modulate the catalytic activity of an enzyme, e.g., allosteric inhibition. In contrast to transcriptional regulation of enzymes, technical limitations have hindered the production of a genome-scale atlas of small molecule-enzyme regulatory interactions. Here, we develop a framework leveraging the vast, but fragmented, biochemical literature to reconstruct and analyze the small molecule regulatory network (SMRN) of the model organism Escherichia coli, including the primary metabolite regulators and enzyme targets. Using metabolic control analysis, we prove a fundamental trade-off between regulation and enzymatic activity, and we combine it with metabolomic measurementsmore » and the SMRN to make inferences on the sensitivity of enzymes to their regulators. By generalizing the analysis to other organisms, we identify highly conserved regulatory interactions across evolutionarily divergent species, further emphasizing a critical role for small molecule interactions in the maintenance of metabolic homeostasis.« less

Essential Cell-Autonomous Role for Interferon (IFN) Regulatory Factor 1 in IFN-γ-Mediated Inhibition of Norovirus Replication in Macrophages

PubMed Central

Maloney, Nicole S.; Thackray, Larissa B.; Goel, Gautam; Hwang, Seungmin; Duan, Erning; Vachharajani, Punit; Xavier, Ramnik

2012-01-01

Noroviruses (NVs) cause the majority of cases of epidemic nonbacterial gastroenteritis worldwide and contribute to endemic enteric disease. However, the molecular mechanisms responsible for immune control of their replication are not completely understood. Here we report that the transcription factor interferon regulatory factor 1 (IRF-1) is required for control of murine NV (MNV) replication and pathogenesis in vivo. This led us to studies documenting a cell-autonomous role for IRF-1 in gamma interferon (IFN-γ)-mediated inhibition of MNV replication in primary macrophages. This role of IRF-1 in the inhibition of MNV replication by IFN-γ is independent of IFN-αβ signaling. While the signal transducer and activator of transcription STAT-1 was also required for IFN-γ-mediated inhibition of MNV replication in vitro, class II transactivator (CIITA), interferon regulatory factor 3 (IRF-3), and interferon regulatory factor 7 (IRF-7) were not required. We therefore hypothesized that there must be a subset of IFN-stimulated genes (ISGs) regulated by IFN-γ in a manner dependent only on STAT-1 and IRF-1. Analysis of transcriptional profiles of macrophages lacking various transcription factors confirmed this hypothesis. These studies identify a key role for IRF-1 in IFN-γ-dependent control of norovirus infection in mice and macrophages. PMID:22973039

Nuclear Import of the Parsley bZIP Transcription Factor CPRF2 Is Regulated by Phytochrome Photoreceptors

PubMed Central

Kircher, Stefan; Wellmer, Frank; Nick, Peter; Rügner, Alexander; Schäfer, Eberhard; Harter, Klaus

1999-01-01

In plants, light perception by photoreceptors leads to differential expression of an enormous number of genes. An important step for differential gene expression is the regulation of transcription factor activities. To understand these processes in light signal transduction we analyzed the three well-known members of the common plant regulatory factor (CPRF) family from parsley (Petroselinum crispum). Here, we demonstrate that these CPRFs, which belong to the basic- region leucine-zipper (bZIP) domain-containing transcription factors, are differentially distributed within parsley cells, indicating different regulatory functions within the regulatory networks of the plant cell. In particular, we show by cell fractionation and immunolocalization approaches that CPRF2 is transported from the cytosol into the nucleus upon irradiation due to action of phytochrome photoreceptors. Two NH2-terminal domains responsible for cytoplasmic localization of CPRF2 in the dark were characterized by deletion analysis using a set of CPRF2-green fluorescent protein (GFP) gene fusion constructs transiently expressed in parsley protoplasts. We suggest that light-induced nuclear import of CPRF2 is an essential step in phytochrome signal transduction. PMID:9922448

Protecting the public or setting the bar too high? Understanding the causes and consequences of regulatory actions of front-line regulators and specialized drug shop operators in Kenya.

PubMed

Wafula, Francis; Molyneux, Catherine; Mackintosh, Maureen; Goodman, Catherine

2013-11-01

The problem of poor regulatory compliance has been widely reported across private health providers in developing countries. Less known are the underlying reasons for poor compliance, especially with regards to the roles played by front-line regulatory staff, and the regulatory institution as a whole. We designed a qualitative study to address this gap, with the study questions and tools drawing on a conceptual framework informed by theoretical literature on regulation. Data were collected from specialized drug shops (SDSs) in two rural districts in Western Kenya in 2011 through eight focus group discussions, and from regulatory staff from organizations governing the pharmaceutical sector through a total of 24 in-depth interviews. We found that relationships between front-line regulators and SDS operators were a strong influence on regulatory behaviour, often resulting in non-compliance and perverse outcomes such as corruption. It emerged that separate regulatory streams operated in urban and rural locations, based mainly on differing relationships between the front-line regulators and SDS operators, and on broader factors such as the competition environment and community expectations. Effective incentive structures for regulatory staff were either absent, or poorly linked to performance in regulatory organizations, resulting in divergences between the purposes of the regulatory organization and activities of front-line staff. Given the rural-urban differences in the practice environment, the introduction of lower retail practice requirements for rural SDSs could be considered. This would allow illegally operated shops to be brought within the regulatory framework, facilitating good quality provision of essential commodities to marginalized areas, without lowering the practice requirements for the better complying urban SDSs. In addition, regulatory organizations need to devise incentives that better link the level of effort to rewards such as professional

Protecting the public or setting the bar too high? Understanding the causes and consequences of regulatory actions of front-line regulators and specialized drug shop operators in Kenya

PubMed Central

Wafula, Francis; Molyneux, Catherine; Mackintosh, Maureen; Goodman, Catherine

2013-01-01

The problem of poor regulatory compliance has been widely reported across private health providers in developing countries. Less known are the underlying reasons for poor compliance, especially with regards to the roles played by front-line regulatory staff, and the regulatory institution as a whole. We designed a qualitative study to address this gap, with the study questions and tools drawing on a conceptual framework informed by theoretical literature on regulation. Data were collected from specialized drug shops (SDSs) in two rural districts in Western Kenya in 2011 through eight focus group discussions, and from regulatory staff from organizations governing the pharmaceutical sector through a total of 24 in-depth interviews. We found that relationships between front-line regulators and SDS operators were a strong influence on regulatory behaviour, often resulting in non-compliance and perverse outcomes such as corruption. It emerged that separate regulatory streams operated in urban and rural locations, based mainly on differing relationships between the front-line regulators and SDS operators, and on broader factors such as the competition environment and community expectations. Effective incentive structures for regulatory staff were either absent, or poorly linked to performance in regulatory organizations, resulting in divergences between the purposes of the regulatory organization and activities of front-line staff. Given the rural-urban differences in the practice environment, the introduction of lower retail practice requirements for rural SDSs could be considered. This would allow illegally operated shops to be brought within the regulatory framework, facilitating good quality provision of essential commodities to marginalized areas, without lowering the practice requirements for the better complying urban SDSs. In addition, regulatory organizations need to devise incentives that better link the level of effort to rewards such as professional

N-3 polyunsaturated fatty acid regulation of hepatic gene transcription

PubMed Central

Jump, Donald B.

2009-01-01

Purpose of review The liver plays a central role in whole body lipid metabolism and adapts rapidly to changes in dietary fat composition. This adaption involves changes in the expression of genes involved in glycolysis, de-novo lipogenesis, fatty acid elongation, desaturation and oxidation. This review brings together metabolic and molecular studies that help explain n-3 (omega-3) polyunsaturated fatty acid regulation of hepatic gene transcription. Recent findings Dietary n-3 polyunsaturated fatty acid regulates hepatic gene expression by targeting three major transcriptional regulatory networks: peroxisome proliferator-activated receptor α, sterol regulatory element binding protein-1 and the carbohydrate regulatory element binding protein/Max-like factor X heterodimer. 22 : 6,n-3, the most prominent n-3 polyunsaturated fatty acid in tissues, is a weak activator of peroxisome proliferator-activated receptor α. Hepatic metabolism of 22 : 6,n-3, however, generates 20 : 5,n-3, a strong peroxisome proliferator-activated receptor α activator. In contrast to peroxisome proliferator-activated receptor α, 22 : 6,n-3 is the most potent fatty acid regulator of hepatic sterol regulatory element binding protein-1. 22 : 6,n-3 suppresses sterol regulatory element binding protein-1 gene expression while enhancing degradation of nuclear sterol regulatory element binding protein-1 through 26S proteasome and Erk1/2-dependent mechanisms. Both n-3 and n-6 polyunsaturated fatty acid suppress carbohydrate regulatory element binding protein and Max-like factor X nuclear abundance and interfere with glucose-regulated hepatic metabolism. Summary These studies have revealed unique mechanisms by which specific polyunsaturated fatty acids control peroxisome proliferator activated receptor α, sterol regulatory element binding protein-1 and carbohydrate regulatory element binding protein/Max-like factor X function. As such, specific metabolic and signal transduction pathways contribute

Regulatory network rewiring for secondary metabolism in Arabidopsis thaliana under various conditions

PubMed Central

2014-01-01

Background Plant secondary metabolites are critical to various biological processes. However, the regulations of these metabolites are complex because of regulatory rewiring or crosstalk. To unveil how regulatory behaviors on secondary metabolism reshape biological processes, we constructed and analyzed a dynamic regulatory network of secondary metabolic pathways in Arabidopsis. Results The dynamic regulatory network was constructed through integrating co-expressed gene pairs and regulatory interactions. Regulatory interactions were either predicted by conserved transcription factor binding sites (TFBSs) or proved by experiments. We found that integrating two data (co-expression and predicted regulatory interactions) enhanced the number of highly confident regulatory interactions by over 10% compared with using single data. The dynamic changes of regulatory network systematically manifested regulatory rewiring to explain the mechanism of regulation, such as in terpenoids metabolism, the regulatory crosstalk of RAV1 (AT1G13260) and ATHB1 (AT3G01470) on HMG1 (hydroxymethylglutaryl-CoA reductase, AT1G76490); and regulation of RAV1 on epoxysqualene biosynthesis and sterol biosynthesis. Besides, we investigated regulatory rewiring with expression, network topology and upstream signaling pathways. Regulatory rewiring was revealed by the variability of genes’ expression: pathway genes and transcription factors (TFs) were significantly differentially expressed under different conditions (such as terpenoids biosynthetic genes in tissue experiments and E2F/DP family members in genotype experiments). Both network topology and signaling pathways supported regulatory rewiring. For example, we discovered correlation among the numbers of pathway genes, TFs and network topology: one-gene pathways (such as δ-carotene biosynthesis) were regulated by a fewer TFs, and were not critical to metabolic network because of their low degrees in topology. Upstream signaling pathways of 50

Single-target regulators form a minor group of transcription factors in Escherichia coli K-12.

PubMed

Shimada, Tomohiro; Ogasawara, Hiroshi; Ishihama, Akira

2018-05-04

The identification of regulatory targets of all TFs is critical for understanding the entire network of the genome regulation. The lac regulon of Escherichia coli K-12 W3110 is composed of the lacZYA operon and its repressor lacI gene, and has long been recognized as the seminal model of transcription regulation in bacteria with only one highly preferred target. After the Genomic SELEX screening in vitro of more than 200 transcription factors (TFs) from E. coli K-12, however, we found that most TFs regulate multiple target genes. With respect to the number of regulatory targets, a total of these 200 E. coli TFs form a hierarchy ranging from a single target to as many as 1000 targets. Here we focus a total of 13 single-target TFs, 9 known TFs (BetI, KdpE, LacI, MarR, NanR, RpiR, TorR, UlaR and UxuR) and 4 uncharacterized TFs (YagI, YbaO, YbiH and YeaM), altogether forming only a minor group of TFs in E. coli. These single-target TFs were classified into three groups based on their functional regulation.

Single-target regulators form a minor group of transcription factors in Escherichia coli K-12

PubMed Central

Shimada, Tomohiro; Ogasawara, Hiroshi; Ishihama, Akira

2018-01-01

Abstract The identification of regulatory targets of all TFs is critical for understanding the entire network of the genome regulation. The lac regulon of Escherichia coli K-12 W3110 is composed of the lacZYA operon and its repressor lacI gene, and has long been recognized as the seminal model of transcription regulation in bacteria with only one highly preferred target. After the Genomic SELEX screening in vitro of more than 200 transcription factors (TFs) from E. coli K-12, however, we found that most TFs regulate multiple target genes. With respect to the number of regulatory targets, a total of these 200 E. coli TFs form a hierarchy ranging from a single target to as many as 1000 targets. Here we focus a total of 13 single-target TFs, 9 known TFs (BetI, KdpE, LacI, MarR, NanR, RpiR, TorR, UlaR and UxuR) and 4 uncharacterized TFs (YagI, YbaO, YbiH and YeaM), altogether forming only a minor group of TFs in E. coli. These single-target TFs were classified into three groups based on their functional regulation. PMID:29529243

BID is a critical factor controlling cell viability regulated by IFN-α.

PubMed

Tsuno, Takaya; Mejido, Josef; Zhao, Tongmao; Phillips, Terry; Myers, Timothy G; Bekisz, Joseph; Zoon, Kathryn C

2012-01-01

Clinical applications of human interferon (IFN)-α have met with varying degrees of success. Nevertheless, key molecules in cell viability regulated by IFN-α have not been clearly identified. Our previous study indicated that IFN (α, β, and ω) receptor (IFNAR) 1/2- and IFN regulatory factor 9-RNA interference (RNAi) completely restored cell viability after IFN-α treatment in human ovarian adenocarcinoma OVCAR3 cells sensitive to IFN-α. In this study, IFNAR1/2- and IFN regulatory factor 9-RNAi inhibited the gene expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), but not of Fas ligand, after IFN-α treatment. In fact, TRAIL but not Fas ligand inhibited the viability of OVCAR3 cells. IFN-α notably upregulated the levels of TRAIL protein in the supernatant and on the membrane of OVCAR3 cells. After TRAIL signaling, caspase 8 inhibitor and BH3 interacting domain death agonist (BID)-RNAi significantly restored cell viability in response to IFN-α and TRAIL in OVCAR3 cells. Furthermore, BID-RNAi prevented both IFN-α and TRAIL from collapsing the mitochondrial membrane potential (ΔΨm). Finally, we provided important evidence that BID overexpression led to significant inhibition of cell viability after IFN-α or TRAIL treatments in human lung carcinoma A549 cells resistant to IFN-α. Thus, this study suggests that BID is crucial for cell viability regulated by IFN-α which can induce mitochondria-mediated apoptosis, indicating a notable potential to be a targeted therapy for IFN-α resistant tumors.

Notification: Implementation of Executive Order 13771, “Reducing Regulation and Controlling Regulatory Costs”

EPA Pesticide Factsheets

Project #OA&E-FY18-0177, April 10, 2018. The OIG plans to begin preliminary research on the Office of the Administrator's Office of Policy implementation of Executive Order 13771, Reducing Regulation and Controlling Regulatory Costs.

Extracytoplasmic function σ factors of the widely distributed group ECF41 contain a fused regulatory domain

PubMed Central

Wecke, Tina; Halang, Petra; Staroń, Anna; Dufour, Yann S; Donohue, Timothy J; Mascher, Thorsten

2012-01-01

Bacteria need signal transducing systems to respond to environmental changes. Next to one- and two-component systems, alternative σ factors of the extra-cytoplasmic function (ECF) protein family represent the third fundamental mechanism of bacterial signal transduction. A comprehensive classification of these proteins identified more than 40 phylogenetically distinct groups, most of which are not experimentally investigated. Here, we present the characterization of such a group with unique features, termed ECF41. Among analyzed bacterial genomes, ECF41 σ factors are widely distributed with about 400 proteins from 10 different phyla. They lack obvious anti-σ factors that typically control activity of other ECF σ factors, but their structural genes are often predicted to be cotranscribed with carboxymuconolactone decarboxylases, oxidoreductases, or epimerases based on genomic context conservation. We demonstrate for Bacillus licheniformis and Rhodobacter sphaeroides that the corresponding genes are preceded by a highly conserved promoter motif and are the only detectable targets of ECF41-dependent gene regulation. In contrast to other ECF σ factors, proteins of group ECF41 contain a large C-terminal extension, which is crucial for σ factor activity. Our data demonstrate that ECF41 σ factors are regulated by a novel mechanism based on the presence of a fused regulatory domain. PMID:22950025

Architecture of the human regulatory network derived from ENCODE data.

PubMed

Gerstein, Mark B; Kundaje, Anshul; Hariharan, Manoj; Landt, Stephen G; Yan, Koon-Kiu; Cheng, Chao; Mu, Xinmeng Jasmine; Khurana, Ekta; Rozowsky, Joel; Alexander, Roger; Min, Renqiang; Alves, Pedro; Abyzov, Alexej; Addleman, Nick; Bhardwaj, Nitin; Boyle, Alan P; Cayting, Philip; Charos, Alexandra; Chen, David Z; Cheng, Yong; Clarke, Declan; Eastman, Catharine; Euskirchen, Ghia; Frietze, Seth; Fu, Yao; Gertz, Jason; Grubert, Fabian; Harmanci, Arif; Jain, Preti; Kasowski, Maya; Lacroute, Phil; Leng, Jing Jane; Lian, Jin; Monahan, Hannah; O'Geen, Henriette; Ouyang, Zhengqing; Partridge, E Christopher; Patacsil, Dorrelyn; Pauli, Florencia; Raha, Debasish; Ramirez, Lucia; Reddy, Timothy E; Reed, Brian; Shi, Minyi; Slifer, Teri; Wang, Jing; Wu, Linfeng; Yang, Xinqiong; Yip, Kevin Y; Zilberman-Schapira, Gili; Batzoglou, Serafim; Sidow, Arend; Farnham, Peggy J; Myers, Richard M; Weissman, Sherman M; Snyder, Michael

2012-09-06

Transcription factors bind in a combinatorial fashion to specify the on-and-off states of genes; the ensemble of these binding events forms a regulatory network, constituting the wiring diagram for a cell. To examine the principles of the human transcriptional regulatory network, we determined the genomic binding information of 119 transcription-related factors in over 450 distinct experiments. We found the combinatorial, co-association of transcription factors to be highly context specific: distinct combinations of factors bind at specific genomic locations. In particular, there are significant differences in the binding proximal and distal to genes. We organized all the transcription factor binding into a hierarchy and integrated it with other genomic information (for example, microRNA regulation), forming a dense meta-network. Factors at different levels have different properties; for instance, top-level transcription factors more strongly influence expression and middle-level ones co-regulate targets to mitigate information-flow bottlenecks. Moreover, these co-regulations give rise to many enriched network motifs (for example, noise-buffering feed-forward loops). Finally, more connected network components are under stronger selection and exhibit a greater degree of allele-specific activity (that is, differential binding to the two parental alleles). The regulatory information obtained in this study will be crucial for interpreting personal genome sequences and understanding basic principles of human biology and disease.

Curated collection of yeast transcription factor DNA binding specificity data reveals novel structural and gene regulatory insights

PubMed Central

2011-01-01

Background Transcription factors (TFs) play a central role in regulating gene expression by interacting with cis-regulatory DNA elements associated with their target genes. Recent surveys have examined the DNA binding specificities of most Saccharomyces cerevisiae TFs, but a comprehensive evaluation of their data has been lacking. Results We analyzed in vitro and in vivo TF-DNA binding data reported in previous large-scale studies to generate a comprehensive, curated resource of DNA binding specificity data for all characterized S. cerevisiae TFs. Our collection comprises DNA binding site motifs and comprehensive in vitro DNA binding specificity data for all possible 8-bp sequences. Investigation of the DNA binding specificities within the basic leucine zipper (bZIP) and VHT1 regulator (VHR) TF families revealed unexpected plasticity in TF-DNA recognition: intriguingly, the VHR TFs, newly characterized by protein binding microarrays in this study, recognize bZIP-like DNA motifs, while the bZIP TF Hac1 recognizes a motif highly similar to the canonical E-box motif of basic helix-loop-helix (bHLH) TFs. We identified several TFs with distinct primary and secondary motifs, which might be associated with different regulatory functions. Finally, integrated analysis of in vivo TF binding data with protein binding microarray data lends further support for indirect DNA binding in vivo by sequence-specific TFs. Conclusions The comprehensive data in this curated collection allow for more accurate analyses of regulatory TF-DNA interactions, in-depth structural studies of TF-DNA specificity determinants, and future experimental investigations of the TFs' predicted target genes and regulatory roles. PMID:22189060

Sequence-based model of gap gene regulatory network.

PubMed

Kozlov, Konstantin; Gursky, Vitaly; Kulakovskiy, Ivan; Samsonova, Maria

2014-01-01

The detailed analysis of transcriptional regulation is crucially important for understanding biological processes. The gap gene network in Drosophila attracts large interest among researches studying mechanisms of transcriptional regulation. It implements the most upstream regulatory layer of the segmentation gene network. The knowledge of molecular mechanisms involved in gap gene regulation is far less complete than that of genetics of the system. Mathematical modeling goes beyond insights gained by genetics and molecular approaches. It allows us to reconstruct wild-type gene expression patterns in silico, infer underlying regulatory mechanism and prove its sufficiency. We developed a new model that provides a dynamical description of gap gene regulatory systems, using detailed DNA-based information, as well as spatial transcription factor concentration data at varying time points. We showed that this model correctly reproduces gap gene expression patterns in wild type embryos and is able to predict gap expression patterns in Kr mutants and four reporter constructs. We used four-fold cross validation test and fitting to random dataset to validate the model and proof its sufficiency in data description. The identifiability analysis showed that most model parameters are well identifiable. We reconstructed the gap gene network topology and studied the impact of individual transcription factor binding sites on the model output. We measured this impact by calculating the site regulatory weight as a normalized difference between the residual sum of squares error for the set of all annotated sites and for the set with the site of interest excluded. The reconstructed topology of the gap gene network is in agreement with previous modeling results and data from literature. We showed that 1) the regulatory weights of transcription factor binding sites show very weak correlation with their PWM score; 2) sites with low regulatory weight are important for the model output; 3

Regulatory physiology discipline science plan

NASA Technical Reports Server (NTRS)

1991-01-01

The focus of the Regulatory Physiology discipline of the Space Physiology and Countermeasures Program is twofold. First, to determine and study how microgravity and associated factors of space flight affect the regulatory mechanisms by which humans adapt and achieve homeostasis and thereby regulate their ability to respond to internal and external signals; and, second, to study selected physiological systems that have been demonstrated to be influenced by gravity. The Regulatory Physiology discipline, as defined here, is composed of seven subdisciplines: (1) Circadian Rhythms, (2) Endocrinology, (3) Fluid and Electrolyte Regulation, (4) Hematology, (5) Immunology, (6) Metabolism and Nutrition, and (7) Temperature Regulation. The purpose of this Discipline Science Plan is to provide a conceptual strategy for NASA's Life Sciences Division research and development activities in the area of regulatory physiology. It covers the research areas critical to NASA's programmatic requirements for the Extended-Duration Orbiter, Space Station Freedom, and exploration mission science activities. These science activities include ground-based and flight; basic, applied, and operational; and animal and human research and development. This document summarizes the current status of the program, outlines available knowledge, establishes goals and objectives, identifies science priorities, and defines critical questions in regulatory physiology. It contains a general plan that will be used by both NASA Headquarters Program Offices and the field centers to review and plan basic, applied, and operational intramural and extramural research and development activities in this area.

Smad7 Protein Induces Interferon Regulatory Factor 1-dependent Transcriptional Activation of Caspase 8 to Restore Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL)-mediated Apoptosis

PubMed Central

Hong, Suntaek; Kim, Hye-Youn; Kim, Jooyoung; Ha, Huyen Trang; Kim, Young-Mi; Bae, Eunjin; Kim, Tae Hyung; Lee, Kang Choon; Kim, Seong-Jin

2013-01-01

Smad7 has been known as a negative regulator for the transforming growth factor-β (TGF-β) signaling pathway through feedback regulation. However, Smad7 has been suspected to have other biological roles through the regulation of gene transcription. By screening differentially regulated genes, we found that the caspase 8 gene was highly up-regulated in Smad7-expressing cells. Smad7 was able to activate the caspase 8 promoter through recruitment of the interferon regulatory factor 1 (IRF1) transcription factor to the interferon-stimulated response element (ISRE) site. Interaction of Smad7 on the caspase 8 promoter was confirmed with electrophoretic mobility shift assay and chromatin immunoprecipitation experiment. Interestingly, Smad7 did not directly interact with the ISRE site, but it increased the binding activity of IRF1 with ISRE. These results support that Smad7 recruits IRF1 protein on the caspase 8 promoter and functions as a transcriptional coactivator. To confirm the biological significance of caspase 8 up-regulation, we tested tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-mediated cell death assay in breast cancer cells. Smad7 in apoptosis-resistant MCF7 cells markedly sensitized the cells to TRAIL-induced cell death by restoring the caspase cascade. Furthermore, restoration of caspase 8-mediated apoptosis pathway repressed the tumor growth in the xenograft model. In conclusion, we suggest a novel role for Smad7 as a transcriptional coactivator for caspase 8 through the interaction with IRF1 in regulation of the cell death pathway. PMID:23255602

Examining parents' ratings of middle-school students' academic self-regulation using principal axis factoring analysis.

PubMed

Chen, Peggy P; Cleary, Timothy J; Lui, Angela M

2015-09-01

This study examined the reliability and validity of a parent rating scale, the Self-Regulation Strategy Inventory: Parent Rating Scale (SRSI-PRS), using a sample of 451 parents of sixth- and seventh-grade middle-school students. Principal axis factoring (PAF) analysis revealed a 3-factor structure for the 23-item SRSI-PRS: (a) Managing Behavior and Learning (α = .92), (b) Maladaptive Regulatory Behaviors (α = .76), and (c) Managing Environment (α = .84). The majority of the observed relations between these 3 subscales, and the SRSI-SR, student motivation beliefs, and student mathematics grades were statistically significant and in the small to medium range. After controlling for various student variables and motivation indices of parental involvement, 2 SRSI-PRS factors (Managing Behavior and Learning, Maladaptive Regulatory Behaviors) reliably predicted students' achievement in their mathematics course. This study provides initial support for the validity and reliability of the SRSI-PRS and underscores the advantages of obtaining parental ratings of students' SRL behaviors. (c) 2015 APA, all rights reserved).

Dynamic integration of splicing within gene regulatory pathways

PubMed Central

Braunschweig, Ulrich; Gueroussov, Serge; Plocik, Alex; Graveley, Brenton R.; Blencowe, Benjamin J.

2013-01-01

Precursor mRNA splicing is one of the most highly regulated processes in metazoan species. In addition to generating vast repertoires of RNAs and proteins, splicing has a profound impact on other gene regulatory layers, including mRNA transcription, turnover, transport and translation. Conversely, factors regulating chromatin and transcription complexes impact the splicing process. This extensive cross-talk between gene regulatory layers takes advantage of dynamic spatial, physical and temporal organizational properties of the cell nucleus, and further emphasizes the importance of developing a multidimensional understanding of splicing control. PMID:23498935

Regulation of platelet activating factor receptor coupled phosphoinositide-specific phospholipase C activity

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

Morrison, W.J.

1988-01-01

The major objectives of this study were two-fold. The first was to establish whether binding of platelet activating factor (PAF) to its receptor was integral to the stimulation of polyphosphoinositide-specific phospholipase C (PLC) in rabbit platelets. The second was to determine regulatory features of this receptor-coupled mechanism. ({sup 3}H)PAF binding demonstrated two binding sites, a high affinity site with a inhibitory constant (Ki) of 2.65 nM and a low affinity site with a Ki of 0.80 {mu}M. PAF receptor coupled activation of phosphoinositide-specific PLC was studied in platelets which were made refractory, by short term pretreatments, to either PAF ormore » thrombin. Saponin-permeabilized rabbit platelets continue to regulate the mechanism(s) coupling PAF receptors to PLC stimulation. However, TRP{gamma}S and GDP{beta}S, which affect guanine nucleotide regulatory protein functions, were unable to modulate the PLC activity to any appreciable extent as compared to PAF. The possible involvement of protein kinase C (PKC) activation in regulating PAF-stimulated PLC activity was studied in rabbit platelets pretreated with staurosporine followed by pretreatments with PAF or phorbol 12-myristate 13-acetate (PMA).« less

Factors associated with regulatory action involving investigation of illnesses associated with Shiga toxin-producing Escherichia coli in products regulated by the Food Safety and Inspection Service.

PubMed

Green, Alice L; Seys, Scott; Douris, Aphrodite; Levine, Jeoff; Robertson, Kis

2014-07-01

We described characteristics of the Escherichia coli O157 and Escherichia coli non-O157 illness investigations conducted by the United States Department of Agriculture's Food Safety and Inspection Service (FSIS) during the 5-year period from 2006 through 2010. We created a multivariable logistic regression model to determine characteristics of these investigations that were associated with FSIS regulatory action, which was defined as having occurred if a product recall occurred or if FSIS personnel performed an environmental health assessment (Food Safety Assessment) at the implicated establishment. During this period, FSIS took regulatory action in 38 of 88 (43%) investigations. Illness investigations in which FoodNet states were involved were more likely to result in regulatory action. Illness investigations in which state and local traceback, or FSIS traceback occurred were more likely to result in regulatory action. Reasons for lack of action included evidence of cross-contamination after the product left a regulated establishment, delayed notification, lack of epidemiological information, and insufficient product information.

Molecular switch-like regulation in motor proteins.

PubMed

Tafoya, Sara; Bustamante, Carlos

2018-06-19

Motor proteins are powered by nucleotide hydrolysis and exert mechanical work to carry out many fundamental biological tasks. To ensure their correct and efficient performance, the motors' activities are allosterically regulated by additional factors that enhance or suppress their NTPase activity. Here, we review two highly conserved mechanisms of ATP hydrolysis activation and repression operating in motor proteins-the glutamate switch and the arginine finger-and their associated regulatory factors. We examine the implications of these regulatory mechanisms in proteins that are formed by multiple ATPase subunits. We argue that the regulatory mechanisms employed by motor proteins display features similar to those described in small GTPases, which require external regulatory elements, such as dissociation inhibitors, exchange factors and activating proteins, to switch the protein's function 'on' and 'off'. Likewise, similar regulatory roles are taken on by the motor's substrate, additional binding factors, and even adjacent subunits in multimeric complexes. However, in motor proteins, more than one regulatory factor and the two mechanisms described here often underlie the machine's operation. Furthermore, ATPase regulation takes place throughout the motor's cycle, which enables a more complex function than the binary 'active' and 'inactive' states.This article is part of a discussion meeting issue 'Allostery and molecular machines'. © 2018 The Author(s).

Regulatory genes and their roles for improvement of antibiotic biosynthesis in Streptomyces.

PubMed

Lu, Fengjuan; Hou, Yanyan; Zhang, Heming; Chu, Yiwen; Xia, Haiyang; Tian, Yongqiang

2017-08-01

The numerous secondary metabolites in Streptomyces spp. are crucial for various applications. For example, cephamycin C is used as an antibiotic, and avermectin is used as an insecticide. Specifically, antibiotic yield is closely related to many factors, such as the external environment, nutrition (including nitrogen and carbon sources), biosynthetic efficiency and the regulatory mechanisms in producing strains. There are various types of regulatory genes that work in different ways, such as pleiotropic (or global) regulatory genes, cluster-situated regulators, which are also called pathway-specific regulatory genes, and many other regulators. The study of regulatory genes that influence antibiotic biosynthesis in Streptomyces spp. not only provides a theoretical basis for antibiotic biosynthesis in Streptomyces but also helps to increase the yield of antibiotics via molecular manipulation of these regulatory genes. Currently, more and more emphasis is being placed on the regulatory genes of antibiotic biosynthetic gene clusters in Streptomyces spp., and many studies on these genes have been performed to improve the yield of antibiotics in Streptomyces. This paper lists many antibiotic biosynthesis regulatory genes in Streptomyces spp. and focuses on frequently investigated regulatory genes that are involved in pathway-specific regulation and pleiotropic regulation and their applications in genetic engineering.

Splicing regulatory factors, ageing and age-related disease.

PubMed

Latorre, Eva; Harries, Lorna W

2017-07-01

Alternative splicing is a co-transcriptional process, which allows for the production of multiple transcripts from a single gene and is emerging as an important control point for gene expression. Alternatively expressed isoforms often have antagonistic function and differential temporal or spatial expression patterns, yielding enormous plasticity and adaptability to cells and increasing their ability to respond to environmental challenge. The regulation of alternative splicing is critical for numerous cellular functions in both pathological and physiological conditions, and deregulated alternative splicing is a key feature of common chronic diseases. Isoform choice is controlled by a battery of splicing regulatory proteins, which include the serine arginine rich (SRSF) proteins and the heterogeneous ribonucleoprotein (hnRNP) classes of genes. These important splicing regulators have been implicated in age-related disease, and in the ageing process itself. This review will outline the important contribution of splicing regulator proteins to ageing and age-related disease. Copyright © 2017 Elsevier B.V. All rights reserved.

Anxiety sensitivity and affect regulatory strategies: individual and interactive risk factors for anxiety-related symptoms.

PubMed

Kashdan, Todd B; Zvolensky, Michael J; McLeish, Alison C

2008-01-01

Studies have shown that anxiety sensitivity (AS) is a risk factor in the development of pathological anxiety. Recent theoretical models emphasize the additional importance of how people handle their anxious experiences. The present study examined whether high AS and being fixated on the control and regulation of unwanted anxious feelings or being unable to properly modulate affect as needed lead to particularly problematic outcomes. We examined the interactive influence of AS and affect regulatory strategies on the frequency and intensity of anxiety symptoms. Questionnaires were completed by 248 young adults in the community. Results showed a general pattern with anxiety symptoms being the most severe when high AS was paired with affect regulatory difficulties. Of participants high in AS, anxious arousal and worry were heightened in the presence of less acceptance of emotional distress; anxious arousal, worry, and agoraphobic cognitions were heightened when fewer resources were available to properly modulate affect; and agoraphobic cognitions were heightened in the presence of high emotion expressiveness. As evidence of construct specificity, an alternative model with anhedonic depressive symptoms as a main effect and interaction effect (with regulatory strategies) failed to predict anxiety symptoms. However, anxiety sensitivity and less acceptance of emotional distress were associated with greater anhedonia. Results are discussed in the context of how and when affect regulatory behavior shifts individuals from normative anxiety to pathology.

Transcription Factor Foxo1 Is a Negative Regulator of NK Cell Maturation and Function

PubMed Central

Deng, Youcai; Kerdiles, Yann; Chu, Jianhong; Yuan, Shunzong; Wang, Youwei; Chen, Xilin; Mao, Hsiaoyin; Zhang, Lingling; Zhang, Jianying; Hughes, Tiffany; Deng, Yafei; Zhang, Qi; Wang, Fangjie; Zou, Xianghong; Liu, Chang-Gong; Freud, Aharon G.; Li, Xiaohui; Caligiuri, Michael A; Vivier, Eric; Yu, Jianhua

2015-01-01

SUMMARY Little is known about the role of negative regulators in controlling natural killer (NK) cell development and effector functions. Foxo1 is a multifunctional transcription factor of the forkhead family. Using a mouse model of conditional deletion in NK cells, we found that Foxo1 negatively controlled NK cell differentiation and function. Immature NK cells expressed abundant Foxo1 and little Tbx21 relative to mature NK cells, but these two transcription factors reversed their expression as NK cells proceeded through development. Foxo1 promoted NK cell homing to lymph nodes through upregulating CD62L expression, and impaired late-stage maturation and effector functions by repressing Tbx21 expression. Loss of Foxo1 rescued the defect in late-stage NK cell maturation in heterozygous Tbx21+/− mice. Collectively, our data reveal a regulatory pathway by which the negative regulator Foxo1 and the positive regulator Tbx21 play opposing roles in controlling NK cell development and effector functions. PMID:25769609

Regulatory networks between neurotrophins and miRNAs in brain diseases and cancers

PubMed Central

Shi, Jian

2015-01-01

Neurotrophins are involved in many physiological and pathological processes in the nervous system. They regulate and modify signal transduction, transcription and translation in neurons. It is recently demonstrated that the neurotrophin expression is regulated by microRNAs (miRNAs), changing our views on neurotrophins and miRNAs. Generally, miRNAs regulate neurotrophins and their receptors in at least two ways: (1) miRNAs bind directly to the 3′ untranslated region (UTR) of isoform-specific mRNAs and post-transcriptionally regulate their expression; (2) miRNAs bind to the 3′ UTR of the regulatory factors of neurotrophins and regulate their expression. On the other hand, neurotrophins can regulate miRNAs. The results of BNDF research show that neurotrophins regulate miRNAs in at least three ways: (1) ERK stimulation enhances the activation of TRBP (HIV-1 TAR RNA-binding protein) and Dicer, leading to the upregulation of miRNA biogenesis; (2) ERK-dependent upregulation of Lin28a (RNA-binding proteins) blocks select miRNA biogenesis; (3) transcriptional regulation of miRNA expression through activation of transcription factors, including CREB and NF-κB. These regulatory processes integrate positive and negative regulatory loops in neurotrophin and miRNA signaling pathways, and also expand the function of neurotrophins and miRNAs. In this review, we summarize the current knowledge of the regulatory networks between neurotrophins and miRNAs in brain diseases and cancers, for which novel cutting edge therapeutic, delivery and diagnostic approaches are emerging. PMID:25544363

Cognitive and Self-regulatory Mechanisms of Obesity Study (COSMOS): Study protocol for a randomized controlled weight loss trial examining change in biomarkers, cognition, and self-regulation across two behavioral treatments.

PubMed

Hawkins, M A W; Colaizzi, Janna; Gunstad, John; Hughes, Joel W; Mullins, Larry L; Betts, Nancy; Smith, Caitlin E; Keirns, Natalie G; Vohs, Kathleen D; Moore, Shirley M; Forman, Evan M; Lovallo, William R

2018-03-01

Obesity is a global epidemic, yet successful interventions are rare. Up to 60% of people fail to achieve clinically meaningful, short-term weight loss (5-10% of start weight), whereas up to 72% are unsuccessful at achieving long-term weight loss (5-10% loss for ≥5years). Understanding how biological, cognitive, and self-regulatory factors work together to promote or to impede weight loss is clearly needed to optimize obesity treatment. This paper describes the methodology of the Cognitive and Self-regulatory Mechanisms of Obesity Study (the COSMOS trial). COSMOS is the first randomized controlled trial to investigate how changes in multiple biopsychosocial and cognitive factors relate to weight loss and one another across two weight loss treatments. The specific aims are to: 1) Confirm that baseline obesity-related physiological dysregulation is linked to cognitive deficits and poorer self-regulation, 2) Evaluate pre- to post-treatment change across time to assess individual differences in biomarkers, cognition, and self-regulation, and 3) Evaluate whether the acceptance-based treatment (ABT) group has greater improvements in outcomes (e.g., greater weight loss and less weight regain, improvements in biomarkers, cognition, and self-regulation), than the standard behavioral treatment group (SBT) from pre- to post-treatment and 1-year follow-up. The results of COSMOS will provide critical information about how dysregulation in biomarkers, cognition, and/or self-regulation is related to weight loss and whether weight loss treatments are differentially associated with these factors. This information will be used to identify promising treatment targets that are informed by biological, cognitive, and self-regulatory factors in order to advance obesity treatment. Copyright © 2017 Elsevier Inc. All rights reserved.

The MYB107 Transcription Factor Positively Regulates Suberin Biosynthesis

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

Gou, Mingyue; Hou, Guichuan; Yang, Huijun

Suberin, a lipophilic polymer deposited in the outer integument of the Arabidopsis ( Arabidopsis thaliana) seed coat, represents an essential sealing component controlling water and solute movement and protecting seed from pathogenic infection. Although many genes responsible for suberin synthesis are identified, the regulatory components controlling its biosynthesis have not been definitively determined. Here, we show that the Arabidopsis MYB107 transcription factor acts as a positive regulator controlling suberin biosynthetic gene expression in the seed coat. MYB107 coexpresses with suberin biosynthetic genes in a temporal manner during seed development. Disrupting MYB107 particularly suppresses the expression of genes involved in suberinmore » but not cutin biosynthesis, lowers seed coat suberin accumulation, alters suberin lamellar structure, and consequently renders higher seed coat permeability and susceptibility to abiotic stresses. Furthermore, MYB107 directly binds to the promoters of suberin biosynthetic genes, verifying its primary role in regulating their expression. Identifying MYB107 as a positive regulator for seed coat suberin synthesis offers a basis for discovering the potential transcriptional network behind one of the most abundant lipid-based polymers in nature.« less

The MYB107 Transcription Factor Positively Regulates Suberin Biosynthesis

DOE PAGES

Gou, Mingyue; Hou, Guichuan; Yang, Huijun; ...

2016-12-13

Suberin, a lipophilic polymer deposited in the outer integument of the Arabidopsis ( Arabidopsis thaliana) seed coat, represents an essential sealing component controlling water and solute movement and protecting seed from pathogenic infection. Although many genes responsible for suberin synthesis are identified, the regulatory components controlling its biosynthesis have not been definitively determined. Here, we show that the Arabidopsis MYB107 transcription factor acts as a positive regulator controlling suberin biosynthetic gene expression in the seed coat. MYB107 coexpresses with suberin biosynthetic genes in a temporal manner during seed development. Disrupting MYB107 particularly suppresses the expression of genes involved in suberinmore » but not cutin biosynthesis, lowers seed coat suberin accumulation, alters suberin lamellar structure, and consequently renders higher seed coat permeability and susceptibility to abiotic stresses. Furthermore, MYB107 directly binds to the promoters of suberin biosynthetic genes, verifying its primary role in regulating their expression. Identifying MYB107 as a positive regulator for seed coat suberin synthesis offers a basis for discovering the potential transcriptional network behind one of the most abundant lipid-based polymers in nature.« less

TCP transcription factors are critical for the coordinated regulation of isochorismate synthase 1 expression in Arabidopsis thaliana.

PubMed

Wang, Xiaoyan; Gao, Jiong; Zhu, Zheng; Dong, Xianxin; Wang, Xiaolei; Ren, Guodong; Zhou, Xin; Kuai, Benke

2015-04-01

Salicylic acid (SA) plays an important role in various aspects of plant development and responses to stresses. To elucidate the sophisticated regulatory mechanism of SA synthesis and signaling, we used a yeast one-hybrid system to screen for regulators of isochorismate synthase 1 (ICS1), a gene encoding the key enzyme in SA biosynthesis in Arabidopsis thaliana. A TCP family transcription factor AtTCP8 was initially identified as a candidate regulator of ICS1. The regulation of ICS1 by TCP proteins is supported by the presence of a typical TCP binding site in the ICS1 promoter. The binding of TCP8 to this site was confirmed by in vitro and in vivo assays. Expression patterns of TCP8 and its corresponding gene TCP9 largely overlapped with ICS1 under pathogen attack. A significant reduction in the expression of ICS1 during immune responses was observed in the tcp8 tcp9 double mutant. We also detected strong interactions between TCP8 and SAR deficient 1 (SARD1), WRKY family transcription factor 28 (WRKY28), NAC (NAM/ATAF1,ATAF2/CUC2) family transcription factor 019 (NAC019), as well as among TCP8, TCP9 and TCP20, suggesting a complex coordinated regulatory mechanism underlying ICS1 expression. Our results collectively demonstrate that TCP proteins are involved in the orchestrated regulation of ICS1 expression, with TCP8 and TCP9 being verified as major representatives. © 2015 The Authors The Plant Journal © 2015 John Wiley & Sons Ltd.

Emerging principles of regulatory evolution.

PubMed

Prud'homme, Benjamin; Gompel, Nicolas; Carroll, Sean B

2007-05-15

Understanding the genetic and molecular mechanisms governing the evolution of morphology is a major challenge in biology. Because most animals share a conserved repertoire of body-building and -patterning genes, morphological diversity appears to evolve primarily through changes in the deployment of these genes during development. The complex expression patterns of developmentally regulated genes are typically controlled by numerous independent cis-regulatory elements (CREs). It has been proposed that morphological evolution relies predominantly on changes in the architecture of gene regulatory networks and in particular on functional changes within CREs. Here, we discuss recent experimental studies that support this hypothesis and reveal some unanticipated features of how regulatory evolution occurs. From this growing body of evidence, we identify three key operating principles underlying regulatory evolution, that is, how regulatory evolution: (i) uses available genetic components in the form of preexisting and active transcription factors and CREs to generate novelty; (ii) minimizes the penalty to overall fitness by introducing discrete changes in gene expression; and (iii) allows interactions to arise among any transcription factor and downstream CRE. These principles endow regulatory evolution with a vast creative potential that accounts for both relatively modest morphological differences among closely related species and more profound anatomical divergences among groups at higher taxonomical levels.

Cosmetic Regulations: A Comparative Study.

PubMed

Suhag, Jyoti; Dureja, Harish

2015-01-01

The regulatory framework, compliance requirement, efficacy, safety, and marketing of cosmetic products are considered the most important factors for growth of the cosmetic industry. There are different regulatory bodies across the globe that have their own insights for regulation; moreover, governments such as the United States, European Union, and Japan follow a stringent regulatory framework, whereas cosmetics are not so much strictly regulated in countries such as India, Brazil, and China. The alignment of a regulatory framework will play a significant role in the removal of barriers to trade, growth of market at an international level, innovation in the development and presentation of new products, and most importantly safety and efficacy of the marketed products. The present contribution gives insight into the important cosmetic regulations in areas of premarket approval, ingredient control, and labeling and warnings, with a special focus on the cosmetic regulatory environments in the United States, European Union, Japan, and India. Most importantly, the authors highlight the dark side of cosmetics associated with allergic reactions and even skin cancer. The importance of cosmetic regulations has been highlighted by dint of which the society can be healthier, accomplished by more stringent and harmonized regulations.

MicroRNA-302a suppresses influenza A virus-stimulated interferon regulatory factor-5 expression and cytokine storm induction.

PubMed

Chen, Xueyuan; Zhou, Li; Peng, Nanfang; Yu, Haisheng; Li, Mengqi; Cao, Zhongying; Lin, Yong; Wang, Xueyu; Li, Qian; Wang, Jun; She, Yinglong; Zhu, Chengliang; Lu, Mengji; Zhu, Ying; Liu, Shi

2017-12-29

During influenza A virus (IAV) infection, cytokine storms play a vital and critical role in clinical outcomes. We have previously reported that microRNA (miR)-302c regulates IAV-induced IFN expression by targeting the 3'-UTR of nuclear factor κB (NF-κB)-inducing kinase. In the current study, we found that miR-302a, another member of the miR-302 cluster, controls the IAV-induced cytokine storm. According to results from cell-based and knockout mouse models, IAV induces a cytokine storm via interferon regulatory factor-5 (IRF-5). We also found that IAV infection up-regulates IRF-5 expression and that IRF-5 in turn promotes IAV replication. Furthermore, we observed that IRF-5 is a direct target of miR-302a, which down-regulated IRF-5 expression by binding its 3'-UTR. Moreover, IAV increased IRF-5 expression by down-regulating miR-302a expression. Interestingly, miR-302a inhibited IAV replication. In IAV-infected patients, miR-302a expression was down-regulated, whereas IRF-5 expression was up-regulated. Taken together, our work uncovers and defines a signaling pathway implicated in an IAV-induced cytokine storm. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Deciphering RNA Regulatory Elements Involved in the Developmental and Environmental Gene Regulation of Trypanosoma brucei.

PubMed

Gazestani, Vahid H; Salavati, Reza

2015-01-01

Trypanosoma brucei is a vector-borne parasite with intricate life cycle that can cause serious diseases in humans and animals. This pathogen relies on fine regulation of gene expression to respond and adapt to variable environments, with implications in transmission and infectivity. However, the involved regulatory elements and their mechanisms of actions are largely unknown. Here, benefiting from a new graph-based approach for finding functional regulatory elements in RNA (GRAFFER), we have predicted 88 new RNA regulatory elements that are potentially involved in the gene regulatory network of T. brucei. We show that many of these newly predicted elements are responsive to both transcriptomic and proteomic changes during the life cycle of the parasite. Moreover, we found that 11 of predicted elements strikingly resemble previously identified regulatory elements for the parasite. Additionally, comparison with previously predicted motifs on T. brucei suggested the superior performance of our approach based on the current limited knowledge of regulatory elements in T. brucei.

Self-perceived successful weight regulators are less affected by self-regulatory depletion in the domain of eating behavior.

PubMed

Friese, Malte; Engeler, Michèle; Florack, Arnd

2015-01-01

Weight loss and maintenance goals are highly prevalent in many affluent societies, but many weight regulators are not successful in the long term. Research started to reveal psychological mechanisms that help successful weight regulators in being successful. In the present study, we tested the assumption that these mechanisms facilitate successful self-regulation particularly under conditions of self-regulatory depletion. Participants exerted or did not exert self-control in a first task before engaging in a taste test of a tempting but unhealthy food. Participants who had initially exerted self-control ate more than participants in the control condition. This effect was reduced in self-perceived successful weight regulators as compared to perceived unsuccessful self-regulators. A reduced susceptibility to self-regulatory depletion may be an important contributor to long-term weight regulation success in successful weight regulators. Copyright © 2014 Elsevier Ltd. All rights reserved.

Metalloproteinase pregnancy-associated plasma protein A is a critical growth regulatory factor during fetal development.

PubMed

Conover, Cheryl A; Bale, Laurie K; Overgaard, Michael T; Johnstone, Edward W; Laursen, Ulla H; Füchtbauer, Ernst-Martin; Oxvig, Claus; van Deursen, Jan

2004-03-01

Pregnancy-associated plasma protein A (PAPPA) is a metzincin superfamily metalloproteinase in the insulin-like growth factor (IGF) system. PAPPA increases IGF bioavailability and mitogenic effectiveness in vitro through regulated cleavage of IGF-binding protein 4 (IGFBP4). To determine its function in vivo, we generated PAPPA-null mice by gene targeting. Mice homozygous for targeted disruption of the PAPPA gene were viable but 60% the size of wild-type littermates at birth. The impact of the mutation was exerted during the early embryonic period prior to organogenesis, resulting in proportional dwarfism. PAPPA, IGF2 and IGFBP4 transcripts co-localized in wild-type embryos, and expression of IGF2 and IGFBP4 mRNA was not altered in PAPPA-deficient embryos. However, IGFBP4 proteolytic activity was completely lacking in fibroblasts derived from PAPPA-deficient embryos, and IGFBP4 effectively inhibited IGF-stimulated mitogenesis in these cells. These results provide the first direct evidence that PAPPA is an essential growth regulatory factor in vivo, and suggest a novel mechanism for regulated IGF bioavailability during early fetal development.

Defining Transcriptional Regulatory Mechanisms for Primary let-7 miRNAs

PubMed Central

Gaeta, Xavier; Le, Luat; Lin, Ying; Xie, Yuan; Lowry, William E.

2017-01-01

The let-7 family of miRNAs have been shown to control developmental timing in organisms from C. elegans to humans; their function in several essential cell processes throughout development is also well conserved. Numerous studies have defined several steps of post-transcriptional regulation of let-7 production; from pri-miRNA through pre-miRNA, to the mature miRNA that targets endogenous mRNAs for degradation or translational inhibition. Less-well defined are modes of transcriptional regulation of the pri-miRNAs for let-7. let-7 pri-miRNAs are expressed in polycistronic fashion, in long transcripts newly annotated based on chromatin-associated RNA-sequencing. Upon differentiation, we found that some let-7 pri-miRNAs are regulated at the transcriptional level, while others appear to be constitutively transcribed. Using the Epigenetic Roadmap database, we further annotated regulatory elements of each polycistron identified putative promoters and enhancers. Probing these regulatory elements for transcription factor binding sites identified factors that regulate transcription of let-7 in both promoter and enhancer regions, and identified novel regulatory mechanisms for this important class of miRNAs. PMID:28052101

R2R3 MYB transcription factors: key regulators of the flavonoid biosynthetic pathway in grapevine.

PubMed

Czemmel, Stefan; Heppel, Simon C; Bogs, Jochen

2012-06-01

Flavonoids compose one of the most abundant and important subgroups of secondary metabolites with more than 6,000 compounds detected so far in higher plants. They are found in various compositions and concentrations in nearly all plant tissues. Besides the attraction of pollinators and dispersers to fruits and flowers, flavonoids also protect against a plethora of stresses including pathogen attack, wounding and UV irradiation. Flavonoid content and composition of fruits such as grapes, bilberries, strawberries and apples as well as food extracts such as green tea, wine and chocolate have been associated with fruit quality including taste, colour and health-promoting effects. To unravel the beneficial potentials of flavonoids on fruit quality, research has been focused recently on the molecular basis of flavonoid biosynthesis and regulation in economically important fruit-producing plants such as grapevine (Vitis vinifera L.). Transcription factors and genes encoding biosynthetic enzymes have been characterized, studies that set a benchmark for future research on the regulatory networks controlling flavonoid biosynthesis and diversity. This review summarizes recent advances in the knowledge of regulatory cascades involved in flavonoid biosynthesis in grapevine. Transcriptional regulation of flavonoid biosynthesis during berry development is highlighted, with a particular focus on MYB transcription factors as molecular clocks, key regulators and powerful biotechnological tools to identify novel pathway enzymes to optimize flavonoid content and composition in grapes.

Transcription factor FBI-1 acts as a dual regulator in adipogenesis by coordinated regulation of cyclin-A and E2F-4.

PubMed

Laudes, Matthias; Bilkovski, Roman; Oberhauser, Frank; Droste, Andrea; Gomolka, Matthias; Leeser, Uschi; Udelhoven, Michael; Krone, Wilhelm

2008-05-01

Generation of new adipocytes plays a major role in the development of obesity. We previously have shown that transcriptional repressor factor that binds to IST (FBI)-1 exerts a dual effect in the process of adipogenesis by inhibiting proliferation and promoting differentiation of preadipocytes. The aim of the present study was to identify FBI-1 regulated molecular effectors that could account for these effects. Overexpressing FBI-1 in preadipocytes resulted in reduced expression of the cell cycle regulator cyclin A, which may explain FBI-1 induced inhibition of proliferation. Interestingly, FBI-1 repressed cyclin A promoter activity through an indirect mechanisms that did not involve direct binding of FBI-1 to the promoter sequence, but rather FBI-1 inhibition of transcriptional activator Sp1 binding to a regulatory element at -452 to -443. We also show that FBI-1 promotes terminal preadipocyte differentiation through a mechanism involving decreased levels of expression of the PPARgamma inhibitor E2F-4. FBI-1 significantly reduced E2F-4 promoter activity. Contrary to cyclin A, we found FBI-1-induced repression of E2F-4 is mediated by a direct mechanism via a FBI-1 regulatory element at -11 to -5. As function of transcriptional repressors normally depends on the presence of regulatory co-factors we also performed expression profiling of potential FBI-1 co-repressors throughout adipogenesis. In these experiments Sin3A and histon deacetylase (HDAC)-1 showed a similar expression pattern compared to FBI-1. Strikingly, co-immunoprecipitation studies revealed that FBI-1 binds Sin3A and HDAC-1 to form a repressor complex. Furthermore, by mutational analysis the amino terminal Poxvirus (POZ) domain of FBI-1 was found to be important for Sin3A and HDAC-1 binding. Taken together, FBI-1 is the first transcriptional repressor shown to act as a dual regulator in adipogenesis exerting repressor activities on target genes by both, direct and indirect mechanisms.

The Membrane-Bound NAC Transcription Factor ANAC013 Functions in Mitochondrial Retrograde Regulation of the Oxidative Stress Response in Arabidopsis[C][W

PubMed Central

De Clercq, Inge; Vermeirssen, Vanessa; Van Aken, Olivier; Vandepoele, Klaas; Murcha, Monika W.; Law, Simon R.; Inzé, Annelies; Ng, Sophia; Ivanova, Aneta; Rombaut, Debbie; van de Cotte, Brigitte; Jaspers, Pinja; Van de Peer, Yves; Kangasjärvi, Jaakko; Whelan, James; Van Breusegem, Frank

2013-01-01

Upon disturbance of their function by stress, mitochondria can signal to the nucleus to steer the expression of responsive genes. This mitochondria-to-nucleus communication is often referred to as mitochondrial retrograde regulation (MRR). Although reactive oxygen species and calcium are likely candidate signaling molecules for MRR, the protein signaling components in plants remain largely unknown. Through meta-analysis of transcriptome data, we detected a set of genes that are common and robust targets of MRR and used them as a bait to identify its transcriptional regulators. In the upstream regions of these mitochondrial dysfunction stimulon (MDS) genes, we found a cis-regulatory element, the mitochondrial dysfunction motif (MDM), which is necessary and sufficient for gene expression under various mitochondrial perturbation conditions. Yeast one-hybrid analysis and electrophoretic mobility shift assays revealed that the transmembrane domain–containing NO APICAL MERISTEM/ARABIDOPSIS TRANSCRIPTION ACTIVATION FACTOR/CUP-SHAPED COTYLEDON transcription factors (ANAC013, ANAC016, ANAC017, ANAC053, and ANAC078) bound to the MDM cis-regulatory element. We demonstrate that ANAC013 mediates MRR-induced expression of the MDS genes by direct interaction with the MDM cis-regulatory element and triggers increased oxidative stress tolerance. In conclusion, we characterized ANAC013 as a regulator of MRR upon stress in Arabidopsis thaliana. PMID:24045019

Gravity, an Regulation Factor in BMSCs Differentiation to osteoblasts

NASA Astrophysics Data System (ADS)

Yan, Huang; Yinghui, Li; Fen, Yang; Zhongquan, Dai

PURPOSE Most studies of regulatory mechanisms of adult stem cell differentiation are concentrated in chemical factors but few efforts are put into physical factors Recent space life science studies indicate mechanical factors participate in the differentiation of cells The aim of this study is to investigate the effects of simulated microgravity or hypergravity on the osteogenic differentiation of rat bone marrow mesenchymal stem cells BMSCs METHODOLOGY The BMSCs at day 7 were added osteogenic inducer 10nM dexamethasone 10mM beta -glycerophosphate and 50 mu M asorbic acid-2-phosphate for 7 days and cultured under simulated microgravity or hypergravity 2g for 1 day 3 days 5 days or 7 days RESULTS After treating BMSCs with osteogenic inducer and hypergravity the cells expressed more ColIA1 Cbfa1 and ALP than in single steogenic inducer treatment Reversely the cells treated with osteogenic inducer and simulated microgravity expressed less ColIA1 Cbfa1 and ALP CONCLUSIONS Our study suggests that hypergravity promotes the osteogenic differentiation of BMSCs and simulated microgravity inhibits this process Gravity is an important regulation factor in BMSCs differentiation to osteoblasts

Analysis of the Salmonella regulatory network suggests involvement of SsrB and H-NS in σ E-regulated SPI-2 gene expression

DOE PAGES

Li, Jie; Overall, Christopher C.; Nakayasu, Ernesto S.; ...

2015-02-10

The extracytoplasmic functioning sigma factor σ E is known to play an essential role for Salmonella enterica serovar Typhimurium to survive and proliferate in macrophages and mice. However, its regulatory network is not well characterized, especially during infection. Here we used microarray to identify genes regulated by σ E in Salmonella grown in three conditions: a nutrient-rich condition and two others that mimic early and late intracellular infection. We found that in each condition σ E regulated different sets of genes, and notably, several global regulators. When comparing nutrient-rich and infection-like conditions, large changes were observed in the expression ofmore » genes involved in Salmonella pathogenesis island (SPI)-1 type-three secretion system (TTSS), SPI-2 TTSS, protein synthesis, and stress responses. In total, the expression of 58% of Salmonella genes was affected by σ E in at least one of the three conditions. An important finding is that σ E up-regulates SPI-2 genes, which are essential for Salmonella intracellular survival, by up-regulating SPI-2 activator ssrB expression at the early stage of infection and down-regulating SPI-2 repressor hns expression at a later stage. Moreover, σ E is capable of countering the silencing of H-NS, releasing the expression of SPI-2 genes. This connection between σ E and SPI-2 genes, combined with the global regulatory effect of σ E, may account for the lethality of rpoE-deficient Salmonella in murine infection.« less

Analysis of the Salmonella regulatory network suggests involvement of SsrB and H-NS in σ E-regulated SPI-2 gene expression

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

Li, Jie; Overall, Christopher C.; Nakayasu, Ernesto S.

The extracytoplasmic functioning sigma factor σ E is known to play an essential role for Salmonella enterica serovar Typhimurium to survive and proliferate in macrophages and mice. However, its regulatory network is not well characterized, especially during infection. Here we used microarray to identify genes regulated by σ E in Salmonella grown in three conditions: a nutrient-rich condition and two others that mimic early and late intracellular infection. We found that in each condition σ E regulated different sets of genes, and notably, several global regulators. When comparing nutrient-rich and infection-like conditions, large changes were observed in the expression ofmore » genes involved in Salmonella pathogenesis island (SPI)-1 type-three secretion system (TTSS), SPI-2 TTSS, protein synthesis, and stress responses. In total, the expression of 58% of Salmonella genes was affected by σ E in at least one of the three conditions. An important finding is that σ E up-regulates SPI-2 genes, which are essential for Salmonella intracellular survival, by up-regulating SPI-2 activator ssrB expression at the early stage of infection and down-regulating SPI-2 repressor hns expression at a later stage. Moreover, σ E is capable of countering the silencing of H-NS, releasing the expression of SPI-2 genes. This connection between σ E and SPI-2 genes, combined with the global regulatory effect of σ E, may account for the lethality of rpoE-deficient Salmonella in murine infection.« less

The regulatory sciences for stem cell-based medicinal products.

PubMed

Yuan, Bao-Zhu; Wang, Junzhi

2014-06-01

Over the past few years, several new achievements have been made from stem cell studies, many of which have moved up from preclinical stages to early, or from early to middle or late, stages thanks to relatively safe profile and preliminary evidence of effectiveness. Moreover, some stem cell-based products have been approved for marketing by different national regulatory authorities. However, many critical issues associated mainly with incomplete understanding of stem cell biology and the relevant risk factors, and lack of effective regulations still exist and need to be urgently addressed, especially in countries where establishment of appropriate regulatory system just commenced. More relevantly, the stem cell regulatory sciences need to be established or improved to more effectively evaluate quality, safety and efficacy of stem cell products, and for building up the appropriate regulatory framework. In this review, we summarize some new achievements in stem cell studies, especially the preclinical and clinical studies, the existing regulations, and the associated challenges, and we then propose some considerations for improving stem cell regulatory sciences with a goal of promoting the steadfast growth of the well-regulated stem cell therapies abreast of evolvement of stem cell sciences and technologies.

78 FR 1562 - Improving Government Regulations; Unified Agenda of Federal Regulatory and Deregulatory Actions

Federal Register 2010, 2011, 2012, 2013, 2014

2013-01-08

... statutory administration requirements as required. Starting with the fall 2007 edition, the Internet became... Agenda database. Because publication in the Federal Register is mandated for the regulatory flexibility.... Michael L. Rhodes, Director, Administration and Management. Defense Acquisition Regulations Council...

Interferon regulatory factor 5 gene polymorphism in Egyptian children with systemic lupus erythematosus.

PubMed

Hammad, A; Mossad, Y M; Nasef, N; Eid, R

2017-07-01

Background Increased expression of interferon-inducible genes is implicated in the pathogenesis of systemic lupus erythematosus (SLE). Interferon regulatory factor 5 (IRF5) is one of the transcription factors regulating interferon and was proved to be implicated in the pathogenesis of SLE in different populations. Objectives The objective of this study was to investigate the correlation between polymorphisms of the IRF5 gene and SLE susceptibility in a cohort of Egyptian children and to investigate their association with clinico-pathological features, especially lupus nephritis. Subjects and methods Typing of interferon regulatory factor 5 rs10954213, rs2004640 and rs2280714 polymorphisms were done using polymerase chain reaction-restriction fragment length polymorphism for 100 children with SLE and 100 matched healthy controls. Results Children with SLE had more frequent T allele and TT genotype of rs2004640 ( P c  = 0.003 and 0.024, respectively) compared to controls. Patients with nephritis had more frequent T allele of rs2004640 compared to controls ( P c  = 0.003). However the allele and genotype frequencies of the three studied polymorphisms did not show any difference in patients with nephritis in comparison to those without nephritis. Haplotype GTA of rs10954213, rs2004640 and rs2280714, respectively, was more frequent in lupus patients in comparison to controls ( p = 0.01) while the haplotype GGG was more frequent in controls than lupus patients ( p = 0.011). Conclusion The rs2004640 T allele and TT genotype and GTA haplotype of rs rs10954213, rs2004640, and rs2280714, respectively, can be considered as risk factors for the development of SLE. The presence of the rs2004640 T allele increases the risk of nephritis development in Egyptian children with SLE.

Stage of perinatal development regulates skeletal muscle mitochondrial biogenesis and myogenic regulatory factor genes with little impact of growth restriction or cross-fostering.

PubMed

Laker, R C; Wadley, G D; McConell, G K; Wlodek, M E

2012-02-01

Foetal growth restriction impairs skeletal muscle development and adult muscle mitochondrial biogenesis. We hypothesized that key genes involved in muscle development and mitochondrial biogenesis would be altered following uteroplacental insufficiency in rat pups, and improving postnatal nutrition by cross-fostering would ameliorate these deficits. Bilateral uterine vessel ligation (Restricted) or sham (Control) surgery was performed on day 18 of gestation. Males and females were investigated at day 20 of gestation (E20), 1 (PN1), 7 (PN7) and 35 (PN35) days postnatally. A separate cohort of Control and Restricted pups were cross-fostered onto a different Control or Restricted mother and examined at PN7. In both sexes, peroxisome proliferator-activated receptor (PPAR)-γ coactivator-1α (PGC-1α), cytochrome c oxidase subunits 3 and 4 (COX III and IV) and myogenic regulatory factor 4 expression increased from late gestation to postnatal life, whereas mitochondrial transcription factor A, myogenic differentiation 1 (MyoD), myogenin and insulin-like growth factor I (IGF-I) decreased. Foetal growth restriction increased MyoD mRNA in females at PN7, whereas in males IGF-I mRNA was higher at E20 and PN1. Cross-fostering Restricted pups onto a Control mother significantly increased COX III mRNA in males and COX IV mRNA in both sexes above controls with little effect on other genes. Developmental age appears to be a major factor regulating skeletal muscle mitochondrial and developmental genes, with growth restriction and cross-fostering having only subtle effects. It therefore appears that reductions in adult mitochondrial biogenesis markers likely develop after weaning.

Challenges for modeling global gene regulatory networks during development: insights from Drosophila.

PubMed

Wilczynski, Bartek; Furlong, Eileen E M

2010-04-15

Development is regulated by dynamic patterns of gene expression, which are orchestrated through the action of complex gene regulatory networks (GRNs). Substantial progress has been made in modeling transcriptional regulation in recent years, including qualitative "coarse-grain" models operating at the gene level to very "fine-grain" quantitative models operating at the biophysical "transcription factor-DNA level". Recent advances in genome-wide studies have revealed an enormous increase in the size and complexity or GRNs. Even relatively simple developmental processes can involve hundreds of regulatory molecules, with extensive interconnectivity and cooperative regulation. This leads to an explosion in the number of regulatory functions, effectively impeding Boolean-based qualitative modeling approaches. At the same time, the lack of information on the biophysical properties for the majority of transcription factors within a global network restricts quantitative approaches. In this review, we explore the current challenges in moving from modeling medium scale well-characterized networks to more poorly characterized global networks. We suggest to integrate coarse- and find-grain approaches to model gene regulatory networks in cis. We focus on two very well-studied examples from Drosophila, which likely represent typical developmental regulatory modules across metazoans. Copyright (c) 2009 Elsevier Inc. All rights reserved.

TCPs, WUSs, and WINDs: families of transcription factors that regulate shoot meristem formation, stem cell maintenance, and somatic cell differentiation.

PubMed

Ikeda, Miho; Ohme-Takagi, Masaru

2014-01-01

In contrast to somatic mammalian cells, which cannot alter their fate, plant cells can dedifferentiate to form totipotent callus cells and regenerate a whole plant, following treatment with specific phytohormones. However, the regulatory mechanisms and key factors that control differentiation-dedifferentiation and cell totipotency have not been completely clarified in plants. Recently, several plant transcription factors that regulate meristem formation and dedifferentiation have been identified and include members of the TEOSINTE BRANCHED1/CYCLOIDEA/PROLIFERATING CELL FACTOR (TCP), WUSCHEL (WUS), and WOUND INDUCED DEDIFFERENTIATION (WIND1) families. WUS and WIND positively control plant cell totipotency, while TCP negatively controls it. Interestingly, TCP is a transcriptional activator that acts as a negative regulator of shoot meristem formation, and WUS is a transcriptional repressor that positively maintains totipotency of the stem cells of the shoot meristem. We describe here the functions of TCP, WUS, and WIND transcription factors in the regulation of differentiation-dedifferentiation by positive and negative transcriptional regulators.

Regulation of endogenous human gene expression by ligand-inducible TALE transcription factors.

PubMed

Mercer, Andrew C; Gaj, Thomas; Sirk, Shannon J; Lamb, Brian M; Barbas, Carlos F

2014-10-17

The construction of increasingly sophisticated synthetic biological circuits is dependent on the development of extensible tools capable of providing specific control of gene expression in eukaryotic cells. Here, we describe a new class of synthetic transcription factors that activate gene expression in response to extracellular chemical stimuli. These inducible activators consist of customizable transcription activator-like effector (TALE) proteins combined with steroid hormone receptor ligand-binding domains. We demonstrate that these ligand-responsive TALE transcription factors allow for tunable and conditional control of gene activation and can be used to regulate the expression of endogenous genes in human cells. Since TALEs can be designed to recognize any contiguous DNA sequence, the conditional gene regulatory system described herein will enable the design of advanced synthetic gene networks.

γδ T cells producing interleukin-17A regulate adipose regulatory T cell homeostasis and thermogenesis.

PubMed

Kohlgruber, Ayano C; Gal-Oz, Shani T; LaMarche, Nelson M; Shimazaki, Moto; Duquette, Danielle; Nguyen, Hung N; Mina, Amir I; Paras, Tyler; Tavakkoli, Ali; von Andrian, Ulrich; Banks, Alexander S; Shay, Tal; Brenner, Michael B; Lynch, Lydia

2018-05-01

γδ T cells are situated at barrier sites and guard the body from infection and damage. However, little is known about their roles outside of host defense in nonbarrier tissues. Here, we characterize a highly enriched tissue-resident population of γδ T cells in adipose tissue that regulate age-dependent regulatory T cell (T reg ) expansion and control core body temperature in response to environmental fluctuations. Mechanistically, innate PLZF + γδ T cells produced tumor necrosis factor and interleukin (IL) 17 A and determined PDGFRα + and Pdpn + stromal-cell production of IL-33 in adipose tissue. Mice lacking γδ T cells or IL-17A exhibited decreases in both ST2 + T reg cells and IL-33 abundance in visceral adipose tissue. Remarkably, these mice also lacked the ability to regulate core body temperature at thermoneutrality and after cold challenge. Together, these findings uncover important physiological roles for resident γδ T cells in adipose tissue immune homeostasis and body-temperature control.

A complex regulatory network controls aerobic ethanol oxidation in Pseudomonas aeruginosa: indication of four levels of sensor kinases and response regulators.

PubMed

Mern, Demissew S; Ha, Seung-Wook; Khodaverdi, Viola; Gliese, Nicole; Görisch, Helmut

2010-05-01

In addition to the known response regulator ErbR (former AgmR) and the two-component regulatory system EraSR (former ExaDE), three additional regulatory proteins have been identified as being involved in controlling transcription of the aerobic ethanol oxidation system in Pseudomonas aeruginosa. Two putative sensor kinases, ErcS and ErcS', and a response regulator, ErdR, were found, all of which show significant similarity to the two-component flhSR system that controls methanol and formaldehyde metabolism in Paracoccus denitrificans. All three identified response regulators, EraR (formerly ExaE), ErbR (formerly AgmR) and ErdR, are members of the luxR family. The three sensor kinases EraS (formerly ExaD), ErcS and ErcS' do not contain a membrane domain. Apparently, they are localized in the cytoplasm and recognize cytoplasmic signals. Inactivation of gene ercS caused an extended lag phase on ethanol. Inactivation of both genes, ercS and ercS', resulted in no growth at all on ethanol, as did inactivation of erdR. Of the three sensor kinases and three response regulators identified thus far, only the EraSR (formerly ExaDE) system forms a corresponding kinase/regulator pair. Using reporter gene constructs of all identified regulatory genes in different mutants allowed the hierarchy of a hypothetical complex regulatory network to be established. Probably, two additional sensor kinases and two additional response regulators, which are hidden among the numerous regulatory genes annotated in the genome of P. aeruginosa, remain to be identified.

Regulatory activities of transposable elements: from conflicts to benefits

PubMed Central

Chuong, Edward B.; Elde, Nels C.; Feschotte, Cédric

2017-01-01

Transposable elements (TEs) are a prolific source of tightly regulated, biochemically active non-coding elements, such as transcription factor binding sites and non-coding RNAs. A wealth of recent studies reinvigorates the idea that these elements are pervasively co-opted for the regulation of host genes. We argue that the inherent genetic properties of TEs and conflicting relationships with their hosts facilitate their recruitment for regulatory functions in diverse genomes. We review recent findings supporting the long-standing hypothesis that the waves of TE invasions endured by organisms for eons have catalyzed the evolution of gene regulatory networks. We also discuss the challenges of dissecting and interpreting the phenotypic impact of regulatory activities encoded by TEs in health and disease. PMID:27867194

Genome-Wide Identification of Regulatory Elements and Reconstruction of Gene Regulatory Networks of the Green Alga Chlamydomonas reinhardtii under Carbon Deprivation

PubMed Central

Vischi Winck, Flavia; Arvidsson, Samuel; Riaño-Pachón, Diego Mauricio; Hempel, Sabrina; Koseska, Aneta; Nikoloski, Zoran; Urbina Gomez, David Alejandro; Rupprecht, Jens; Mueller-Roeber, Bernd

2013-01-01

The unicellular green alga Chlamydomonas reinhardtii is a long-established model organism for studies on photosynthesis and carbon metabolism-related physiology. Under conditions of air-level carbon dioxide concentration [CO2], a carbon concentrating mechanism (CCM) is induced to facilitate cellular carbon uptake. CCM increases the availability of carbon dioxide at the site of cellular carbon fixation. To improve our understanding of the transcriptional control of the CCM, we employed FAIRE-seq (formaldehyde-assisted Isolation of Regulatory Elements, followed by deep sequencing) to determine nucleosome-depleted chromatin regions of algal cells subjected to carbon deprivation. Our FAIRE data recapitulated the positions of known regulatory elements in the promoter of the periplasmic carbonic anhydrase (Cah1) gene, which is upregulated during CCM induction, and revealed new candidate regulatory elements at a genome-wide scale. In addition, time series expression patterns of 130 transcription factor (TF) and transcription regulator (TR) genes were obtained for cells cultured under photoautotrophic condition and subjected to a shift from high to low [CO2]. Groups of co-expressed genes were identified and a putative directed gene-regulatory network underlying the CCM was reconstructed from the gene expression data using the recently developed IOTA (inner composition alignment) method. Among the candidate regulatory genes, two members of the MYB-related TF family, Lcr1 (Low-CO 2 response regulator 1) and Lcr2 (Low-CO 2 response regulator 2), may play an important role in down-regulating the expression of a particular set of TF and TR genes in response to low [CO2]. The results obtained provide new insights into the transcriptional control of the CCM and revealed more than 60 new candidate regulatory genes. Deep sequencing of nucleosome-depleted genomic regions indicated the presence of new, previously unknown regulatory elements in the C. reinhardtii genome. Our work can

Roles and regulations of the ETS transcription factor ELF4/MEF

PubMed Central

Suico, Mary Ann; Shuto, Tsuyoshi; Kai, Hirofumi

2017-01-01

Abstract Most E26 transformation-specific (ETS) transcription factors are involved in the pathogenesis and progression of cancer. This is in part due to the roles of ETS transcription factors in basic biological processes such as growth, proliferation, and differentiation, and also because of their regulatory functions that have physiological relevance in tumorigenesis, immunity, and basal cellular homoeostasis. A member of the E74-like factor (ELF) subfamily of the ETS transcription factor family—myeloid elf-1-like factor (MEF), designated as ELF4—has been shown to be critically involved in immune response and signalling, osteogenesis, adipogenesis, cancer, and stem cell quiescence. ELF4 carries out these functions as a transcriptional activator or through interactions with its partner proteins. Mutations in ELF4 cause aberrant interactions and induce downstream processes that may lead to diseased cells. Knowing how ELF4 impinges on certain cellular processes and how it is regulated in the cells can lead to a better understanding of the physiological and pathological consequences of modulated ELF4 activity. PMID:27932483

SATRAT: Staphylococcus aureus transcript regulatory network analysis tool.

PubMed

Gopal, Tamilselvi; Nagarajan, Vijayaraj; Elasri, Mohamed O

2015-01-01

Staphylococcus aureus is a commensal organism that primarily colonizes the nose of healthy individuals. S. aureus causes a spectrum of infections that range from skin and soft-tissue infections to fatal invasive diseases. S. aureus uses a large number of virulence factors that are regulated in a coordinated fashion. The complex regulatory mechanisms have been investigated in numerous high-throughput experiments. Access to this data is critical to studying this pathogen. Previously, we developed a compilation of microarray experimental data to enable researchers to search, browse, compare, and contrast transcript profiles. We have substantially updated this database and have built a novel exploratory tool-SATRAT-the S. aureus transcript regulatory network analysis tool, based on the updated database. This tool is capable of performing deep searches using a query and generating an interactive regulatory network based on associations among the regulators of any query gene. We believe this integrated regulatory network analysis tool would help researchers explore the missing links and identify novel pathways that regulate virulence in S. aureus. Also, the data model and the network generation code used to build this resource is open sourced, enabling researchers to build similar resources for other bacterial systems.

The MYB107 Transcription Factor Positively Regulates Suberin Biosynthesis1[OPEN

PubMed Central

Yang, Huijun; Cai, Yuanheng; Kai, Guoyin

2017-01-01

Suberin, a lipophilic polymer deposited in the outer integument of the Arabidopsis (Arabidopsis thaliana) seed coat, represents an essential sealing component controlling water and solute movement and protecting seed from pathogenic infection. Although many genes responsible for suberin synthesis are identified, the regulatory components controlling its biosynthesis have not been definitively determined. Here, we show that the Arabidopsis MYB107 transcription factor acts as a positive regulator controlling suberin biosynthetic gene expression in the seed coat. MYB107 coexpresses with suberin biosynthetic genes in a temporal manner during seed development. Disrupting MYB107 particularly suppresses the expression of genes involved in suberin but not cutin biosynthesis, lowers seed coat suberin accumulation, alters suberin lamellar structure, and consequently renders higher seed coat permeability and susceptibility to abiotic stresses. Furthermore, MYB107 directly binds to the promoters of suberin biosynthetic genes, verifying its primary role in regulating their expression. Identifying MYB107 as a positive regulator for seed coat suberin synthesis offers a basis for discovering the potential transcriptional network behind one of the most abundant lipid-based polymers in nature. PMID:27965303

A Predictive Model of the Oxygen and Heme Regulatory Network in Yeast

PubMed Central

Kundaje, Anshul; Xin, Xiantong; Lan, Changgui; Lianoglou, Steve; Zhou, Mei; Zhang, Li; Leslie, Christina

2008-01-01

Deciphering gene regulatory mechanisms through the analysis of high-throughput expression data is a challenging computational problem. Previous computational studies have used large expression datasets in order to resolve fine patterns of coexpression, producing clusters or modules of potentially coregulated genes. These methods typically examine promoter sequence information, such as DNA motifs or transcription factor occupancy data, in a separate step after clustering. We needed an alternative and more integrative approach to study the oxygen regulatory network in Saccharomyces cerevisiae using a small dataset of perturbation experiments. Mechanisms of oxygen sensing and regulation underlie many physiological and pathological processes, and only a handful of oxygen regulators have been identified in previous studies. We used a new machine learning algorithm called MEDUSA to uncover detailed information about the oxygen regulatory network using genome-wide expression changes in response to perturbations in the levels of oxygen, heme, Hap1, and Co2+. MEDUSA integrates mRNA expression, promoter sequence, and ChIP-chip occupancy data to learn a model that accurately predicts the differential expression of target genes in held-out data. We used a novel margin-based score to extract significant condition-specific regulators and assemble a global map of the oxygen sensing and regulatory network. This network includes both known oxygen and heme regulators, such as Hap1, Mga2, Hap4, and Upc2, as well as many new candidate regulators. MEDUSA also identified many DNA motifs that are consistent with previous experimentally identified transcription factor binding sites. Because MEDUSA's regulatory program associates regulators to target genes through their promoter sequences, we directly tested the predicted regulators for OLE1, a gene specifically induced under hypoxia, by experimental analysis of the activity of its promoter. In each case, deletion of the candidate

Comparing anterior and posterior Hox complex formation reveals guidelines for predicting cis-regulatory elements

PubMed Central

Uhl, Juli D.; Cook, Tiffany A.; Gebelein, Brian

2010-01-01

Hox transcription factors specify numerous cell fates along the anterior-posterior axis by regulating the expression of downstream target genes. While expression analysis has uncovered large numbers of de-regulated genes in cells with altered Hox activity, determining which are direct versus indirect targets has remained a significant challenge. Here, we characterize the DNA binding activity of Hox transcription factor complexes on eight experimentally verified cis-regulatory elements. Hox factors regulate the activity of each element by forming protein complexes with two cofactor proteins, Extradenticle (Exd) and Homothorax (Hth). Using comparative DNA binding assays, we found that a number of flexible arrangements of Hox, Exd, and Hth binding sites mediate cooperative transcription factor complexes. Moreover, analysis of a Distal-less regulatory element (DMXR) that is repressed by abdominal Hox factors revealed that suboptimal binding sites can be combined to form high affinity transcription complexes. Lastly, we determined that the anterior Hox factors are more dependent upon Exd and Hth for complex formation than posterior Hox factors. Based upon these findings, we suggest a general set of guidelines to serve as a basis for designing bioinformatics algorithms aimed at identifying Hox regulatory elements using the wealth of recently sequenced genomes. PMID:20398649

Scientific foundation of regulating ionizing radiation: application of metrics for evaluation of regulatory science information.

PubMed

Moghissi, A Alan; Gerraa, Vikrham Kumar; McBride, Dennis K; Swetnam, Michael

2014-11-01

This paper starts by describing the historical evolution of assessment of biologic effects of ionizing radiation leading to the linear non-threshold (LNT) system currently used to regulate exposure to ionizing radiation. The paper describes briefly the concept of Best Available Science (BAS) and Metrics for Evaluation of Scientific Claims (MESC) derived for BAS. It identifies three phases of regulatory science consisting of the initial phase, when the regulators had to develop regulations without having the needed scientific information; the exploratory phase, when relevant tools were developed; and the standard operating phase, when the tools were applied to regulations. Subsequently, an attempt is made to apply the BAS/MESC system to various stages of LNT. This paper then compares the exposure limits imposed by regulatory agencies and also compares them with naturally occurring radiation at several cities. Controversies about LNT are addressed, including judgments of the U.S. National Academies and their French counterpart. The paper concludes that, based on the BAS/MESC system, there is no disagreement between the two academies on the scientific foundation of LNT; instead, the disagreement is based on their judgment or speculation.

Shaping nursing profession regulation through history - a systematic review.

PubMed

Stievano, A; Caruso, R; Pittella, F; Shaffer, F A; Rocco, G; Fairman, J

2018-03-23

The aim of this systematic review was to provide a critical synthesis of the factors that historically shaped the advancements of nursing regulators worldwide. An in-depth examination of the different factors that moulded regulatory changes over time is pivotal to comprehend current issues in nursing. In the light of global health scenarios, the researchers explored the factors that historically influenced the socio-contextual circumstances upon which governments made regulatory changes. A systematic search was performed on the following databases: PubMed, CINAHL, Scopus, OpenGrey and ScienceDirect. The review included papers from January 2000 to October 2016 published in English. The authors used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and an inductive thematic approach for synthesis. Two main themes were identified: factors underpinning current challenges and historical and contextual triggers of regulation. The first theme was composed of three aspects: education, migration and internationalization, and policy and regulation; the second theme consisted of four attributes: demographics, economics, history of registration and wars, and historical changes in nursing practice. Factors that shaped nursing regulation were linked to changing demographics and economics, education, history of nursing registration, shifting patterns of migration and internationalization, nursing practice, policy and regulation and significant societal turns often prompted by wars. A deeper understanding of the developments of the nursing regulatory institutions provides the foundation for portable standards that can be applied across an array of jurisdictions to guarantee a better public safety. Understanding factors that socially, legislatively and politically have influenced the development of regulatory bodies over time helps to mould local, national and international policies that have a stronger impact on health worldwide. To achieve this

Tumor Necrosis Factor α and Regulatory T Cells in Oncoimmunology

PubMed Central

Salomon, Benoît L.; Leclerc, Mathieu; Tosello, Jimena; Ronin, Emilie; Piaggio, Eliane; Cohen, José L.

2018-01-01

Tumor necrosis factor α (TNF) is a potent pro-inflammatory cytokine that has deleterious effect in some autoimmune diseases, which led to the use of anti-TNF drugs in some of these diseases. However, some rare patients treated with these drugs paradoxically develop an aggravation of their disease or new onset autoimmunity, revealing an immunosuppressive facet of TNF. A possible mechanism of this observation is the direct and positive effect of TNF on regulatory T cells (Tregs) through its binding to the TNF receptor type 2 (TNFR2). Indeed, TNF is able to increase expansion, stability, and possibly function of Tregs via TNFR2. In this review, we discuss the role of TNF in graft-versus-host disease as an example of the ambivalence of this cytokine in the pathophysiology of an immunopathology, highlighting the therapeutic potential of triggering TNFR2 to boost Treg expansion. We also describe new targets in immunotherapy of cancer, emphasizing on the putative suppressive effect of TNF in antitumor immunity and of the interest of blocking TNFR2 to regulate the Treg compartment. PMID:29593717

Basic aspects of tumor cell fatty acid-regulated signaling and transcription factors.

PubMed

Comba, Andrea; Lin, Yi-Hui; Eynard, Aldo Renato; Valentich, Mirta Ana; Fernandez-Zapico, Martín Ernesto; Pasqualini, Marìa Eugenia

2011-12-01

This article reviews the current knowledge and experimental research about the mechanisms by which fatty acids and their derivatives control specific gene expression involved during carcinogenesis. Changes in dietary fatty acids, specifically the polyunsaturated fatty acids of the ω-3 and ω-6 families and some derived eicosanoids from lipoxygenases, cyclooxygenases, and cytochrome P-450, seem to control the activity of transcription factor families involved in cancer cell proliferation or cell death. Their regulation may be carried out either through direct binding to DNA as peroxisome proliferator-activated receptors or via modulation in an indirect manner of signaling pathway molecules (e.g., protein kinase C) and other transcription factors (nuclear factor kappa B and sterol regulatory element binding protein). Knowledge of the mechanisms by which fatty acids control specific gene expression may identify important risk factors for cancer and provide insight into the development of new therapeutic strategies for a better management of whole body lipid metabolism.

Creating and validating cis-regulatory maps of tissue-specific gene expression regulation

PubMed Central

O'Connor, Timothy R.; Bailey, Timothy L.

2014-01-01

Predicting which genomic regions control the transcription of a given gene is a challenge. We present a novel computational approach for creating and validating maps that associate genomic regions (cis-regulatory modules–CRMs) with genes. The method infers regulatory relationships that explain gene expression observed in a test tissue using widely available genomic data for ‘other’ tissues. To predict the regulatory targets of a CRM, we use cross-tissue correlation between histone modifications present at the CRM and expression at genes within 1 Mbp of it. To validate cis-regulatory maps, we show that they yield more accurate models of gene expression than carefully constructed control maps. These gene expression models predict observed gene expression from transcription factor binding in the CRMs linked to that gene. We show that our maps are able to identify long-range regulatory interactions and improve substantially over maps linking genes and CRMs based on either the control maps or a ‘nearest neighbor’ heuristic. Our results also show that it is essential to include CRMs predicted in multiple tissues during map-building, that H3K27ac is the most informative histone modification, and that CAGE is the most informative measure of gene expression for creating cis-regulatory maps. PMID:25200088

Executive Function in Adolescence: Associations with Child and Family Risk Factors and Self-Regulation in Early Childhood.

PubMed

Berthelsen, Donna; Hayes, Nicole; White, Sonia L J; Williams, Kate E

2017-01-01

Executive functions are important higher-order cognitive skills for goal-directed thought and action. These capacities contribute to successful school achievement and lifelong wellbeing. The importance of executive functions to children's education begins in early childhood and continues throughout development. This study explores contributions of child and family factors in early childhood to the development of executive function in adolescence. Analyses draw on data from the nationally representative study, Growing up in Australia: The Longitudinal Study of Australian Children . Participants are 4819 children in the Kindergarten Cohort who were recruited at age 4-5 years. Path analyses were employed to examine contributions of early childhood factors, including family socio-economic position (SEP), parenting behaviors, maternal mental health, and a child behavioral risk index, to the development of executive function in adolescence. The influence of children's early self-regulatory behaviors (attentional regulation at 4-5 years and approaches to learning at 6-7 years) were also taken into account. A composite score for the outcome measure of executive function was constructed from scores on three Cogstate computerized tasks for assessing cognition and measured visual attention, visual working memory, and spatial problem-solving. Covariates included child gender, age at assessment of executive function, Aboriginal and Torres Strait Islander status, speaking a language other than English at home, and child's receptive vocabulary skills. There were significant indirect effects involving child and family risk factors measured at 4-5 years on executive function at age 14-15 years, mediated by measures of self-regulatory behavior. Child behavioral risk, family SEP and parenting behaviors (anger, warmth, and consistency) were associated with attentional regulation at 4-5 years which, in turn, was significantly associated with approaches to learning at 6-7 years. Both

PcFKH1, a novel regulatory factor from the forkhead family, controls the biosynthesis of penicillin in Penicillium chrysogenum.

PubMed

Domínguez-Santos, Rebeca; García-Estrada, Carlos; Kosalková, Katarina; Prieto, Carlos; Santamarta, Irene; Martín, Juan-Francisco

2015-08-01

Penicillin biosynthesis in Penicillium chrysogenum (re-identified as Penicillium rubens) is a good example of a biological process subjected to complex global regulatory networks and serves as a model to study fungal secondary metabolism. The winged-helix family of transcription factors recently described, which includes the forkhead type of proteins, is a key type of regulatory proteins involved in this process. In yeasts and humans, forkhead transcription factors are involved in different processes (cell cycle regulation, cell death control, pre-mRNA processing and morphogenesis); one member of this family of proteins has been identified in the P. chrysogenum genome (Pc18g00430). In this work, we have characterized this novel transcription factor (named PcFKH1) by generating knock-down mutants and overexpression strains. Results clearly indicate that PcFKH1 positively controls antibiotic biosynthesis through the specific interaction with the promoter region of the penDE gene, thus regulating penDE mRNA levels. PcFKH1 also binds to the pcbC promoter, but with low affinity. In addition, it also controls other ancillary genes of the penicillin biosynthetic process, such as phlA (encoding phenylacetyl CoA ligase) and ppt (encoding phosphopantetheinyl transferase). PcFKH1 also plays a role in conidiation and spore pigmentation, but it does not seem to be involved in hyphal morphology or cell division in the improved laboratory reference strain Wisconsin 54-1255. A genome-wide analysis of processes putatively coregulated by PcFKH1 and PcRFX1 (another winged-helix transcription factor) in P. chrysogenum provided evidence of the global effect of these transcription factors in P. chrysogenum metabolism. Copyright © 2015 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

Biphasic regulation of the transcription factor ABORTED MICROSPORES (AMS) is essential for tapetum and pollen development in Arabidopsis.

PubMed

Ferguson, Alison C; Pearce, Simon; Band, Leah R; Yang, Caiyun; Ferjentsikova, Ivana; King, John; Yuan, Zheng; Zhang, Dabing; Wilson, Zoe A

2017-01-01

Viable pollen is essential for plant reproduction and crop yield. Its production requires coordinated expression at specific stages during anther development, involving early meiosis-associated events and late pollen wall formation. The ABORTED MICROSPORES (AMS) transcription factor is a master regulator of sporopollenin biosynthesis, secretion and pollen wall formation in Arabidopsis. Here we show that it has complex regulation and additional essential roles earlier in pollen formation. An inducible-AMS reporter was created for functional rescue, protein expression pattern analysis, and to distinguish between direct and indirect targets. Mathematical modelling was used to create regulatory networks based on wild-type RNA and protein expression. Dual activity of AMS was defined by biphasic protein expression in anther tapetal cells, with an initial peak around pollen meiosis and then later during pollen wall development. Direct AMS-regulated targets exhibit temporal regulation, indicating that additional factors are associated with their regulation. We demonstrate that AMS biphasic expression is essential for pollen development, and defines distinct functional activities during early and late pollen development. Mathematical modelling suggests that AMS may competitively form a protein complex with other tapetum-expressed transcription factors, and that biphasic regulation is due to repression of upstream regulators and promotion of AMS protein degradation. © 2016 The Authors. New Phytologist © 2016 New Phytologist Trust.

Regulating the path from legacy recognition, through recovery to release from regulatory control.

PubMed

Sneve, Malgorzata Karpow; Smith, Graham

2015-04-01

Past development of processes and technologies using radioactive material led to construction of many facilities worldwide. Some of these facilities were built and operated before the regulatory infrastructure was in place to ensure adequate control of radioactive material during operation and decommissioning. In other cases, controls were in place but did not meet modern standards, leading to what is now considered to have been inadequate control. Accidents and other events have occurred resulting in loss of control of radioactive material and unplanned releases to the environment. The legacy from these circumstances is that many countries have areas or facilities at which abnormal radiation conditions exist at levels that give rise to concerns about environmental and human health of potential interest to regulatory authorities. Regulation of these legacy situations is complex. This paper examines the regulatory challenges associated with such legacy management and brings forward suggestions for finding the path from: legacy recognition; implementation, as necessary, of urgent mitigation measures; development of a longer-term management strategy, through to release from regulatory control. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

A system-level model for the microbial regulatory genome.

PubMed

Brooks, Aaron N; Reiss, David J; Allard, Antoine; Wu, Wei-Ju; Salvanha, Diego M; Plaisier, Christopher L; Chandrasekaran, Sriram; Pan, Min; Kaur, Amardeep; Baliga, Nitin S

2014-07-15

Microbes can tailor transcriptional responses to diverse environmental challenges despite having streamlined genomes and a limited number of regulators. Here, we present data-driven models that capture the dynamic interplay of the environment and genome-encoded regulatory programs of two types of prokaryotes: Escherichia coli (a bacterium) and Halobacterium salinarum (an archaeon). The models reveal how the genome-wide distributions of cis-acting gene regulatory elements and the conditional influences of transcription factors at each of those elements encode programs for eliciting a wide array of environment-specific responses. We demonstrate how these programs partition transcriptional regulation of genes within regulons and operons to re-organize gene-gene functional associations in each environment. The models capture fitness-relevant co-regulation by different transcriptional control mechanisms acting across the entire genome, to define a generalized, system-level organizing principle for prokaryotic gene regulatory networks that goes well beyond existing paradigms of gene regulation. An online resource (http://egrin2.systemsbiology.net) has been developed to facilitate multiscale exploration of conditional gene regulation in the two prokaryotes. © 2014 The Authors. Published under the terms of the CC BY 4.0 license.

Mechanisms and Evolution of Control Logic in Prokaryotic Transcriptional Regulation

PubMed Central

van Hijum, Sacha A. F. T.; Medema, Marnix H.; Kuipers, Oscar P.

2009-01-01

Summary: A major part of organismal complexity and versatility of prokaryotes resides in their ability to fine-tune gene expression to adequately respond to internal and external stimuli. Evolution has been very innovative in creating intricate mechanisms by which different regulatory signals operate and interact at promoters to drive gene expression. The regulation of target gene expression by transcription factors (TFs) is governed by control logic brought about by the interaction of regulators with TF binding sites (TFBSs) in cis-regulatory regions. A factor that in large part determines the strength of the response of a target to a given TF is motif stringency, the extent to which the TFBS fits the optimal TFBS sequence for a given TF. Advances in high-throughput technologies and computational genomics allow reconstruction of transcriptional regulatory networks in silico. To optimize the prediction of transcriptional regulatory networks, i.e., to separate direct regulation from indirect regulation, a thorough understanding of the control logic underlying the regulation of gene expression is required. This review summarizes the state of the art of the elements that determine the functionality of TFBSs by focusing on the molecular biological mechanisms and evolutionary origins of cis-regulatory regions. PMID:19721087

Mycobacterium tuberculosis RsdA provides a conformational rationale for selective regulation of σ-factor activity by proteolysis

PubMed Central

Jaiswal, Ravi K.; Prabha, Tangirala Surya; Manjeera, Gowravaram; Gopal, Balasubramanian

2013-01-01

The relative levels of different σ factors dictate the expression profile of a bacterium. Extracytoplasmic function σ factors synchronize the transcriptional profile with environmental conditions. The cellular concentration of free extracytoplasmic function σ factors is regulated by the localization of this protein in a σ/anti-σ complex. Anti-σ factors are multi-domain proteins with a receptor to sense environmental stimuli and a conserved anti-σ domain (ASD) that binds a σ factor. Here we describe the structure of Mycobacterium tuberculosis anti-σD (RsdA) in complex with the -35 promoter binding domain of σD (σD4). We note distinct conformational features that enable the release of σD by the selective proteolysis of the ASD in RsdA. The structural and biochemical features of the σD/RsdA complex provide a basis to reconcile diverse regulatory mechanisms that govern σ/anti-σ interactions despite high overall structural similarity. Multiple regulatory mechanisms embedded in an ASD scaffold thus provide an elegant route to rapidly re-engineer the expression profile of a bacterium in response to an environmental stimulus. PMID:23314154

Regulatory principles governing Salmonella and Yersinia virulence

PubMed Central

Erhardt, Marc; Dersch, Petra

2015-01-01

Enteric pathogens such as Salmonella and Yersinia evolved numerous strategies to survive and proliferate in different environmental reservoirs and mammalian hosts. Deciphering common and pathogen-specific principles for how these bacteria adjust and coordinate spatiotemporal expression of virulence determinants, stress adaptation, and metabolic functions is fundamental to understand microbial pathogenesis. In order to manage sudden environmental changes, attacks by the host immune systems and microbial competition, the pathogens employ a plethora of transcriptional and post-transcriptional control elements, including transcription factors, sensory and regulatory RNAs, RNAses, and proteases, to fine-tune and control complex gene regulatory networks. Many of the contributing global regulators and the molecular mechanisms of regulation are frequently conserved between Yersinia and Salmonella. However, the interplay, arrangement, and composition of the control elements vary between these closely related enteric pathogens, which generate phenotypic differences leading to distinct pathogenic properties. In this overview we present common and different regulatory networks used by Salmonella and Yersinia to coordinate the expression of crucial motility, cell adhesion and invasion determinants, immune defense strategies, and metabolic adaptation processes. We highlight evolutionary changes of the gene regulatory circuits that result in different properties of the regulatory elements and how this influences the overall outcome of the infection process. PMID:26441883

FK506 biosynthesis is regulated by two positive regulatory elements in Streptomyces tsukubaensis

PubMed Central

2012-01-01

Background FK506 (Tacrolimus) is an important immunosuppressant, produced by industrial biosynthetic processes using various Streptomyces species. Considering the complex structure of FK506, it is reasonable to expect complex regulatory networks controlling its biosynthesis. Regulatory elements, present in gene clusters can have a profound influence on the final yield of target product and can play an important role in development of industrial bioprocesses. Results Three putative regulatory elements, namely fkbR, belonging to the LysR-type family, fkbN, a large ATP-binding regulator of the LuxR family (LAL-type) and allN, a homologue of AsnC family regulatory proteins, were identified in the FK506 gene cluster from Streptomyces tsukubaensis NRRL 18488, a progenitor of industrial strains used for production of FK506. Inactivation of fkbN caused a complete disruption of FK506 biosynthesis, while inactivation of fkbR resulted in about 80% reduction of FK506 yield. No functional role in the regulation of the FK506 gene cluster has been observed for the allN gene. Using RT-PCR and a reporter system based on a chalcone synthase rppA, we demonstrated, that in the wild type as well as in fkbN- and fkbR-inactivated strains, fkbR is transcribed in all stages of cultivation, even before the onset of FK506 production, whereas fkbN expression is initiated approximately with the initiation of FK506 production. Surprisingly, inactivation of fkbN (or fkbR) does not abolish the transcription of the genes in the FK506 gene cluster in general, but may reduce expression of some of the tested biosynthetic genes. Finally, introduction of a second copy of the fkbR or fkbN genes under the control of the strong ermE* promoter into the wild type strain resulted in 30% and 55% of yield improvement, respectively. Conclusions Our results clearly demonstrate the positive regulatory role of fkbR and fkbN genes in FK506 biosynthesis in S. tsukubaensis NRRL 18488. We have shown that regulatory

Reconstructing blood stem cell regulatory network models from single-cell molecular profiles

PubMed Central

Hamey, Fiona K.; Nestorowa, Sonia; Kinston, Sarah J.; Kent, David G.; Wilson, Nicola K.

2017-01-01

Adult blood contains a mixture of mature cell types, each with specialized functions. Single hematopoietic stem cells (HSCs) have been functionally shown to generate all mature cell types for the lifetime of the organism. Differentiation of HSCs toward alternative lineages must be balanced at the population level by the fate decisions made by individual cells. Transcription factors play a key role in regulating these decisions and operate within organized regulatory programs that can be modeled as transcriptional regulatory networks. As dysregulation of single HSC fate decisions is linked to fatal malignancies such as leukemia, it is important to understand how these decisions are controlled on a cell-by-cell basis. Here we developed and applied a network inference method, exploiting the ability to infer dynamic information from single-cell snapshot expression data based on expression profiles of 48 genes in 2,167 blood stem and progenitor cells. This approach allowed us to infer transcriptional regulatory network models that recapitulated differentiation of HSCs into progenitor cell types, focusing on trajectories toward megakaryocyte–erythrocyte progenitors and lymphoid-primed multipotent progenitors. By comparing these two models, we identified and subsequently experimentally validated a difference in the regulation of nuclear factor, erythroid 2 (Nfe2) and core-binding factor, runt domain, alpha subunit 2, translocated to, 3 homolog (Cbfa2t3h) by the transcription factor Gata2. Our approach confirms known aspects of hematopoiesis, provides hypotheses about regulation of HSC differentiation, and is widely applicable to other hierarchical biological systems to uncover regulatory relationships. PMID:28584094

76 FR 38597 - Regulatory Guidance: Applicability of the Federal Motor Carrier Safety Regulations to Operators...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-07-01

... DEPARTMENT OF TRANSPORTATION Federal Motor Carrier Safety Administration 49 CFR Parts 383 and 390 [Docket No. FMCSA-2011-0146] Regulatory Guidance: Applicability of the Federal Motor Carrier Safety Regulations to Operators of Certain Farm Vehicles and Off-Road Agricultural Equipment AGENCY: Federal Motor...

76 FR 50433 - Regulatory Guidance: Applicability of the Federal Motor Carrier Safety Regulations to Operators...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-08-15

... DEPARTMENT OF TRANSPORTATION Federal Motor Carrier Safety Administration 49 CFR Parts 383 and 390 [Docket No. FMCSA-2011-0146] Regulatory Guidance: Applicability of the Federal Motor Carrier Safety Regulations to Operators of Certain Farm Vehicles and Off-Road Agricultural Equipment AGENCY: Federal Motor...

The MADS transcription factor XAL2/AGL14 modulates auxin transport during Arabidopsis root development by regulating PIN expression

PubMed Central

Garay-Arroyo, Adriana; Ortiz-Moreno, Enrique; de la Paz Sánchez, María; Murphy, Angus S; García-Ponce, Berenice; Marsch-Martínez, Nayelli; de Folter, Stefan; Corvera-Poiré, Adriana; Jaimes-Miranda, Fabiola; Pacheco-Escobedo, Mario A; Dubrovsky, Joseph G; Pelaz, Soraya; Álvarez-Buylla, Elena R

2013-01-01

Elucidating molecular links between cell-fate regulatory networks and dynamic patterning modules is a key for understanding development. Auxin is important for plant patterning, particularly in roots, where it establishes positional information for cell-fate decisions. PIN genes encode plasma membrane proteins that serve as auxin efflux transporters; mutations in members of this gene family exhibit smaller roots with altered root meristems and stem-cell patterning. Direct regulators of PIN transcription have remained elusive. Here, we establish that a MADS-box gene (XAANTAL2, XAL2/AGL14) controls auxin transport via PIN transcriptional regulation during Arabidopsis root development; mutations in this gene exhibit altered stem-cell patterning, root meristem size, and root growth. XAL2 is necessary for normal shootward and rootward auxin transport, as well as for maintaining normal auxin distribution within the root. Furthermore, this MADS-domain transcription factor upregulates PIN1 and PIN4 by direct binding to regulatory regions and it is required for PIN4-dependent auxin response. In turn, XAL2 expression is regulated by auxin levels thus establishing a positive feedback loop between auxin levels and PIN regulation that is likely to be important for robust root patterning. PMID:24121311

A growth-dependent transcription initiation factor (TIF-IA) interacting with RNA polymerase I regulates mouse ribosomal RNA synthesis.

PubMed

Schnapp, A; Pfleiderer, C; Rosenbauer, H; Grummt, I

1990-09-01

Control of mouse ribosomal RNA synthesis in response to extracellular signals is mediated by TIF-IA, a regulatory factor whose amount or activity correlates with cell proliferation. Factor TIF-IA interacts with RNA polymerase I (pol I), thus converting it into a transcriptionally active holoenzyme, which is able to initiate specifically at the rDNA promoter in the presence of the other auxiliary transcription initiation factors, designated TIF-IB, TIF-IC and UBF. With regard to several criteria, the growth-dependent factor TIF-IA behaves like a bacterial sigma factor: (i) it associates physically with pol I, (ii) it is required for initiation of transcription, (iii) it is present in limiting amounts and (iv) under certain salt conditions, it is chromatographically separable from the polymerase. In addition, evidence is presented that dephosphorylation of pol I abolishes in vitro transcription initiation from the ribosomal gene promoter without significantly affecting the polymerizing activity of the enzyme at nonspecific templates. The involvement of both a regulatory factor and post-translational modification of the transcribing enzyme provides an efficient and versatile mechanism of rDNA transcription regulation which enables the cell to adapt ribosome synthesis rapidly to a variety of extracellular signals.

The simple neuroendocrine-immune regulatory network in oyster Crassostrea gigas mediates complex functions.

PubMed

Liu, Zhaoqun; Wang, Lingling; Zhou, Zhi; Sun, Ying; Wang, Mengqiang; Wang, Hao; Hou, Zhanhui; Gao, Dahai; Gao, Qiang; Song, Linsheng

2016-05-19

The neuroendocrine-immune (NEI) regulatory network is a complex system, which plays an indispensable role in the immunity of the host. In the present study, the bioinformatical analysis of the transcriptomic data from oyster Crassostrea gigas and further biological validation revealed that oyster TNF (CgTNF-1 CGI_10018786) could activate the transcription factors NF-κB and HSF (heat shock transcription factor) through MAPK signaling pathway, and then regulate apoptosis, redox reaction, neuro-regulation and protein folding in oyster haemocytes. The activated immune cells then released neurotransmitters including acetylcholine, norepinephrine and [Met(5)]-enkephalin to regulate the immune response by arising the expression of three TNF (CGI_10005109, CGI_10005110 and CGI_10006440) and translocating two NF-κB (Cgp65, CGI_10018142 and CgRel, CGI_10021567) between the cytoplasm and nuclei of haemocytes. Neurotransmitters exhibited the immunomodulation effects by influencing apoptosis and phagocytosis of oyster haemocytes. Acetylcholine and norepinephrine could down-regulate the immune response, while [Met(5)]-enkephalin up-regulate the immune response. These results suggested that the simple neuroendocrine-immune regulatory network in oyster might be activated by oyster TNF and then regulate the immune response by virtue of neurotransmitters, cytokines and transcription factors.

The simple neuroendocrine-immune regulatory network in oyster Crassostrea gigas mediates complex functions

NASA Astrophysics Data System (ADS)

Liu, Zhaoqun; Wang, Lingling; Zhou, Zhi; Sun, Ying; Wang, Mengqiang; Wang, Hao; Hou, Zhanhui; Gao, Dahai; Gao, Qiang; Song, Linsheng

2016-05-01

The neuroendocrine-immune (NEI) regulatory network is a complex system, which plays an indispensable role in the immunity of the host. In the present study, the bioinformatical analysis of the transcriptomic data from oyster Crassostrea gigas and further biological validation revealed that oyster TNF (CgTNF-1 CGI_10018786) could activate the transcription factors NF-κB and HSF (heat shock transcription factor) through MAPK signaling pathway, and then regulate apoptosis, redox reaction, neuro-regulation and protein folding in oyster haemocytes. The activated immune cells then released neurotransmitters including acetylcholine, norepinephrine and [Met5]-enkephalin to regulate the immune response by arising the expression of three TNF (CGI_10005109, CGI_10005110 and CGI_10006440) and translocating two NF-κB (Cgp65, CGI_10018142 and CgRel, CGI_10021567) between the cytoplasm and nuclei of haemocytes. Neurotransmitters exhibited the immunomodulation effects by influencing apoptosis and phagocytosis of oyster haemocytes. Acetylcholine and norepinephrine could down-regulate the immune response, while [Met5]-enkephalin up-regulate the immune response. These results suggested that the simple neuroendocrine-immune regulatory network in oyster might be activated by oyster TNF and then regulate the immune response by virtue of neurotransmitters, cytokines and transcription factors.

Branching of the PIF3 regulatory network in Arabidopsis: roles of PIF3-regulated MIDAs in seedling development in the dark and in response to light.

PubMed

Sentandreu, Maria; Leivar, Pablo; Martín, Guiomar; Monte, Elena

2012-04-01

Plants need to accurately adjust their development after germination in the underground darkness to ensure survival of the seedling, both in the dark and in the light upon reaching the soil surface. Recent studies have established that the photoreceptors phytochromes and the bHLH phytochrome interacting factors PIFs regulate seedling development to adjust it to the prevailing light environment during post-germinative growth. However, complete understanding of the downstream regulatory network implementing these developmental responses is still lacking. In a recent work, published in The Plant Cell, we report a subset of PIF3-regulated genes in dark-grown seedlings that we have named MIDAs (MISREGULATED IN DARK). Analysis of their functional relevance using mutants showed that four of them present phenotypic alterations in the dark, and that each affected a particular facet of seedling development, suggesting organ-specific branching in the signal that PIF3 relays downstream. Furthermore, our results also showed an altered response to light in seedlings with an impaired PIF3/MIDA regulatory network, indicating that these factors might also be essential to initiate and optimize the developmental adjustment of the seedling to the light environment.

From Genes to Networks: Characterizing Gene-Regulatory Interactions in Plants.

PubMed

Kaufmann, Kerstin; Chen, Dijun

2017-01-01

Plants, like other eukaryotes, have evolved complex mechanisms to coordinate gene expression during development, environmental response, and cellular homeostasis. Transcription factors (TFs), accompanied by basic cofactors and posttranscriptional regulators, are key players in gene-regulatory networks (GRNs). The coordinated control of gene activity is achieved by the interplay of these factors and by physical interactions between TFs and DNA. Here, we will briefly outline recent technological progress made to elucidate GRNs in plants. We will focus on techniques that allow us to characterize physical interactions in GRNs in plants and to analyze their regulatory consequences. Targeted manipulation allows us to test the relevance of specific gene-regulatory interactions. The combination of genome-wide experimental approaches with mathematical modeling allows us to get deeper insights into key-regulatory interactions and combinatorial control of important processes in plants.

Regulatory role of the 90-kDa-heat-shock protein (Hsp90) and associated factors on gene expression.

PubMed

Erlejman, Alejandra G; Lagadari, Mariana; Toneatto, Judith; Piwien-Pilipuk, Graciela; Galigniana, Mario D

2014-02-01

The term molecular chaperone was first used to describe the ability of nucleoplasmin to prevent the aggregation of histones with DNA during the assembly of nucleosomes. Subsequently, the name was extended to proteins that mediate the post-translational assembly of oligomeric complexes protecting them from denaturation and/or aggregation. Hsp90 is a 90-kDa molecular chaperone that represents the major soluble protein of the cell. In contrast to most conventional chaperones, Hsp90 functions as a refined sensor of protein function and its principal role in the cell is to facilitate biological activity to properly folded client proteins that already have a preserved tertiary structure. Consequently, Hsp90 is related to basic cell functions such as cytoplasmic transport of soluble proteins, translocation of client proteins to organelles, and regulation of the biological activity of key signaling factors such as protein kinases, ubiquitin ligases, steroid receptors, cell cycle regulators, and transcription factors. A growing amount of evidence links the protective action of this molecular chaperone to mechanisms related to posttranslational modifications of soluble nuclear factors as well as histones. In this article, we discuss some aspects of the regulatory action of Hsp90 on transcriptional regulation and how this effect could have impacted genetic assimilation mechanism in some organisms. Copyright © 2013 Elsevier B.V. All rights reserved.

The transcriptional regulatory network mediated by banana (Musa acuminata) dehydration-responsive element binding (MaDREB) transcription factors in fruit ripening.

PubMed

Kuang, Jian-Fei; Chen, Jian-Ye; Liu, Xun-Cheng; Han, Yan-Chao; Xiao, Yun-Yi; Shan, Wei; Tang, Yang; Wu, Ke-Qiang; He, Jun-Xian; Lu, Wang-Jin

2017-04-01

Fruit ripening is a complex, genetically programmed process involving the action of critical transcription factors (TFs). Despite the established significance of dehydration-responsive element binding (DREB) TFs in plant abiotic stress responses, the involvement of DREBs in fruit ripening is yet to be determined. Here, we identified four genes encoding ripening-regulated DREB TFs in banana (Musa acuminata), MaDREB1, MaDREB2, MaDREB3, and MaDREB4, and demonstrated that they play regulatory roles in fruit ripening. We showed that MaDREB1-MaDREB4 are nucleus-localized, induced by ethylene and encompass transcriptional activation activities. We performed a genome-wide chromatin immunoprecipitation and high-throughput sequencing (ChIP-Seq) experiment for MaDREB2 and identified 697 genomic regions as potential targets of MaDREB2. MaDREB2 binds to hundreds of loci with diverse functions and its binding sites are distributed in the promoter regions proximal to the transcriptional start site (TSS). Most of the MaDREB2-binding targets contain the conserved (A/G)CC(G/C)AC motif and MaDREB2 appears to directly regulate the expression of a number of genes involved in fruit ripening. In combination with transcriptome profiling (RNA sequencing) data, our results indicate that MaDREB2 may serve as both transcriptional activator and repressor during banana fruit ripening. In conclusion, our study suggests a hierarchical regulatory model of fruit ripening in banana and that the MaDREB TFs may act as transcriptional regulators in the regulatory network. © 2017 The Authors. New Phytologist © 2017 New Phytologist Trust.

Mga2 Transcription Factor Regulates an Oxygen-responsive Lipid Homeostasis Pathway in Fission Yeast*

PubMed Central

Burr, Risa; Stewart, Emerson V.; Shao, Wei; Zhao, Shan; Hannibal-Bach, Hans Kristian; Ejsing, Christer S.; Espenshade, Peter J.

2016-01-01

Eukaryotic lipid synthesis is oxygen-dependent with cholesterol synthesis requiring 11 oxygen molecules and fatty acid desaturation requiring 1 oxygen molecule per double bond. Accordingly, organisms evaluate oxygen availability to control lipid homeostasis. The sterol regulatory element-binding protein (SREBP) transcription factors regulate lipid homeostasis. In mammals, SREBP-2 controls cholesterol biosynthesis, whereas SREBP-1 controls triacylglycerol and glycerophospholipid biosynthesis. In the fission yeast Schizosaccharomyces pombe, the SREBP-2 homolog Sre1 regulates sterol homeostasis in response to changing sterol and oxygen levels. However, notably missing is an SREBP-1 analog that regulates triacylglycerol and glycerophospholipid homeostasis in response to low oxygen. Consistent with this, studies have shown that the Sre1 transcription factor regulates only a fraction of all genes up-regulated under low oxygen. To identify new regulators of low oxygen adaptation, we screened the S. pombe nonessential haploid deletion collection and identified 27 gene deletions sensitive to both low oxygen and cobalt chloride, a hypoxia mimetic. One of these genes, mga2, is a putative transcriptional activator. In the absence of mga2, fission yeast exhibited growth defects under both normoxia and low oxygen conditions. Mga2 transcriptional targets were enriched for lipid metabolism genes, and mga2Δ cells showed disrupted triacylglycerol and glycerophospholipid homeostasis, most notably with an increase in fatty acid saturation. Indeed, addition of exogenous oleic acid to mga2Δ cells rescued the observed growth defects. Together, these results establish Mga2 as a transcriptional regulator of triacylglycerol and glycerophospholipid homeostasis in S. pombe, analogous to mammalian SREBP-1. PMID:27053105

40 CFR 92.6 - Regulatory structure.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 20 2010-07-01 2010-07-01 false Regulatory structure. 92.6 Section 92... Regulations for Locomotives and Locomotive Engines § 92.6 Regulatory structure. This section provides an overview of the regulatory structure of this part. (a) The regulations of this part 92 are intended to...

The RNA-binding protein CsrA plays a central role in positively regulating virulence factors in Erwinia amylovora

PubMed Central

Ancona, Veronica; Lee, Jae Hoon; Zhao, Youfu

2016-01-01

The GacS/GacA two-component system (also called GrrS/GrrA) is a global regulatory system which is highly conserved among gamma-proteobacteria. This system positively regulates non-coding small regulatory RNA csrB, which in turn binds to the RNA-binding protein CsrA. However, how GacS/GacA-Csr system regulates virulence traits in E. amylovora remains unknown. Results from mutant characterization showed that the csrB mutant was hypermotile, produced higher amount of exopolysaccharide amylovoran, and had increased expression of type III secretion (T3SS) genes in vitro. In contrast, the csrA mutant exhibited complete opposite phenotypes, including non-motile, reduced amylovoran production and expression of T3SS genes. Furthermore, the csrA mutant did not induce hypersensitive response on tobacco or cause disease on immature pear fruits, indicating that CsrA is a positive regulator of virulence factors. These findings demonstrated that CsrA plays a critical role in E. amylovora virulence and suggested that negative regulation of virulence by GacS/GacA acts through csrB sRNA, which binds to CsrA and neutralizes its positive effect on T3SS gene expression, flagellar formation and amylovoran production. Future research will be focused on determining the molecular mechanism underlying the positive regulation of virulence traits by CsrA. PMID:27845410

The RNA-binding protein CsrA plays a central role in positively regulating virulence factors in Erwinia amylovora.

PubMed

Ancona, Veronica; Lee, Jae Hoon; Zhao, Youfu

2016-11-15

The GacS/GacA two-component system (also called GrrS/GrrA) is a global regulatory system which is highly conserved among gamma-proteobacteria. This system positively regulates non-coding small regulatory RNA csrB, which in turn binds to the RNA-binding protein CsrA. However, how GacS/GacA-Csr system regulates virulence traits in E. amylovora remains unknown. Results from mutant characterization showed that the csrB mutant was hypermotile, produced higher amount of exopolysaccharide amylovoran, and had increased expression of type III secretion (T3SS) genes in vitro. In contrast, the csrA mutant exhibited complete opposite phenotypes, including non-motile, reduced amylovoran production and expression of T3SS genes. Furthermore, the csrA mutant did not induce hypersensitive response on tobacco or cause disease on immature pear fruits, indicating that CsrA is a positive regulator of virulence factors. These findings demonstrated that CsrA plays a critical role in E. amylovora virulence and suggested that negative regulation of virulence by GacS/GacA acts through csrB sRNA, which binds to CsrA and neutralizes its positive effect on T3SS gene expression, flagellar formation and amylovoran production. Future research will be focused on determining the molecular mechanism underlying the positive regulation of virulence traits by CsrA.

Skeletal muscle hypertrophy and regeneration: interplay between the myogenic regulatory factors (MRFs) and insulin-like growth factors (IGFs) pathways.

PubMed

Zanou, Nadège; Gailly, Philippe

2013-11-01

Adult skeletal muscle can regenerate in response to muscle damage. This ability is conferred by the presence of myogenic stem cells called satellite cells. In response to stimuli such as injury or exercise, these cells become activated and express myogenic regulatory factors (MRFs), i.e., transcription factors of the myogenic lineage including Myf5, MyoD, myogenin, and Mrf4 to proliferate and differentiate into myofibers. The MRF family of proteins controls the transcription of important muscle-specific proteins such as myosin heavy chain and muscle creatine kinase. Different growth factors are secreted during muscle repair among which insulin-like growth factors (IGFs) are the only ones that promote both muscle cell proliferation and differentiation and that play a key role in muscle regeneration and hypertrophy. Different isoforms of IGFs are expressed during muscle repair: IGF-IEa, IGF-IEb, or IGF-IEc (also known as mechano growth factor, MGF) and IGF-II. MGF is expressed first and is observed in satellite cells and in proliferating myoblasts whereas IGF-Ia and IGF-II expression occurs at the state of muscle fiber formation. Interestingly, several studies report the induction of MRFs in response to IGFs stimulation. Inversely, IGFs expression may also be regulated by MRFs. Various mechanisms are proposed to support these interactions. In this review, we describe the general process of muscle hypertrophy and regeneration and decipher the interactions between the two groups of factors involved in the process.

Initial deployment of the cardiogenic gene regulatory network in the basal chordate, Ciona intestinalis.

PubMed

Woznica, Arielle; Haeussler, Maximilian; Starobinska, Ella; Jemmett, Jessica; Li, Younan; Mount, David; Davidson, Brad

2012-08-01

The complex, partially redundant gene regulatory architecture underlying vertebrate heart formation has been difficult to characterize. Here, we dissect the primary cardiac gene regulatory network in the invertebrate chordate, Ciona intestinalis. The Ciona heart progenitor lineage is first specified by Fibroblast Growth Factor/Map Kinase (FGF/MapK) activation of the transcription factor Ets1/2 (Ets). Through microarray analysis of sorted heart progenitor cells, we identified the complete set of primary genes upregulated by FGF/Ets shortly after heart progenitor emergence. Combinatorial sequence analysis of these co-regulated genes generated a hypothetical regulatory code consisting of Ets binding sites associated with a specific co-motif, ATTA. Through extensive reporter analysis, we confirmed the functional importance of the ATTA co-motif in primary heart progenitor gene regulation. We then used the Ets/ATTA combination motif to successfully predict a number of additional heart progenitor gene regulatory elements, including an intronic element driving expression of the core conserved cardiac transcription factor, GATAa. This work significantly advances our understanding of the Ciona heart gene network. Furthermore, this work has begun to elucidate the precise regulatory architecture underlying the conserved, primary role of FGF/Ets in chordate heart lineage specification. Copyright © 2012 Elsevier Inc. All rights reserved.

[Inconsistencies between building regulations in force in Italy for indoor environment and wellness factors].

PubMed

Faggioli, A; Capasso, L

2015-01-01

Indoor environment is one of major health determinants, and the regulations that set the sanitary requirements are of primary importance for the protection of public health. The authors analyse the critical aspects of the complex Italian regulatory system, starting from the EU regulations, through national and regional laws, and finally the municipal regulations. They underline the need for more uniformity and clarity in the determination of health standards, as well as for a simplification of the existing legislation. Moreover, they highlight the importance of controlling and monitoring indoor environment, currently almost completely absent in Italy due to the effects of the regulatory changes of the latest years.

Intrinsic limits to gene regulation by global crosstalk

PubMed Central

Friedlander, Tamar; Prizak, Roshan; Guet, Călin C.; Barton, Nicholas H.; Tkačik, Gašper

2016-01-01

Gene regulation relies on the specificity of transcription factor (TF)–DNA interactions. Limited specificity may lead to crosstalk: a regulatory state in which a gene is either incorrectly activated due to noncognate TF–DNA interactions or remains erroneously inactive. As each TF can have numerous interactions with noncognate cis-regulatory elements, crosstalk is inherently a global problem, yet has previously not been studied as such. We construct a theoretical framework to analyse the effects of global crosstalk on gene regulation. We find that crosstalk presents a significant challenge for organisms with low-specificity TFs, such as metazoans. Crosstalk is not easily mitigated by known regulatory schemes acting at equilibrium, including variants of cooperativity and combinatorial regulation. Our results suggest that crosstalk imposes a previously unexplored global constraint on the functioning and evolution of regulatory networks, which is qualitatively distinct from the known constraints that act at the level of individual gene regulatory elements. PMID:27489144

EGRINs (Environmental Gene Regulatory Influence Networks) in Rice That Function in the Response to Water Deficit, High Temperature, and Agricultural Environments[OPEN

PubMed Central

Hafemeister, Christoph; Nicotra, Adrienne B.; Jagadish, S.V. Krishna; Bonneau, Richard; Purugganan, Michael

2016-01-01

Environmental gene regulatory influence networks (EGRINs) coordinate the timing and rate of gene expression in response to environmental signals. EGRINs encompass many layers of regulation, which culminate in changes in accumulated transcript levels. Here, we inferred EGRINs for the response of five tropical Asian rice (Oryza sativa) cultivars to high temperatures, water deficit, and agricultural field conditions by systematically integrating time-series transcriptome data, patterns of nucleosome-free chromatin, and the occurrence of known cis-regulatory elements. First, we identified 5447 putative target genes for 445 transcription factors (TFs) by connecting TFs with genes harboring known cis-regulatory motifs in nucleosome-free regions proximal to their transcriptional start sites. We then used network component analysis to estimate the regulatory activity for each TF based on the expression of its putative target genes. Finally, we inferred an EGRIN using the estimated transcription factor activity (TFA) as the regulator. The EGRINs include regulatory interactions between 4052 target genes regulated by 113 TFs. We resolved distinct regulatory roles for members of the heat shock factor family, including a putative regulatory connection between abiotic stress and the circadian clock. TFA estimation using network component analysis is an effective way of incorporating multiple genome-scale measurements into network inference. PMID:27655842

Basic Aspects of Tumor Cell Fatty Acid-Regulated Signaling and Transcription Factors

PubMed Central

Comba, Andrea; Lin, Yi-Hui; Eynard, Aldo Renato; Valentich, Mirta Ana; Fernandez-Zapico, Martin Ernesto; Pasqualini, Marìa Eugenia

2012-01-01

This article reviews the current knowledge and experimental research about the mechanisms by which fatty acids and their derivatives control specific gene expression involved during carcinogenesis. Changes in dietary fatty acids, specifically the polyunsaturated fatty acids (PUFAs) of the ω-3 and ω-6 families and some derived eicosanoids from lipoxygenases (LOXs), cyclooxygenases (COXs), and cytochrome P-450 (CYP-450), seem to control the activity of transcription factor families involved in cancer cell proliferation or cell death. Their regulation may be carried out either through direct binding to DNA as peroxisome proliferator–activated receptors (PPARs) or via modulation in an indirect manner of signaling pathway molecules (e.g., protein kinase C [PKC]) and other transcription factors (nuclear factor kappa B [NFκB] and sterol regulatory element binding protein [SREBP]). Knowledge of the mechanisms by which fatty acids control specific gene expression may identify important risk factors for cancer, and provide insight into the development of new therapeutic strategies for a better management of whole-body lipid metabolism. PMID:22048864

Ethical and Regulatory Challenges with Autologous Adult Stem Cells: A Comparative Review of International Regulations.

PubMed

Lysaght, Tamra; Kerridge, Ian H; Sipp, Douglas; Porter, Gerard; Capps, Benjamin J

2017-06-01

Cell and tissue-based products, such as autologous adult stem cells, are being prescribed by physicians across the world for diseases and illnesses that they have neither been approved for or been demonstrated as safe and effective in formal clinical trials. These doctors often form part of informal transnational networks that exploit differences and similarities in the regulatory systems across geographical contexts. In this paper, we examine the regulatory infrastructure of five geographically diverse but socio-economically comparable countries with the aim of identifying similarities and differences in how these products are regulated and governed within clinical contexts. We find that while there are many subtle technical differences in how these regulations are implemented, they are sufficiently similar that it is difficult to explain why these practices appear more prevalent in some countries and not in others. We conclude with suggestions for how international governance frameworks might be improved to discourage the exploitation of vulnerable patient populations while enabling innovation in the clinical application of cellular therapies.

Gene regulation is governed by a core network in hepatocellular carcinoma.

PubMed

Gu, Zuguang; Zhang, Chenyu; Wang, Jin

2012-05-01

Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide, and the mechanisms that lead to the disease are still relatively unclear. However, with the development of high-throughput technologies it is possible to gain a systematic view of biological systems to enhance the understanding of the roles of genes associated with HCC. Thus, analysis of the mechanism of molecule interactions in the context of gene regulatory networks can reveal specific sub-networks that lead to the development of HCC. In this study, we aimed to identify the most important gene regulations that are dysfunctional in HCC generation. Our method for constructing gene regulatory network is based on predicted target interactions, experimentally-supported interactions, and co-expression model. Regulators in the network included both transcription factors and microRNAs to provide a complete view of gene regulation. Analysis of gene regulatory network revealed that gene regulation in HCC is highly modular, in which different sets of regulators take charge of specific biological processes. We found that microRNAs mainly control biological functions related to mitochondria and oxidative reduction, while transcription factors control immune responses, extracellular activity and the cell cycle. On the higher level of gene regulation, there exists a core network that organizes regulations between different modules and maintains the robustness of the whole network. There is direct experimental evidence for most of the regulators in the core gene regulatory network relating to HCC. We infer it is the central controller of gene regulation. Finally, we explored the influence of the core gene regulatory network on biological pathways. Our analysis provides insights into the mechanism of transcriptional and post-transcriptional control in HCC. In particular, we highlight the importance of the core gene regulatory network; we propose that it is highly related to HCC and we believe further

A Synopsis of Factors Regulating Beta Cell Development and Beta Cell Mass

PubMed Central

Prasadan, Krishna; Shiota, Chiyo; Xiangwei, Xiao; Ricks, David; Fusco, Joseph; Gittes, George

2016-01-01

The insulin-secreting beta cells in the endocrine pancreas regulate blood glucose levels, and loss of functional beta cells leads to insulin deficiency, hyperglycemia (high blood glucose) and diabetes mellitus. Current treatment strategies for type-1 (autoimmune) diabetes are islet transplantation, which has significant risks and limitations, or normalization of blood glucose with insulin injections, which is clearly not ideal. The type-1 patients can lack insulin counter-regulatory mechanism; therefore, hypoglycemia is a potential risk. Hence, a cell-based therapy offers a better alternative for the treatment of diabetes. Past research was focused on attempting to generate replacement beta cells from stem cells, however, recently there has been an increasing interest in identifying mechanisms that will lead to the conversion of pre-existing differentiated endocrine cells into beta cells. The goal of this review is to provide an overview of several of the key factors that regulate new beta cell formation (neogenesis) and beta cell proliferation. PMID:27105622

Current Regulations and Regulatory Actions

EPA Pesticide Factsheets

This site will provide basic information on clean air permitting under the title V operating permits program, provide access to state and regional permitting programs, and maintain access to proposed and final regulatory requirements.

The regulation of reproductive neuroendocrine function by insulin and insulin-like growth factor-1 (IGF-1)

PubMed Central

Wolfe, Andrew; Divall, Sara; Wu, Sheng

2014-01-01

The mammalian reproductive hormone axis regulates gonadal steroid hormone levels and gonadal function essential for reproduction. The neuroendocrine control of the axis integrates signals from a wide array of inputs. The regulatory pathways important for mediating these inputs have been the subject of numerous studies. One class of proteins that have been shown to mediate metabolic and growth signals to the CNS includes Insulin and IGF-1. These proteins are structurally related and can exert endocrine and growth factor like action via related receptor tyrosine kinases. The role that insulin and IGF-1 play in controlling the hypothalamus and pituitary and their role in regulating puberty and nutritional control of reproduction has been studied extensively. This review summarizes the in vitro and in vivo models that have been used to study these neuroendocrine structures and the influence of these growth factors on neuroendocrine control of reproduction. PMID:24929098

Functional Impairment of Myeloid Dendritic Cells during Advanced Stage of HIV-1 Infection: Role of Factors Regulating Cytokine Signaling.

PubMed

Sachdeva, Meenakshi; Sharma, Aman; Arora, Sunil K

2015-01-01

Severely immunocompromised state during advanced stage of HIV-1 infection has been linked to functionally defective antigen presentation by dendritic cells (DCs). The molecular mechanisms behind DC impairment are still obscure. We investigated changes in DC function and association of key regulators of cytokine signaling during different stages of HIV-1 infection and following antiretroviral therapy (ART). Phenotypic and functional characteristics of circulating myeloid DCs (mDCs) in 56 ART-naive patients (23 in early and 33 in advanced stage of disease), 36 on ART and 24 healthy controls were evaluated. Sixteen patients were studied longitudinally prior-to and 6 months after the start of ART. For functional studies, monocyte-derived DCs (Mo-DCs) were evaluated for endocytosis, allo-stimulation and cytokine secretion. The expression of suppressor of cytokine signaling (SOCS)-1 and other regulators of cytokine signaling was evaluated by real-time RT-PCR. The ability to respond to an antigenic stimulation was severely impaired in patients in advanced HIV-1 disease which showed partial recovery in the treated group. Mo-DCs from patients with advanced HIV-disease remained immature with low allo-stimulation and reduced cytokine secretion even after TLR-4 mediated stimulation ex-vivo. The cells had an increased expression of negative regulatory factors like SOCS-1, SOCS-3, SH2-containing phosphatase (SHP)-1 and a reduced expression of positive regulators like Janus kinase (JAK)2 and Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)1. A functional recovery after siRNA mediated silencing of SOCS-1 in these mo-DCs confirms the role of negative regulatory factors in functional impairment of these cells. Functionally defective DCs in advanced stage of HIV-1 infection seems to be due to imbalanced state of negative and positive regulatory gene expression. Whether this is a cause or effect of increased viral replication at this stage of disease, needs

Executive Function in Adolescence: Associations with Child and Family Risk Factors and Self-Regulation in Early Childhood

PubMed Central

Berthelsen, Donna; Hayes, Nicole; White, Sonia L. J.; Williams, Kate E.

2017-01-01

Executive functions are important higher-order cognitive skills for goal-directed thought and action. These capacities contribute to successful school achievement and lifelong wellbeing. The importance of executive functions to children’s education begins in early childhood and continues throughout development. This study explores contributions of child and family factors in early childhood to the development of executive function in adolescence. Analyses draw on data from the nationally representative study, Growing up in Australia: The Longitudinal Study of Australian Children. Participants are 4819 children in the Kindergarten Cohort who were recruited at age 4–5 years. Path analyses were employed to examine contributions of early childhood factors, including family socio-economic position (SEP), parenting behaviors, maternal mental health, and a child behavioral risk index, to the development of executive function in adolescence. The influence of children’s early self-regulatory behaviors (attentional regulation at 4–5 years and approaches to learning at 6–7 years) were also taken into account. A composite score for the outcome measure of executive function was constructed from scores on three Cogstate computerized tasks for assessing cognition and measured visual attention, visual working memory, and spatial problem-solving. Covariates included child gender, age at assessment of executive function, Aboriginal and Torres Strait Islander status, speaking a language other than English at home, and child’s receptive vocabulary skills. There were significant indirect effects involving child and family risk factors measured at 4–5 years on executive function at age 14–15 years, mediated by measures of self-regulatory behavior. Child behavioral risk, family SEP and parenting behaviors (anger, warmth, and consistency) were associated with attentional regulation at 4–5 years which, in turn, was significantly associated with approaches to learning at 6

Fatty Acid–Regulated Transcription Factors in the Liver

PubMed Central

Jump, Donald B.; Tripathy, Sasmita; Depner, Christopher M.

2014-01-01

Fatty acid regulation of hepatic gene transcription was first reported in the early 1990s. Several transcription factors have been identified as targets of fatty acid regulation. This regulation is achieved by direct fatty acid binding to the transcription factor or by indirect mechanisms where fatty acids regulate signaling pathways controlling the expression of transcription factors or the phosphorylation, ubiquitination, or proteolytic cleavage of the transcription factor. Although dietary fatty acids are well-established regulators of hepatic transcription factors, emerging evidence indicates that endogenously generated fatty acids are equally important in controlling transcription factors in the context of glucose and lipid homeostasis. Our first goal in this review is to provide an up-to-date examination of the molecular and metabolic bases of fatty acid regulation of key transcription factors controlling hepatic metabolism. Our second goal is to link these mechanisms to nonalcoholic fatty liver disease (NAFLD), a growing health concern in the obese population. PMID:23528177

Transcriptional and posttranscriptional regulation of cyanobacterial photosynthesis.

PubMed

Wilde, Annegret; Hihara, Yukako

2016-03-01

Cyanobacteria are well established model organisms for the study of oxygenic photosynthesis, nitrogen metabolism, toxin biosynthesis, and salt acclimation. However, in comparison to other model bacteria little is known about regulatory networks, which allow cyanobacteria to acclimate to changing environmental conditions. The current work has begun to illuminate how transcription factors modulate expression of different photosynthetic regulons. During the past few years, the research on other regulatory principles like RNA-based regulation showed the importance of non-protein regulators for bacterial lifestyle. Investigations on modulation of photosynthetic components should elucidate the contributions of all factors within the context of a larger regulatory network. Here, we focus on regulation of photosynthetic processes including transcriptional and posttranscriptional mechanisms, citing examples from a limited number of cyanobacterial species. Though, the general idea holds true for most species, important differences exist between various organisms, illustrating diversity of acclimation strategies in the very heterogeneous cyanobacterial clade. This article is part of a Special Issue entitled Organization and dynamics of bioenergetic systems in bacteria, edited by Prof Conrad Mullineaux. Copyright © 2015 Elsevier B.V. All rights reserved.

hCG-dependent regulation of angiogenic factors in human granulosa lutein cells.

PubMed

Phan, B; Rakenius, A; Pietrowski, D; Bettendorf, H; Keck, C; Herr, D

2006-07-01

As prerequisite for development and maintenance of many diseases angiogenesis is of particular interest in medicine. Pathologic angiogenesis takes place in chronic arthritis, collagen diseases, arteriosclerosis, retinopathy associated with diabetes, and particularly in cancers. However, angiogenesis as a physiological process regularly occurs in the ovary. After ovulation the corpus luteum is formed by rapid vascularization of initially avascular granulosa lutein cell tissue. This process is regulated by gonadotropic hormones. In order to gain further insights in the regulatory mechanisms of angiogenesis in the ovary, we investigated these mechanisms in cell culture of human granulosa lutein cells. In particular, we determined the expression and production of several angiogenic factors including tissue inhibitor of matrix metalloproteinases-1 (TIMP-1), Leptin, connective tissue growth factor (CTGF), meningioma-associated complimentary DNA (Mac25), basic fibroblast growth factor (bFGF), and Midkine. In addition, we showed that human chorionic gonadotropin (hCG) has distinct effects on their expression and production. hCG enhances the expression and production of TIMP-1, whereas it downregulates the expression of CTGF and Mac25. Furthermore it decreases the expression of Leptin. Our results provide evidence that hCG determines growth and development of the corpus luteum by mediating angiogenic pathways in human granulosa lutein cells. Hence we describe a further approach to understand the regulation of angiogenesis in the ovary.

Smad Ubiquitylation Regulatory Factor 1/2 (Smurf1/2) Promotes p53 Degradation by Stabilizing the E3 Ligase MDM2*

PubMed Central

Nie, Jing; Xie, Ping; Liu, Lin; Xing, Guichun; Chang, Zhijie; Yin, Yuxin; Tian, Chunyan; He, Fuchu; Zhang, Lingqiang

2010-01-01

The tumor suppressor p53 protein is tightly regulated by a ubiquitin-proteasomal degradation mechanism. Several E3 ubiquitin ligases, including MDM2 (mouse double minute 2), have been reported to play an essential role in the regulation of p53 stability. However, it remains unclear how the activity of these E3 ligases is regulated. Here, we show that the HECT-type E3 ligase Smurf1/2 (Smad ubiquitylation regulatory factor 1/2) promotes p53 degradation by enhancing the activity of the E3 ligase MDM2. We provide evidence that the role of Smurf1/2 on the p53 stability is not dependent on the E3 activity of Smurf1/2 but rather is dependent on the activity of MDM2. We find that Smurf1/2 stabilizes MDM2 by enhancing the heterodimerization of MDM2 with MDMX, during which Smurf1/2 interacts with MDM2 and MDMX. We finally provide evidence that Smurf1/2 regulates apoptosis through p53. To our knowledge, this is the first report to demonstrate that Smurf1/2 functions as a factor to stabilize MDM2 protein rather than as a direct E3 ligase in regulation of p53 degradation. PMID:20484049

Regulatory Mechanisms Controlling Maturation of Serotonin Neuron Identity and Function

PubMed Central

Spencer, William C.; Deneris, Evan S.

2017-01-01

The brain serotonin (5-hydroxytryptamine; 5-HT) system has been extensively studied for its role in normal physiology and behavior, as well as, neuropsychiatric disorders. The broad influence of 5-HT on brain function, is in part due to the vast connectivity pattern of 5-HT-producing neurons throughout the CNS. 5-HT neurons are born and terminally specified midway through embryogenesis, then enter a protracted period of maturation, where they functionally integrate into CNS circuitry and then are maintained throughout life. The transcriptional regulatory networks controlling progenitor cell generation and terminal specification of 5-HT neurons are relatively well-understood, yet the factors controlling 5-HT neuron maturation are only recently coming to light. In this review, we first provide an update on the regulatory network controlling 5-HT neuron development, then delve deeper into the properties and regulatory strategies governing 5-HT neuron maturation. In particular, we discuss the role of the 5-HT neuron terminal selector transcription factor (TF) Pet-1 as a key regulator of 5-HT neuron maturation. Pet-1 was originally shown to positively regulate genes needed for 5-HT synthesis, reuptake and vesicular transport, hence 5-HT neuron-type transmitter identity. It has now been shown to regulate, both positively and negatively, many other categories of genes in 5-HT neurons including ion channels, GPCRs, transporters, neuropeptides, and other transcription factors. Its function as a terminal selector results in the maturation of 5-HT neuron excitability, firing characteristics, and synaptic modulation by several neurotransmitters. Furthermore, there is a temporal requirement for Pet-1 in the control of postmitotic gene expression trajectories thus indicating a direct role in 5-HT neuron maturation. Proper regulation of the maturation of cellular identity is critical for normal neuronal functioning and perturbations in the gene regulatory networks controlling

Regulatory Mechanisms Controlling Maturation of Serotonin Neuron Identity and Function.

PubMed

Spencer, William C; Deneris, Evan S

2017-01-01

The brain serotonin (5-hydroxytryptamine; 5-HT) system has been extensively studied for its role in normal physiology and behavior, as well as, neuropsychiatric disorders. The broad influence of 5-HT on brain function, is in part due to the vast connectivity pattern of 5-HT-producing neurons throughout the CNS. 5-HT neurons are born and terminally specified midway through embryogenesis, then enter a protracted period of maturation, where they functionally integrate into CNS circuitry and then are maintained throughout life. The transcriptional regulatory networks controlling progenitor cell generation and terminal specification of 5-HT neurons are relatively well-understood, yet the factors controlling 5-HT neuron maturation are only recently coming to light. In this review, we first provide an update on the regulatory network controlling 5-HT neuron development, then delve deeper into the properties and regulatory strategies governing 5-HT neuron maturation. In particular, we discuss the role of the 5-HT neuron terminal selector transcription factor (TF) Pet-1 as a key regulator of 5-HT neuron maturation. Pet-1 was originally shown to positively regulate genes needed for 5-HT synthesis, reuptake and vesicular transport, hence 5-HT neuron-type transmitter identity. It has now been shown to regulate, both positively and negatively, many other categories of genes in 5-HT neurons including ion channels, GPCRs, transporters, neuropeptides, and other transcription factors. Its function as a terminal selector results in the maturation of 5-HT neuron excitability, firing characteristics, and synaptic modulation by several neurotransmitters. Furthermore, there is a temporal requirement for Pet-1 in the control of postmitotic gene expression trajectories thus indicating a direct role in 5-HT neuron maturation. Proper regulation of the maturation of cellular identity is critical for normal neuronal functioning and perturbations in the gene regulatory networks controlling

Characterization of an apple TT2-type R2R3 MYB transcription factor functionally similar to the poplar proanthocyanidin regulator PtMYB134.

PubMed

Gesell, Andreas; Yoshida, Kazuko; Tran, Lan T; Constabel, C Peter

2014-09-01

The apple MdMYB9 gene encodes a positive regulator of proanthocyanidin synthesis that activates anthocyanidin reductase promoters from apple and poplar via interaction with basic helix-loop-helix proteins. The regulation of proanthocyanidins (PAs, condensed tannins) is of great importance in food plants due to the many benefits of PAs in the human diet. Two candidate flavonoid MYB regulators, MdMYB9 and MdMYB11, were cloned from apple (Malus × domestica) based on their similarity to known MYB PA regulators. Transcript accumulation of both MdMYB9 and MdMYB11 was induced by high light and wounding, similar to the poplar (Populus spp) PA regulator PtMYB134. In transient activation assays with various basic helix-loop-helix (bHLH) co-regulators, MdMYB9 activated apple and poplar anthocyanidin reductase (ANR) promoters, while MdMYB11 showed no activity. Potential transcription factor binding elements were found within several ANR promoters, and the importance of the bHLH binding site (E-box) on ANR promoter activation was demonstrated via mutational analysis. The ability of MdMYB9 and PtMYB134 to reciprocally activate ANR promoters from both apple and poplar and to partner with heterologous bHLH co-factors from these plants confirms the high degree of conservation of PA regulatory complexes across species. The similarity in apple and poplar PA regulation suggests that regulatory genes from poplar could be effectively employed for metabolic engineering of the PA pathway in apple.

The Chinese health care regulatory institutions in an era of transition.

PubMed

Fang, Jing

2008-02-01

The purpose of this paper is to contribute to a better understanding of Chinese health care regulation in an era of transition. It describes the major health care regulatory institutions operating currently in China and analyzes the underlying factors. The paper argues that in the transition from a planned to a market economy, the Chinese government has been employing a hybrid approach where both old and new institutions have a role in the management of emerging markets, including the health care market. This approach is consistent with the incremental reform strategy adopted by the Party-state. Although a health care regulatory framework has gradually taken shape, the framework is incomplete, with a particular lack of emphasis on professional self-regulation. In addition, its effectiveness is limited despite the existence of many regulatory institutions. In poor rural areas, the effectiveness of the regulatory framework is further undermined or distorted by the extremely difficult financial position that local governments find themselves in. The interpretations of the principle of 'rule of law' by policy makers and officials at different levels and the widespread informal network of relations between known individuals (Guanxi) play an important role in the operation of the regulatory framework. The findings of this paper reveal the complex nature of regulating health care in transitional China.

A trans-acting Variant within the Transcription Factor RIM101 Interacts with Genetic Background to Determine its Regulatory Capacity.

PubMed

Read, Timothy; Richmond, Phillip A; Dowell, Robin D

2016-01-01

Most genetic variants associated with disease occur within regulatory regions of the genome, underscoring the importance of defining the mechanisms underlying differences in regulation of gene expression between individuals. We discovered a pair of co-regulated, divergently oriented transcripts, AQY2 and ncFRE6, that are expressed in one strain of Saccharomyces cerevisiae, ∑1278b, but not in another, S288c. By combining classical genetics techniques with high-throughput sequencing, we identified a trans-acting single nucleotide polymorphism within the transcription factor RIM101 that causes the background-dependent expression of both transcripts. Subsequent RNA-seq experiments revealed that RIM101 regulates many more targets in S288c than in ∑1278b and that deletion of RIM101 in both backgrounds abrogates the majority of differential expression between the strains. Strikingly, only three transcripts undergo a significant change in expression after swapping RIM101 alleles between backgrounds, implying that the differences in the RIM101 allele lead to a remarkably focused transcriptional response. However, hundreds of RIM101-dependent targets undergo a subtle but consistent shift in expression in the S288c RIM101-swapped strain, but not its ∑1278b counterpart. We conclude that ∑1278b may harbor a variant(s) that buffers against widespread transcriptional dysregulation upon introduction of a non-native RIM101 allele, emphasizing the importance of accounting for genetic background when assessing the impact of a regulatory variant.

Shewregdb: Database and visualization environment for experimental and predicted regulatory information in Shewanella oneidensis mr-1

PubMed Central

Syed, Mustafa H; Karpinets, Tatiana V; Leuze, Michael R; Kora, Guruprasad H; Romine, Margaret R; Uberbacher, Edward C

2009-01-01

Shewanella oneidensis MR-1 is an important model organism for environmental research as it has an exceptional metabolic and respiratory versatility regulated by a complex regulatory network. We have developed a database to collect experimental and computational data relating to regulation of gene and protein expression, and, a visualization environment that enables integration of these data types. The regulatory information in the database includes predictions of DNA regulator binding sites, sigma factor binding sites, transcription units, operons, promoters, and RNA regulators including non-coding RNAs, riboswitches, and different types of terminators. Availability http://shewanella-knowledgebase.org:8080/Shewanella/gbrowserLanding.jsp PMID:20198195

Enhancers and super-enhancers have an equivalent regulatory role in embryonic stem cells through regulation of single or multiple genes

PubMed Central

Moorthy, Sakthi D.; Davidson, Scott; Shchuka, Virlana M.; Singh, Gurdeep; Malek-Gilani, Nakisa; Langroudi, Lida; Martchenko, Alexandre; So, Vincent; Macpherson, Neil N.; Mitchell, Jennifer A.

2017-01-01

Transcriptional enhancers are critical for maintaining cell-type–specific gene expression and driving cell fate changes during development. Highly transcribed genes are often associated with a cluster of individual enhancers such as those found in locus control regions. Recently, these have been termed stretch enhancers or super-enhancers, which have been predicted to regulate critical cell identity genes. We employed a CRISPR/Cas9-mediated deletion approach to study the function of several enhancer clusters (ECs) and isolated enhancers in mouse embryonic stem (ES) cells. Our results reveal that the effect of deleting ECs, also classified as ES cell super-enhancers, is highly variable, resulting in target gene expression reductions ranging from 12% to as much as 92%. Partial deletions of these ECs which removed only one enhancer or a subcluster of enhancers revealed partially redundant control of the regulated gene by multiple enhancers within the larger cluster. Many highly transcribed genes in ES cells are not associated with a super-enhancer; furthermore, super-enhancer predictions ignore 81% of the potentially active regulatory elements predicted by cobinding of five or more pluripotency-associated transcription factors. Deletion of these additional enhancer regions revealed their robust regulatory role in gene transcription. In addition, select super-enhancers and enhancers were identified that regulated clusters of paralogous genes. We conclude that, whereas robust transcriptional output can be achieved by an isolated enhancer, clusters of enhancers acting on a common target gene act in a partially redundant manner to fine tune transcriptional output of their target genes. PMID:27895109

76 FR 25397 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Order Approving...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-05-04

...-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Order Approving Proposed Rule Change To Amend the By- Laws of FINRA Regulation, Inc. With Regard to District Committees April 28, 2011. I. Introduction On February 25, 2011, the Financial Industry Regulatory Authority, Inc. (``FINRA'') filed with the...

Expression of Hoxa2 in rhombomere 4 is regulated by a conserved cross-regulatory mechanism dependent upon Hoxb1.

PubMed

Tümpel, Stefan; Cambronero, Francisco; Ferretti, Elisabetta; Blasi, Francesco; Wiedemann, Leanne M; Krumlauf, Robb

2007-02-15

The Hoxa2 gene is an important component of regulatory events during hindbrain segmentation and head development in vertebrates. In this study we have used sequenced comparisons of the Hoxa2 locus from 12 vertebrate species in combination with detailed regulatory analyses in mouse and chicken embryos to characterize the mechanistic basis for the regulation of Hoxa2 in rhombomere (r) 4. A highly conserved region in the Hoxa2 intron functions as an r4 enhancer. In vitro binding studies demonstrate that within the conserved region three bipartite Hox/Pbx binding sites (PH1-PH3) in combination with a single binding site for Pbx-Prep/Meis (PM) heterodimers co-operate to regulate enhancer activity in r4. Mutational analysis reveals that these sites are required for activity of the enhancer, suggesting that the r4 enhancer from Hoxa2 functions in vivo as a Hox-response module in combination with the Hox cofactors, Pbx and Prep/Meis. Furthermore, this r4 enhancer is capable of mediating a response to ectopic HOXB1 expression in the hindbrain. These findings reveal that Hoxa2 is a target gene of Hoxb1 and permit us to develop a gene regulatory network for r4, whereby Hoxa2, along with Hoxb1, Hoxb2 and Hoxa1, is integrated into a series of auto- and cross-regulatory loops between Hox genes. These data highlight the important role played by direct cross-talk between Hox genes in regulating hindbrain patterning.

Relationship of Initial Self-Regulatory Ability with Changes in Self-Regulation and Associated Fruit and Vegetable Consumption in Severely Obese Women Initiating an Exercise and Nutrition Treatment: Moderation of Mood and Self-Efficacy

PubMed Central

Annesi, James J.

2011-01-01

An emphasis on increasing self-regulation is an alternate to nutrition education, which has had poor results in the behavioral treatment of obesity. Although appropriately designed weight-loss treatments may enhance one’s self-regulatory ability to control eating, whether improvements are moderated by psychosocial factors such as initial self-regulatory skills use, self-efficacy to control eating, and mood is unknown. Severely obese women (BMI 35-50 kg·m-2) were randomized into 26-week treatments of exercise supported by cognitive-behavioral methods paired with either nutrition education (n = 114) or cognitive-behavioral methods applied to controlled eating (n = 121). Improvement in self-regulation for controlled eating was 36.9% greater (p < 0.01) for the group incorporating cognitive-behavioral methods for controlled eating. Change in self-regulation was significantly associated with self-regulation at baseline (β = -0.33). Both mood and self-efficacy for controlled eating significantly moderated this relationship. Increased self-regulation was associated with both increases in fruit and vegetable consumption and fruit and vegetable intake at treatment end. The present findings increase our understanding of psychosocial variables associated with increased self-regulatory skills usage and improvements in eating that, after replication, may be used to improve the effects of behavioral weight-loss treatments. Key points Initial self-regulatory abilities do not appear to affect improvements in self-regulation for eating, however direct training in behavioral skills are predictors of change. The relationship of self-regulation improvements and improved eating is significant, and affected by mood and self-efficacy in women with obesity. Instruction in behavioral skills such as cognitive restructuring and relapse prevention is associated with better improvements in eating than typical methods of nutrition education. Cognitive-behavioral methods for exercise may be

Comparative Bioinformatics Analysis of Transcription Factor Genes Indicates Conservation of Key Regulatory Domains among Babesia bovis, Babesia microti, and Theileria equi.

PubMed

Alzan, Heba F; Knowles, Donald P; Suarez, Carlos E

2016-11-01

Apicomplexa tick-borne hemoparasites, including Babesia bovis, Babesia microti, and Theileria equi are responsible for bovine and human babesiosis and equine theileriosis, respectively. These parasites of vast medical, epidemiological, and economic impact have complex life cycles in their vertebrate and tick hosts. Large gaps in knowledge concerning the mechanisms used by these parasites for gene regulation remain. Regulatory genes coding for DNA binding proteins such as members of the Api-AP2, HMG, and Myb families are known to play crucial roles as transcription factors. Although the repertoire of Api-AP2 has been defined and a HMG gene was previously identified in the B. bovis genome, these regulatory genes have not been described in detail in B. microti and T. equi. In this study, comparative bioinformatics was used to: (i) identify and map genes encoding for these transcription factors among three parasites' genomes; (ii) identify a previously unreported HMG gene in B. microti; (iii) define a repertoire of eight conserved Myb genes; and (iv) identify AP2 correlates among B. bovis and the better-studied Plasmodium parasites. Searching the available transcriptome of B. bovis defined patterns of transcription of these three gene families in B. bovis erythrocyte stage parasites. Sequence comparisons show conservation of functional domains and general architecture in the AP2, Myb, and HMG proteins, which may be significant for the regulation of common critical parasite life cycle transitions in B. bovis, B. microti, and T. equi. A detailed understanding of the role of gene families encoding DNA binding proteins will provide new tools for unraveling regulatory mechanisms involved in B. bovis, B. microti, and T. equi life cycles and environmental adaptive responses and potentially contributes to the development of novel convergent strategies for improved control of babesiosis and equine piroplasmosis.

Regulating the Adaptive Immune Response to Blood-Stage Malaria: Role of Dendritic Cells and CD4+Foxp3+ Regulatory T Cells

PubMed Central

Stevenson, Mary M.; Ing, Rebecca; Berretta, Floriana; Miu, Jenny

2011-01-01

Although a clearer understanding of the underlying mechanisms involved in protection and immunopathology during blood-stage malaria has emerged, the mechanisms involved in regulating the adaptive immune response especially those required to maintain a balance between beneficial and deleterious responses remain unclear. Recent evidence suggests the importance of CD11c+ dendritic cells (DC) and CD4+Foxp3+ regulatory T cells in regulating immune responses during infection and autoimmune disease, but information concerning the contribution of these cells to regulating immunity to malaria is limited. Here, we review recent findings from our laboratory and others in experimental models of malaria in mice and in Plasmodium-infected humans on the roles of DC and natural regulatory T cells in regulating adaptive immunity to blood-stage malaria. PMID:22110383

The Transcription Factor Rbf1 Is the Master Regulator for b-Mating Type Controlled Pathogenic Development in Ustilago maydis

PubMed Central

Vranes, Miroslav; Wahl, Ramon; Pothiratana, Chetsada; Schuler, David; Vincon, Volker; Finkernagel, Florian; Flor-Parra, Ignacio; Kämper, Jörg

2010-01-01

In the phytopathogenic basidiomycete Ustilago maydis, sexual and pathogenic development are tightly connected and controlled by the heterodimeric bE/bW transcription factor complex encoded by the b-mating type locus. The formation of the active bE/bW heterodimer leads to the formation of filaments, induces a G2 cell cycle arrest, and triggers pathogenicity. Here, we identify a set of 345 bE/bW responsive genes which show altered expression during these developmental changes; several of these genes are associated with cell cycle coordination, morphogenesis and pathogenicity. 90% of the genes that show altered expression upon bE/bW-activation require the zinc finger transcription factor Rbf1, one of the few factors directly regulated by the bE/bW heterodimer. Rbf1 is a novel master regulator in a multilayered network of transcription factors that facilitates the complex regulatory traits of sexual and pathogenic development. PMID:20700446

A gene regulatory network controlled by the NAC transcription factor ANAC092/AtNAC2/ORE1 during salt-promoted senescence.

PubMed

Balazadeh, Salma; Siddiqui, Hamad; Allu, Annapurna D; Matallana-Ramirez, Lilian P; Caldana, Camila; Mehrnia, Mohammad; Zanor, Maria-Inés; Köhler, Barbara; Mueller-Roeber, Bernd

2010-04-01

The onset and progression of senescence are under genetic and environmental control. The Arabidopsis thaliana NAC transcription factor ANAC092 (also called AtNAC2 and ORE1) has recently been shown to control age-dependent senescence, but its mode of action has not been analysed yet. To explore the regulatory network administered by ANAC092 we performed microarray-based expression profiling using estradiol-inducible ANAC092 overexpression lines. Approximately 46% of the 170 genes up-regulated upon ANAC092 induction are known senescence-associated genes, suggesting that the NAC factor exerts its role in senescence through a regulatory network that includes many of the genes previously reported to be senescence regulated. We selected 39 candidate genes and confirmed their time-dependent response to enhanced ANAC092 expression by quantitative RT-PCR. We also found that the majority of them (24 genes) are up-regulated by salt stress, a major promoter of plant senescence, in a manner similar to that of ANAC092, which itself is salt responsive. Furthermore, 24 genes like ANAC092 turned out to be stage-dependently expressed during seed growth with low expression at early and elevated expression at late stages of seed development. Disruption of ANAC092 increased the rate of seed germination under saline conditions, whereas the opposite occurred in respective overexpression plants. We also detected a delay of salinity-induced chlorophyll loss in detached anac092-1 mutant leaves. Promoter-reporter (GUS) studies revealed transcriptional control of ANAC092 expression during leaf and flower ageing and in response to salt stress. We conclude that ANAC092 exerts its functions during senescence and seed germination through partly overlapping target gene sets.

An apple MYB transcription factor, MdMYB3, is involved in regulation of anthocyanin biosynthesis and flower development.

PubMed

Vimolmangkang, Sornkanok; Han, Yuepeng; Wei, Guochao; Korban, Schuyler S

2013-11-07

Red coloration of fruit is an important trait in apple, and it is mainly attributed to the accumulation of anthocyanins, a class of plant flavonoid metabolites. Anthocyanin biosynthesis is genetically determined by structural and regulatory genes. Plant tissue pigmentation patterns are mainly controlled by expression profiles of regulatory genes. Among these regulatory genes are MYB transcription factors (TFs), wherein the class of two-repeats (R2R3) is deemed the largest, and these are associated with the anthocyanin biosynthesis pathway. Although three MdMYB genes, almost identical in nucleotide sequences, have been identified in apple, it is likely that there are other R2R3 MYB TFs that are present in the apple genome that are also involved in the regulation of coloration of red color pigmentation of the skin of apple fruits. In this study, a novel R2R3 MYB gene has been isolated and characterized in apple. This MYB gene is closely related to the Arabidopsis thaliana AtMYB3, and has been designated as MdMYB3. This TF belongs to the subgroup 4 R2R3 family of plant MYB transcription factors. This apple MdMYB3 gene is mapped onto linkage group 15 of the integrated apple genetic map. Transcripts of MdMYB3 are detected in all analyzed tissues including leaves, flowers, and fruits. However, transcripts of MdMYB3 are higher in excocarp of red-skinned apple cultivars than that in yellowish-green skinned apple cultivars. When this gene is ectopically expressed in Nicotiana tabacum cv. Petite Havana SR1, flowers of transgenic tobacco lines carrying MdMYB3 have exhibited increased pigmentation and accumulate higher levels of anthocyanins and flavonols than wild-type flowers. Overexpression of MdMYB3 has resulted in transcriptional activation of several flavonoid pathway genes, including CHS, CHI, UFGT, and FLS. Moreover, peduncles of flowers and styles of pistils of transgenic plants overexpressing MdMYB3 are longer than those of wild-type plants, thus suggesting that this

REGULATORY STRATEGIES TO MINIMIZE GENERATION OF REGULATED WASTES FROM CLEANUP, CONTINUED USE OR DECOMMISSIONING OF NUCLEAR FACILITIES CONTAMINATED WITH POLYCHLORINATED BIPHENYLS (PCBS) - 11198

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

Lowry, N.

Disposal costs for liquid PCB radioactive waste are among the highest of any category of regulated waste. The high cost is driven by the fact that disposal options are extremely limited. Toxic Substances Control Act (TSCA) regulations require most liquids with PCBs at concentration of {ge} 50 parts-per-million to be disposed by incineration or equivalent destructive treatment. Disposal fees can be as high as $200 per gallon. This figure does not include packaging and the cost to transport the waste to the disposal facility, or the waste generator's labor costs for managing the waste prior to shipment. Minimizing the generationmore » of liquid radioactive PCB waste is therefore a significant waste management challenge. PCB spill cleanups often generate large volumes of waste. That is because the removal of PCBs typically requires the liberal use of industrial solvents followed by a thorough rinsing process. In a nuclear facility, the cleanup process may be complicated by the presence of radiation and other occupational hazards. Building design and construction features, e.g., the presence of open grating or trenches, may also complicate cleanup. In addition to the technical challenges associated with spill cleanup, selection of the appropriate regulatory requirements and approach may be challenging. The TSCA regulations include three different sections relating to the cleanup of PCB contamination or spills. EPA has also promulgated a separate guidance policy for fresh PCB spills that is published as Subpart G of 40 CFR 761 although it is not an actual regulation. Applicability is based on the circumstances of each contamination event or situation. Other laws or regulations may also apply. Identification of the allowable regulatory options is important. Effective communication with stakeholders, particularly regulators, is just as important. Depending on the regulatory path that is taken, cleanup may necessitate the generation of large quantities of regulated waste

Macrophage depletion impairs skeletal muscle regeneration: The roles of regulatory factors for muscle regeneration.

PubMed

Liu, Xiaoguang; Liu, Yu; Zhao, Linlin; Zeng, Zhigang; Xiao, Weihua; Chen, Peijie

2017-03-01

Though macrophages are essential for skeletal muscle regeneration, which is a complex process, the roles and mechanisms of the macrophages in the process of muscle regeneration are still not fully understood. The objective of this study is to explore the roles of macrophages and the mechanisms involved in the regeneration of injured skeletal muscle. One hundred and twelve C57BL/6 mice were randomly divided into muscle contusion and macrophages depleted groups. Their gastrocnemius muscles were harvested at the time points of 12 h, 1, 3, 5, 7, 14 d post-injury. The changes in skeletal muscle morphology were assessed by hematoxylin and eosin (HE) stain. The gene expression was analyzed by real-time polymerase chain reaction. The data showed that CL-liposomes treatment did affect the expression of myogenic regulatory factors (MyoD, myogenin) after injury. In addition, CL-liposomes treatment decreased the expression of regulatory factors of muscle regeneration (HGF, uPA, COX-2, IGF-1, MGF, FGF6) and increased the expression of inflammatory cytokines (TGF-β1, TNF-α, IL-1β, RANTES) in the late stage of regeneration. Moreover, there were significant correlations between macrophages and some regulatory factors (such as HGF, uPA) for muscle regeneration. These results suggested that macrophages depletion impairs skeletal muscle regeneration and that the regulatory factors for muscle regeneration may play important roles in this process. © 2017 International Federation for Cell Biology.

Scientists versus regulators: precaution, novelty & regulatory oversight as predictors of perceived risks of engineered nanomaterials.

PubMed

Beaudrie, Christian E H; Satterfield, Terre; Kandlikar, Milind; Harthorn, Barbara H

2014-01-01

Engineered nanoscale materials (ENMs) present a difficult challenge for risk assessors and regulators. Continuing uncertainty about the potential risks of ENMs means that expert opinion will play an important role in the design of policies to minimize harmful implications while supporting innovation. This research aims to shed light on the views of 'nano experts' to understand which nanomaterials or applications are regarded as more risky than others, to characterize the differences in risk perceptions between expert groups, and to evaluate the factors that drive these perceptions. Our analysis draws from a web-survey (N = 404) of three groups of US and Canadian experts: nano-scientists and engineers, nano-environmental health and safety scientists, and regulatory scientists and decision-makers. Significant differences in risk perceptions were found across expert groups; differences found to be driven by underlying attitudes and perceptions characteristic of each group. Nano-scientists and engineers at the upstream end of the nanomaterial life cycle perceived the lowest levels of risk, while those who are responsible for assessing and regulating risks at the downstream end perceived the greatest risk. Perceived novelty of nanomaterial risks, differing preferences for regulation (i.e. the use of precaution versus voluntary or market-based approaches), and perceptions of the risk of technologies in general predicted variation in experts' judgments of nanotechnology risks. Our findings underscore the importance of involving a diverse selection of experts, particularly those with expertise at different stages along the nanomaterial lifecycle, during policy development.

12 CFR 562.2 - Regulatory reports.

Code of Federal Regulations, 2010 CFR

2010-01-01

... § 562.2 Regulatory reports. (a) Definition and scope. This section applies to all regulatory reports, as... (TFR) are examples of regulatory reports. Regulatory reports are regulatory documents, not accounting... limited to, the accounting instructions provided in the TFR, guidance contained in OTS regulations...

Effects of Goal Relations on Self-Regulated Learning in Multiple Goal Pursuits: Performance, the Self-Regulatory Process, and Task Enjoyment

ERIC Educational Resources Information Center

Lee, Hyunjoo

2012-01-01

The purpose of this study was to investigate the effects of goal relations on self-regulation in the pursuit of multiple goals, focusing on self-regulated performance, the self-regulatory process, and task enjoyment. The effect of multiple goal relations on self-regulation was explored in a set of three studies. Goal relations were divided into…

Extensive cross-regulation of post-transcriptional regulatory networks in Drosophila

DOE PAGES

Stoiber, Marcus H.; Olson, Sara; May, Gemma E.; ...

2015-08-20

In eukaryotic cells, RNAs exist as ribonucleoprotein particles (RNPs). Despite the importance of these complexes in many biological processes, including splicing, polyadenylation, stability, transportation, localization, and translation, their compositions are largely unknown. We affinity-purified 20 distinct RNA-binding proteins (RBPs) from cultured Drosophila melanogaster cells under native conditions and identified both the RNA and protein compositions of these RNP complexes. We identified “high occupancy target” (HOT) RNAs that interact with the majority of the RBPs we surveyed. HOT RNAs encode components of the nonsense-mediated decay and splicing machinery, as well as RNA-binding and translation initiation proteins. The RNP complexes contain proteinsmore » and mRNAs involved in RNA binding and post-transcriptional regulation. Genes with the capacity to produce hundreds of mRNA isoforms, ultracomplex genes, interact extensively with heterogeneous nuclear ribonuclear proteins (hnRNPs). Our data are consistent with a model in which subsets of RNPs include mRNA and protein products from the same gene, indicating the widespread existence of auto-regulatory RNPs. Lastly, from the simultaneous acquisition and integrative analysis of protein and RNA constituents of RNPs, we identify extensive cross-regulatory and hierarchical interactions in post-transcriptional control.« less

Extensive cross-regulation of post-transcriptional regulatory networks in Drosophila

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

Stoiber, Marcus H.; Olson, Sara; May, Gemma E.

In eukaryotic cells, RNAs exist as ribonucleoprotein particles (RNPs). Despite the importance of these complexes in many biological processes, including splicing, polyadenylation, stability, transportation, localization, and translation, their compositions are largely unknown. We affinity-purified 20 distinct RNA-binding proteins (RBPs) from cultured Drosophila melanogaster cells under native conditions and identified both the RNA and protein compositions of these RNP complexes. We identified “high occupancy target” (HOT) RNAs that interact with the majority of the RBPs we surveyed. HOT RNAs encode components of the nonsense-mediated decay and splicing machinery, as well as RNA-binding and translation initiation proteins. The RNP complexes contain proteinsmore » and mRNAs involved in RNA binding and post-transcriptional regulation. Genes with the capacity to produce hundreds of mRNA isoforms, ultracomplex genes, interact extensively with heterogeneous nuclear ribonuclear proteins (hnRNPs). Our data are consistent with a model in which subsets of RNPs include mRNA and protein products from the same gene, indicating the widespread existence of auto-regulatory RNPs. Lastly, from the simultaneous acquisition and integrative analysis of protein and RNA constituents of RNPs, we identify extensive cross-regulatory and hierarchical interactions in post-transcriptional control.« less

Interferon Regulatory Factors IRF5 and IRF7 Inhibit Growth and Induce Senescence in Immortal Li-Fraumeni Fibroblasts

PubMed Central

Li, Qunfang; Tang, Lin; Roberts, Paul Christopher; Kraniak, Janice M.; Fridman, Aviva Levine; Kulaeva, Olga I.; Tehrani, Omid S.; Tainsky, Michael A.

2013-01-01

Cellular immortalization is one of the prerequisite steps in carcinogenesis. By gene expression profiling, we have found that genes in the interferon (IFN) pathway were dysregulated during the spontaneous cellular immortalization of fibroblasts from Li-Fraumeni syndrome (LFS) patients with germ-line mutations in p53. IFN signaling pathway genes were down-regulated by epigenetic silencing during immortalization, and some of these same IFN-regulated genes were activated during replicative senescence. Bisulfite sequencing of the promoter regions of two IFN regulatory transcription factors (IRF5 and IRF7) revealed that IRF7, but not IRF5, was epigenetically silenced by methylation of CpG islands in immortal LFS cells. The induction of IRF7 gene by IFNα in immortal LFS cells was potentiated by pretreatment with the demethylation agent 5-aza-2′-deoxycytidine. Overexpression of IRF5 and IRF7 revealed that they can act either alone or in tandem to activate other IFN-regulated genes. In addition, they serve to inhibit the proliferation rate and induce a senescence-related phenotype in immortal LFS cells. Furthermore, polyinosinic:polycytidylic acid treatment of the IRF-overexpressing cells showed a more rapid induction of several IFN-regulated genes. We conclude that the epigenetic inactivation of the IFN pathway plays a critical role in cellular immortalization, and the reactivation of IFN-regulated genes by transcription factors IRF5 and/or IRF7 is sufficient to induce cellular senescence. The IFN pathway may provide valuable molecular targets for therapeutic interventions at early stages of cancer development. PMID:18505922

Interferon regulatory factors IRF5 and IRF7 inhibit growth and induce senescence in immortal Li-Fraumeni fibroblasts.

PubMed

Li, Qunfang; Tang, Lin; Roberts, Paul Christopher; Kraniak, Janice M; Fridman, Aviva Levine; Kulaeva, Olga I; Tehrani, Omid S; Tainsky, Michael A

2008-05-01

Cellular immortalization is one of the prerequisite steps in carcinogenesis. By gene expression profiling, we have found that genes in the interferon (IFN) pathway were dysregulated during the spontaneous cellular immortalization of fibroblasts from Li-Fraumeni syndrome (LFS) patients with germ-line mutations in p53. IFN signaling pathway genes were down-regulated by epigenetic silencing during immortalization, and some of these same IFN-regulated genes were activated during replicative senescence. Bisulfite sequencing of the promoter regions of two IFN regulatory transcription factors (IRF5 and IRF7) revealed that IRF7, but not IRF5, was epigenetically silenced by methylation of CpG islands in immortal LFS cells. The induction of IRF7 gene by IFNalpha in immortal LFS cells was potentiated by pretreatment with the demethylation agent 5-aza-2'-deoxycytidine. Overexpression of IRF5 and IRF7 revealed that they can act either alone or in tandem to activate other IFN-regulated genes. In addition, they serve to inhibit the proliferation rate and induce a senescence-related phenotype in immortal LFS cells. Furthermore, polyinosinic:polycytidylic acid treatment of the IRF-overexpressing cells showed a more rapid induction of several IFN-regulated genes. We conclude that the epigenetic inactivation of the IFN pathway plays a critical role in cellular immortalization, and the reactivation of IFN-regulated genes by transcription factors IRF5 and/or IRF7 is sufficient to induce cellular senescence. The IFN pathway may provide valuable molecular targets for therapeutic interventions at early stages of cancer development.

Genome-scale cold stress response regulatory networks in ten Arabidopsis thaliana ecotypes

PubMed Central

2013-01-01

Background Low temperature leads to major crop losses every year. Although several studies have been conducted focusing on diversity of cold tolerance level in multiple phenotypically divergent Arabidopsis thaliana (A. thaliana) ecotypes, genome-scale molecular understanding is still lacking. Results In this study, we report genome-scale transcript response diversity of 10 A. thaliana ecotypes originating from different geographical locations to non-freezing cold stress (10°C). To analyze the transcriptional response diversity, we initially compared transcriptome changes in all 10 ecotypes using Arabidopsis NimbleGen ATH6 microarrays. In total 6061 transcripts were significantly cold regulated (p < 0.01) in 10 ecotypes, including 498 transcription factors and 315 transposable elements. The majority of the transcripts (75%) showed ecotype specific expression pattern. By using sequence data available from Arabidopsis thaliana 1001 genome project, we further investigated sequence polymorphisms in the core cold stress regulon genes. Significant numbers of non-synonymous amino acid changes were observed in the coding region of the CBF regulon genes. Considering the limited knowledge about regulatory interactions between transcription factors and their target genes in the model plant A. thaliana, we have adopted a powerful systems genetics approach- Network Component Analysis (NCA) to construct an in-silico transcriptional regulatory network model during response to cold stress. The resulting regulatory network contained 1,275 nodes and 7,720 connections, with 178 transcription factors and 1,331 target genes. Conclusions A. thaliana ecotypes exhibit considerable variation in transcriptome level responses to non-freezing cold stress treatment. Ecotype specific transcripts and related gene ontology (GO) categories were identified to delineate natural variation of cold stress regulated differential gene expression in the model plant A. thaliana. The predicted

The regulation of reproductive neuroendocrine function by insulin and insulin-like growth factor-1 (IGF-1).

PubMed

Wolfe, Andrew; Divall, Sara; Wu, Sheng

2014-10-01

The mammalian reproductive hormone axis regulates gonadal steroid hormone levels and gonadal function essential for reproduction. The neuroendocrine control of the axis integrates signals from a wide array of inputs. The regulatory pathways important for mediating these inputs have been the subject of numerous studies. One class of proteins that have been shown to mediate metabolic and growth signals to the CNS includes Insulin and IGF-1. These proteins are structurally related and can exert endocrine and growth factor like action via related receptor tyrosine kinases. The role that insulin and IGF-1 play in controlling the hypothalamus and pituitary and their role in regulating puberty and nutritional control of reproduction has been studied extensively. This review summarizes the in vitro and in vivo models that have been used to study these neuroendocrine structures and the influence of these growth factors on neuroendocrine control of reproduction. Copyright © 2014 Elsevier Inc. All rights reserved.

Is the iron regulatory hormone hepcidin a risk factor for alcoholic liver disease?

PubMed Central

Harrison-Findik, Duygu Dee

2009-01-01

Despite heavy consumption over a long period of time, only a small number of alcoholics develop alcoholic liver disease. This alludes to the possibility that other factors, besides alcohol, may be involved in the progression of the disease. Over the years, many such factors have indeed been identified, including iron. Despite being crucial for various important biological processes, iron can also be harmful due to its ability to catalyze Fenton chemistry. Alcohol and iron have been shown to interact synergistically to cause liver injury. Iron-mediated cell signaling has been reported to be involved in the pathogenesis of experimental alcoholic liver disease. Hepcidin is an iron-regulatory hormone synthesized by the liver, which plays a pivotal role in iron homeostasis. Both acute and chronic alcohol exposure suppress hepcidin expression in the liver. The sera of patients with alcoholic liver disease, particularly those exhibiting higher serum iron indices, have also been reported to display reduced prohepcidin levels. Alcohol-mediated oxidative stress is involved in the inhibition of hepcidin promoter activity and transcription in the liver. This in turn leads to an increase in intestinal iron transport and liver iron storage. Hepcidin is expressed primarily in hepatocytes. It is noteworthy that both hepatocytes and Kupffer cells are involved in the progression of alcoholic liver disease. However, the activation of Kupffer cells and TNF-α signaling has been reported not to be involved in the down-regulation of hepcidin expression by alcohol in the liver. Alcohol acts within the parenchymal cells of the liver to suppress the synthesis of hepcidin. Due to its crucial role in the regulation of body iron stores, hepcidin may act as a secondary risk factor in the progression of alcoholic liver disease. The clarification of the mechanisms by which alcohol disrupts iron homeostasis will allow for further understanding of the pathogenesis of alcoholic liver disease. PMID

Clonorchis sinensis excretory-secretory products regulate migration and invasion in cholangiocarcinoma cells via extracellular signal-regulated kinase 1/2/nuclear factor-κB-dependent matrix metalloproteinase-9 expression.

PubMed

Pak, Jhang Ho; Shin, Jimin; Song, In-Sung; Shim, Sungbo; Jang, Sung-Wuk

2017-01-01

Matrix metalloproteinase-9 plays an important role in the invasion and metastasis of various types of cancer cells. We have previously reported that excretory-secretory products from Clonorchis sinensis increases matrix metalloproteinase-9 expression. However, the regulatory mechanisms through which matrix metalloproteinase-9 expression affects cholangiocarcinoma development remain unclear. In the current study, we examined the potential role of excretory-secretory products in regulating the migration and invasion of various cholangiocarcinoma cell lines. We demonstrated that excretory-secretory products significantly induced matrix metalloproteinase-9 expression and activity in a concentration-dependent manner. Reporter gene and chromatin immunoprecipitation assays showed that excretory-secretory products induced matrix metalloproteinase-9 expression by enhancing the activity of nuclear factor-kappa B. Moreover, excretory-secretory products induced the degradation and phosphorylation of IκBα and stimulated nuclear factor-kappa B p65 nuclear translocation, which was regulated by extracellular signal-regulated kinase 1/2. Taken together, our findings indicated that the excretory-secretory product-dependent enhancement of matrix metalloproteinase-9 activity and subsequent induction of IκBα and nuclear factor-kappa B activities may contribute to the progression of cholangiocarcinoma. Copyright © 2016 Australian Society for Parasitology. Published by Elsevier Ltd. All rights reserved.

5 CFR 340.201 - Regulatory requirements.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 340.201 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT CIVIL SERVICE REGULATIONS OTHER THAN FULL-TIME CAREER EMPLOYMENT (PART-TIME, SEASONAL, ON-CALL, AND INTERMITTENT) Regulatory Requirements-Part-Time Employment § 340.201 Regulatory requirements. This subpart contains the regulations of the...

Comprehensive identification and analysis of human accelerated regulatory DNA

PubMed Central

Gittelman, Rachel M.; Hun, Enna; Ay, Ferhat; Madeoy, Jennifer; Pennacchio, Len; Noble, William S.; Hawkins, R. David; Akey, Joshua M.

2015-01-01

It has long been hypothesized that changes in gene regulation have played an important role in human evolution, but regulatory DNA has been much more difficult to study compared with protein-coding regions. Recent large-scale studies have created genome-scale catalogs of DNase I hypersensitive sites (DHSs), which demark potentially functional regulatory DNA. To better define regulatory DNA that has been subject to human-specific adaptive evolution, we performed comprehensive evolutionary and population genetics analyses on over 18 million DHSs discovered in 130 cell types. We identified 524 DHSs that are conserved in nonhuman primates but accelerated in the human lineage (haDHS), and estimate that 70% of substitutions in haDHSs are attributable to positive selection. Through extensive computational and experimental analyses, we demonstrate that haDHSs are often active in brain or neuronal cell types; play an important role in regulating the expression of developmentally important genes, including many transcription factors such as SOX6, POU3F2, and HOX genes; and identify striking examples of adaptive regulatory evolution that may have contributed to human-specific phenotypes. More generally, our results reveal new insights into conserved and adaptive regulatory DNA in humans and refine the set of genomic substrates that distinguish humans from their closest living primate relatives. PMID:26104583

A Regulatory Pathway, Ecdysone-Transcription Factor Relish-Cathepsin L, Is Involved in Insect Fat Body Dissociation

PubMed Central

Zhang, Yao; Lu, Yu-Xuan; Liu, Jian; Yang, Cui; Feng, Qi-Li; Xu, Wei-Hua

2013-01-01

Insect fat body is the organ for intermediary metabolism, comparable to vertebrate liver and adipose tissue. Larval fat body is disintegrated to individual fat body cells and then adult fat body is remodeled at the pupal stage. However, little is known about the dissociation mechanism. We find that the moth Helicoverpa armigera cathepsin L (Har-CL) is expressed heavily in the fat body and is released from fat body cells into the extracellular matrix. The inhibitor and RNAi experiments demonstrate that Har-CL functions in the fat body dissociation in H. armigera. Further, a nuclear protein is identified to be transcription factor Har-Relish, which was found in insect immune response and specifically binds to the promoter of Har-CL gene to regulate its activity. Har-Relish also responds to the steroid hormone ecdysone. Thus, the dissociation of the larval fat body is involved in the hormone (ecdysone)-transcription factor (Relish)-target gene (cathepsin L) regulatory pathway. PMID:23459255

The global regulator of pathogenesis PnCon7 positively regulates Tox3 effector gene expression through direct interaction in the wheat pathogen Parastagonospora nodorum.

PubMed

Lin, Shao-Yu; Chooi, Yit-Heng; Solomon, Peter S

2018-05-03

To investigate effector gene regulation in the wheat pathogenic fungus Parastagonospora nodorum, the promoter and expression of Tox3 was characterised through a series of complementary approaches. Promoter deletion and DNase I footprinting experiments identified a 25 bp region in the Tox3 promoter as being required for transcription. Subsequent yeast one-hybrid analysis using the DNA sequence as bait identified that interacting partner as the C2H2 zinc finger transcription factor PnCon7, a putative master regulator of pathogenesis. Silencing of PnCon7 resulted in the down-regulation of Tox3 demonstrating that the transcription factor has a positive regulatory role on gene expression. Analysis of Tox3 expression in the PnCon7 silenced strains revealed a strong correlation with PnCon7 transcript levels, supportive of a direct regulatory role. Subsequent pathogenicity assays using PnCon7-silenced isolates revealed that the transcription factor was required for Tox3-mediated disease. The expression of two other necrotrophic effectors (ToxA and Tox1) was also affected but in a non-dose dependent manner suggesting that the regulatory role of PnCon7 on these genes was indirect. Collectively, these data have advanced our fundamental understanding of the Con7 master regulator of pathogenesis by demonstrating its positive regulatory role on the Tox3 effector in P. nodorum through direct interaction. This article is protected by copyright. All rights reserved. © 2018 John Wiley & Sons Ltd.

Reconstruction of the regulatory network for Bacillus subtilis and reconciliation with gene expression data

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

Faria, Jose P.; Overbeek, Ross; Taylor, Ronald C.

Here, we introduce a manually constructed and curated regulatory network model that describes the current state of knowledge of transcriptional regulation of B. subtilis. The model corresponds to an updated and enlarged version of the regulatory model of central metabolism originally proposed in 2008. We extended the original network to the whole genome by integration of information from DBTBS, a compendium of regulatory data that includes promoters, transcription factors (TFs), binding sites, motifs and regulated operons. Additionally, we consolidated our network with all the information on regulation included in the SporeWeb and Subtiwiki community-curated resources on B. subtilis. Finally, wemore » reconciled our network with data from RegPrecise, which recently released their own less comprehensive reconstruction of the regulatory network for B. subtilis. Our model describes 275 regulators and their target genes, representing 30 different mechanisms of regulation such as TFs, RNA switches, Riboswitches and small regulatory RNAs. Overall, regulatory information is included in the model for approximately 2500 of the ~4200 genes in B. subtilis 168. In an effort to further expand our knowledge of B. subtilis regulation, we reconciled our model with expression data. For this process, we reconstructed the Atomic Regulons (ARs) for B. subtilis, which are the sets of genes that share the same “ON” and “OFF” gene expression profiles across multiple samples of experimental data. We show how atomic regulons for B. subtilis are able to capture many sets of genes corresponding to regulated operons in our manually curated network. Additionally, we demonstrate how atomic regulons can be used to help expand or validate the knowledge of the regulatory networks by looking at highly correlated genes in the ARs for which regulatory information is lacking. During this process, we were also able to infer novel stimuli for hypothetical genes by exploring the genome

Reconstruction of the regulatory network for Bacillus subtilis and reconciliation with gene expression data

DOE PAGES

Faria, Jose P.; Overbeek, Ross; Taylor, Ronald C.; ...

2016-03-18

Here, we introduce a manually constructed and curated regulatory network model that describes the current state of knowledge of transcriptional regulation of B. subtilis. The model corresponds to an updated and enlarged version of the regulatory model of central metabolism originally proposed in 2008. We extended the original network to the whole genome by integration of information from DBTBS, a compendium of regulatory data that includes promoters, transcription factors (TFs), binding sites, motifs and regulated operons. Additionally, we consolidated our network with all the information on regulation included in the SporeWeb and Subtiwiki community-curated resources on B. subtilis. Finally, wemore » reconciled our network with data from RegPrecise, which recently released their own less comprehensive reconstruction of the regulatory network for B. subtilis. Our model describes 275 regulators and their target genes, representing 30 different mechanisms of regulation such as TFs, RNA switches, Riboswitches and small regulatory RNAs. Overall, regulatory information is included in the model for approximately 2500 of the ~4200 genes in B. subtilis 168. In an effort to further expand our knowledge of B. subtilis regulation, we reconciled our model with expression data. For this process, we reconstructed the Atomic Regulons (ARs) for B. subtilis, which are the sets of genes that share the same “ON” and “OFF” gene expression profiles across multiple samples of experimental data. We show how atomic regulons for B. subtilis are able to capture many sets of genes corresponding to regulated operons in our manually curated network. Additionally, we demonstrate how atomic regulons can be used to help expand or validate the knowledge of the regulatory networks by looking at highly correlated genes in the ARs for which regulatory information is lacking. During this process, we were also able to infer novel stimuli for hypothetical genes by exploring the genome

Expression of AtWRKY33 encoding a pathogen- or PAMP-responsive WRKY transcription factor is regulated by a composite DNA motif containing W box elements.

PubMed

Lippok, Bernadette; Birkenbihl, Rainer P; Rivory, Gaelle; Brümmer, Janna; Schmelzer, Elmon; Logemann, Elke; Somssich, Imre E

2007-04-01

WRKY transcription factors regulate distinct parts of the plant defense transcriptome. Expression of many WRKY genes themselves is induced by pathogens or pathogen-mimicking molecules. Here, we demonstrate that Arabidopsis WRKY33 responds to various stimuli associated with plant defense as well as to different kinds of phytopathogens. Although rapid pathogen-induced AtWRKY33 expression does not require salicylic acid (SA) signaling, it is dependent on PAD4, a key regulator upstream of SA. Activation of AtWRKY33 is independent of de novo protein synthesis, suggesting that it is at least partly under negative regulatory control. We show that a set of three WRKY-specific cis-acting DNA elements (W boxes) within the AtWRKY33 promoter is required for efficient pathogen- or PAMP-triggered gene activation. This strongly indicates that WRKY transcription factors are major components of the regulatory machinery modulating immediate to early expression of this gene in response to pathogen attack.

Regulation of cell wall biosynthesis.

PubMed

Zhong, Ruiqin; Ye, Zheng-Hua

2007-12-01

Plant cell walls differ in their amount and composition among various cell types and even in different microdomains of the wall of a given cell. Plants must have evolved regulatory mechanisms controlling biosynthesis, targeted secretion, and assembly of wall components to achieve the heterogeneity in cell walls. A number of factors, including hormones, the cytoskeleton, glycosylphosphatidylinositol-anchored proteins, phosphoinositides, and sugar nucleotide supply, have been implicated in the regulation of cell wall biosynthesis or deposition. In the past two years, there have been important discoveries in transcriptional regulation of secondary wall biosynthesis. Several transcription factors in the NAC and MYB families have been shown to be the key switches for activation of secondary wall biosynthesis. These studies suggest a transcriptional network comprised of a hierarchy of transcription factors is involved in regulating secondary wall biosynthesis. Further investigation and integration of the regulatory players participating in the making of cell walls will certainly lead to our understanding of how wall amounts and composition are controlled in a given cell type. This may eventually allow custom design of plant cell walls on the basis of our needs.

Control of regulatory T cell lineage commitment and maintenance.

PubMed

Josefowicz, Steven Z; Rudensky, Alexander

2009-05-01

Foxp3-expressing regulatory T (Treg) cells suppress pathology mediated by immune responses against self and foreign antigens and commensal microorganisms. Sustained expression of the transcription factor Foxp3, a key distinguishing feature of Treg cells, is required for their differentiation and suppressor function. In addition, Foxp3 expression prevents deviation of Treg cells into effector T cell lineages and confers dependence of Treg cell survival and expansion on growth factors, foremost interleukin-2, provided by activated effector T cells. In this review we discuss Treg cell differentiation and maintenance with a particular emphasis on molecular regulation of Foxp3 expression, arguably a key to mechanistic understanding of biology of regulatory T cells.

Regulatory Divergence between Parental Alleles Determines Gene Expression Patterns in Hybrids

PubMed Central

Combes, Marie-Christine; Hueber, Yann; Dereeper, Alexis; Rialle, Stéphanie; Herrera, Juan-Carlos; Lashermes, Philippe

2015-01-01

Both hybridization and allopolyploidization generate novel phenotypes by conciliating divergent genomes and regulatory networks in the same cellular context. To understand the rewiring of gene expression in hybrids, the total expression of 21,025 genes and the allele-specific expression of over 11,000 genes were quantified in interspecific hybrids and their parental species, Coffea canephora and Coffea eugenioides using RNA-seq technology. Between parental species, cis- and trans-regulatory divergences affected around 32% and 35% of analyzed genes, respectively, with nearly 17% of them showing both. The relative importance of trans-regulatory divergences between both species could be related to their low genetic divergence and perennial habit. In hybrids, among divergently expressed genes between parental species and hybrids, 77% was expressed like one parent (expression level dominance), including 65% like C. eugenioides. Gene expression was shown to result from the expression of both alleles affected by intertwined parental trans-regulatory factors. A strong impact of C. eugenioides trans-regulatory factors on the upregulation of C. canephora alleles was revealed. The gene expression patterns appeared determined by complex combinations of cis- and trans-regulatory divergences. In particular, the observed biased expression level dominance seemed to be derived from the asymmetric effects of trans-regulatory parental factors on regulation of alleles. More generally, this study illustrates the effects of divergent trans-regulatory parental factors on the gene expression pattern in hybrids. The characteristics of the transcriptional response to hybridization appear to be determined by the compatibility of gene regulatory networks and therefore depend on genetic divergences between the parental species and their evolutionary history. PMID:25819221

Dynamics and function of distal regulatory elements during neurogenesis and neuroplasticity

PubMed Central

Thakurela, Sudhir; Sahu, Sanjeeb Kumar; Garding, Angela; Tiwari, Vijay K.

2015-01-01

Gene regulation in mammals involves a complex interplay between promoters and distal regulatory elements that function in concert to drive precise spatiotemporal gene expression programs. However, the dynamics of the distal gene regulatory landscape and its function in the transcriptional reprogramming that underlies neurogenesis and neuronal activity remain largely unknown. Here, we performed a combinatorial analysis of genome-wide data sets for chromatin accessibility (FAIRE-seq) and the enhancer mark H3K27ac, revealing the highly dynamic nature of distal gene regulation during neurogenesis, which gets progressively restricted to distinct genomic regions as neurons acquire a post-mitotic, terminally differentiated state. We further find that the distal accessible and active regions serve as target sites for distinct transcription factors that function in a stage-specific manner to contribute to the transcriptional program underlying neuronal commitment and maturation. Mature neurons respond to a sustained activity of NMDA receptors by epigenetic reprogramming at a large number of distal regulatory regions as well as dramatic reorganization of super-enhancers. Such massive remodeling of the distal regulatory landscape in turn results in a transcriptome that confers a transient loss of neuronal identity and gain of cellular plasticity. Furthermore, NMDA receptor activity also induces many novel prosurvival genes that function in neuroprotective pathways. Taken together, these findings reveal the dynamics of the distal regulatory landscape during neurogenesis and uncover novel regulatory elements that function in concert with epigenetic mechanisms and transcription factors to generate the transcriptome underlying neuronal development and activity. PMID:26170447

Regulatory Teaching and Self-Regulated Learning in College Students: Confirmatory Validation Study of the IATLP Scales

ERIC Educational Resources Information Center

de la Fuente, Jesus; Zapata, Lucia; Martinez-Vicente, J. M.; Cardelle-Elawar, Maria; Sander, Paul; Justicia, Fernando; Pichardo, M. C.; Garcia-Belen, A. B.

2012-01-01

Introduction: The purpose of this study was to empirically confirm two conceptual interactions proposed by the IATLP Scales: (1) the combination of the teacher's regulatory teaching and the student's self-regulated learning, in order to produce satisfaction with learning; (2) the relationship of this interaction with students' prior…

Identification of active miRNA and transcription factor regulatory pathways in human obesity-related inflammation.

PubMed

Zhang, Xi-Mei; Guo, Lin; Chi, Mei-Hua; Sun, Hong-Mei; Chen, Xiao-Wen

2015-03-07

Obesity-induced chronic inflammation plays a fundamental role in the pathogenesis of metabolic syndrome (MS). Recently, a growing body of evidence supports that miRNAs are largely dysregulated in obesity and that specific miRNAs regulate obesity-associated inflammation. We applied an approach aiming to identify active miRNA-TF-gene regulatory pathways in obesity. Firstly, we detected differentially expressed genes (DEGs) and differentially expressed miRNAs (DEmiRs) from mRNA and miRNA expression profiles, respectively. Secondly, by mapping the DEGs and DEmiRs to the curated miRNA-TF-gene regulatory network as active seed nodes and connect them with their immediate neighbors, we obtained the potential active miRNA-TF-gene regulatory subnetwork in obesity. Thirdly, using a Breadth-First-Search (BFS) algorithm, we identified potential active miRNA-TF-gene regulatory pathways in obesity. Finally, through the hypergeometric test, we identified the active miRNA-TF-gene regulatory pathways that were significantly related to obesity. The potential active pathways with FDR < 0.0005 were considered to be the active miRNA-TF regulatory pathways in obesity. The union of the active pathways is visualized and identical nodes of the active pathways were merged. We identified 23 active miRNA-TF-gene regulatory pathways that were significantly related to obesity-related inflammation.

Combining inferred regulatory and reconstructed metabolic networks enhances phenotype prediction in yeast.

PubMed

Wang, Zhuo; Danziger, Samuel A; Heavner, Benjamin D; Ma, Shuyi; Smith, Jennifer J; Li, Song; Herricks, Thurston; Simeonidis, Evangelos; Baliga, Nitin S; Aitchison, John D; Price, Nathan D

2017-05-01

Gene regulatory and metabolic network models have been used successfully in many organisms, but inherent differences between them make networks difficult to integrate. Probabilistic Regulation Of Metabolism (PROM) provides a partial solution, but it does not incorporate network inference and underperforms in eukaryotes. We present an Integrated Deduced And Metabolism (IDREAM) method that combines statistically inferred Environment and Gene Regulatory Influence Network (EGRIN) models with the PROM framework to create enhanced metabolic-regulatory network models. We used IDREAM to predict phenotypes and genetic interactions between transcription factors and genes encoding metabolic activities in the eukaryote, Saccharomyces cerevisiae. IDREAM models contain many fewer interactions than PROM and yet produce significantly more accurate growth predictions. IDREAM consistently outperformed PROM using any of three popular yeast metabolic models and across three experimental growth conditions. Importantly, IDREAM's enhanced accuracy makes it possible to identify subtle synthetic growth defects. With experimental validation, these novel genetic interactions involving the pyruvate dehydrogenase complex suggested a new role for fatty acid-responsive factor Oaf1 in regulating acetyl-CoA production in glucose grown cells.

Identification of the Staphylococcus aureus vfrAB operon, a novel virulence factor regulatory locus.

PubMed

Bose, Jeffrey L; Daly, Seth M; Hall, Pamela R; Bayles, Kenneth W

2014-05-01

During a screen of the Nebraska Transposon Mutant Library, we identified 71 mutations in the Staphylococcus aureus genome that altered hemolysis on blood agar medium. Although many of these mutations disrupted genes known to affect the production of alpha-hemolysin, two of them were associated with an apparent operon, designated vfrAB, that had not been characterized previously. Interestingly, a ΔvfrB mutant exhibited only minor effects on the transcription of the hla gene, encoding alpha-hemolysin, when grown in broth, as well as on RNAIII, a posttranscriptional regulatory RNA important for alpha-hemolysin translation, suggesting that VfrB may function at the posttranscriptional level. Indeed, a ΔvfrB mutant had increased aur and sspAB protease expression under these conditions. However, disruption of the known secreted proteases in the ΔvfrB mutant did not restore hemolytic activity in the ΔvfrB mutant on blood agar. Further analysis revealed that, in contrast to the minor effects of VfrB on hla transcription when strains were cultured in liquid media, the level of hla transcription was decreased 50-fold in the absence of VfrB on solid media. These results demonstrate that while VfrB represses protease expression when strains are grown in broth, hla regulation is highly responsive to factors associated with growth on solid media. Intriguingly, the ΔvfrB mutant displayed increased pathogenesis in a model of S. aureus dermonecrosis, further highlighting the complexity of VfrB-dependent virulence regulation. The results of this study describe a phenotype associated with a class of highly conserved yet uncharacterized proteins found in Gram-positive bacteria, and they shed new light on the regulation of virulence factors necessary for S. aureus pathogenesis.

Mechanistic and regulatory aspects of intestinal iron absorption

PubMed Central

Gulec, Sukru; Anderson, Gregory J.

2014-01-01

Iron is an essential trace mineral that plays a number of important physiological roles in humans, including oxygen transport, energy metabolism, and neurotransmitter synthesis. Iron absorption by the proximal small bowel is a critical checkpoint in the maintenance of whole-body iron levels since, unlike most other essential nutrients, no regulated excretory systems exist for iron in humans. Maintaining proper iron levels is critical to avoid the adverse physiological consequences of either low or high tissue iron concentrations, as commonly occurs in iron-deficiency anemia and hereditary hemochromatosis, respectively. Exquisite regulatory mechanisms have thus evolved to modulate how much iron is acquired from the diet. Systemic sensing of iron levels is accomplished by a network of molecules that regulate transcription of the HAMP gene in hepatocytes, thus modulating levels of the serum-borne, iron-regulatory hormone hepcidin. Hepcidin decreases intestinal iron absorption by binding to the iron exporter ferroportin 1 on the basolateral surface of duodenal enterocytes, causing its internalization and degradation. Mucosal regulation of iron transport also occurs during low-iron states, via transcriptional (by hypoxia-inducible factor 2α) and posttranscriptional (by the iron-sensing iron-regulatory protein/iron-responsive element system) mechanisms. Recent studies demonstrated that these regulatory loops function in tandem to control expression or activity of key modulators of iron homeostasis. In health, body iron levels are maintained at appropriate levels; however, in several inherited disorders and in other pathophysiological states, iron sensing is perturbed and intestinal iron absorption is dysregulated. The iron-related phenotypes of these diseases exemplify the necessity of precisely regulating iron absorption to meet body demands. PMID:24994858

Transcriptional master regulator analysis in breast cancer genetic networks.

PubMed

Tovar, Hugo; García-Herrera, Rodrigo; Espinal-Enríquez, Jesús; Hernández-Lemus, Enrique

2015-12-01

Gene regulatory networks account for the delicate mechanisms that control gene expression. Under certain circumstances, gene regulatory programs may give rise to amplification cascades. Such transcriptional cascades are events in which activation of key-responsive transcription factors called master regulators trigger a series of gene expression events. The action of transcriptional master regulators is then important for the establishment of certain programs like cell development and differentiation. However, such cascades have also been related with the onset and maintenance of cancer phenotypes. Here we present a systematic implementation of a series of algorithms aimed at the inference of a gene regulatory network and analysis of transcriptional master regulators in the context of primary breast cancer cells. Such studies were performed in a highly curated database of 880 microarray gene expression experiments on biopsy-captured tissue corresponding to primary breast cancer and healthy controls. Biological function and biochemical pathway enrichment analyses were also performed to study the role that the processes controlled - at the transcriptional level - by such master regulators may have in relation to primary breast cancer. We found that transcription factors such as AGTR2, ZNF132, TFDP3 and others are master regulators in this gene regulatory network. Sets of genes controlled by these regulators are involved in processes that are well-known hallmarks of cancer. This kind of analyses may help to understand the most upstream events in the development of phenotypes, in particular, those regarding cancer biology. Copyright © 2015 Elsevier Ltd. All rights reserved.

Factor H: A Complement Regulator in Health and Disease, and a Mediator of Cellular Interactions

PubMed Central

Kopp, Anne; Hebecker, Mario; Svobodová, Eliška; Józsi, Mihály

2012-01-01

Complement is an essential part of innate immunity as it participates in host defense against infections, disposal of cellular debris and apoptotic cells, inflammatory processes and modulation of adaptive immune responses. Several soluble and membrane-bound regulators protect the host from the potentially deleterious effects of uncontrolled and misdirected complement activation. Factor H is a major soluble regulator of the alternative complement pathway, but it can also bind to host cells and tissues, protecting them from complement attack. Interactions of factor H with various endogenous ligands, such as pentraxins, extracellular matrix proteins and DNA are important in limiting local complement-mediated inflammation. Impaired regulatory as well as ligand and cell recognition functions of factor H, caused by mutations or autoantibodies, are associated with the kidney diseases: atypical hemolytic uremic syndrome and dense deposit disease and the eye disorder: age-related macular degeneration. In addition, factor H binds to receptors on host cells and is involved in adhesion, phagocytosis and modulation of cell activation. In this review we discuss current concepts on the physiological and pathophysiological roles of factor H in light of new data and recent developments in our understanding of the versatile roles of factor H as an inhibitor of complement activation and inflammation, as well as a mediator of cellular interactions. A detailed knowledge of the functions of factor H in health and disease is expected to unravel novel therapeutic intervention possibilities and to facilitate the development or improvement of therapies. PMID:24970127

A Network of HMG-box Transcription Factors Regulates Sexual Cycle in the Fungus Podospora anserina

PubMed Central

Ait Benkhali, Jinane; Coppin, Evelyne; Brun, Sylvain; Peraza-Reyes, Leonardo; Martin, Tom; Dixelius, Christina; Lazar, Noureddine; van Tilbeurgh, Herman; Debuchy, Robert

2013-01-01

High-mobility group (HMG) B proteins are eukaryotic DNA-binding proteins characterized by the HMG-box functional motif. These transcription factors play a pivotal role in global genomic functions and in the control of genes involved in specific developmental or metabolic pathways. The filamentous ascomycete Podospora anserina contains 12 HMG-box genes. Of these, four have been previously characterized; three are mating-type genes that control fertilization and development of the fruit-body, whereas the last one encodes a factor involved in mitochondrial DNA stability. Systematic deletion analysis of the eight remaining uncharacterized HMG-box genes indicated that none were essential for viability, but that seven were involved in the sexual cycle. Two HMG-box genes display striking features. PaHMG5, an ortholog of SpSte11 from Schizosaccharomyces pombe, is a pivotal activator of mating-type genes in P. anserina, whereas PaHMG9 is a repressor of several phenomena specific to the stationary phase, most notably hyphal anastomoses. Transcriptional analyses of HMG-box genes in HMG-box deletion strains indicated that PaHMG5 is at the hub of a network of several HMG-box factors that regulate mating-type genes and mating-type target genes. Genetic analyses revealed that this network also controls fertility genes that are not regulated by mating-type transcription factors. This study points to the critical role of HMG-box members in sexual reproduction in fungi, as 11 out of 12 members were involved in the sexual cycle in P. anserina. PaHMG5 and SpSte11 are conserved transcriptional regulators of mating-type genes, although P. anserina and S. pombe diverged 550 million years ago. Two HMG-box genes, SOX9 and its upstream regulator SRY, also play an important role in sex determination in mammals. The P. anserina and S. pombe mating-type genes and their upstream regulatory factor form a module of HMG-box genes analogous to the SRY/SOX9 module, revealing a commonality of sex

Integrating Transcriptomic and Proteomic Data Using Predictive Regulatory Network Models of Host Response to Pathogens

PubMed Central

Chasman, Deborah; Walters, Kevin B.; Lopes, Tiago J. S.; Eisfeld, Amie J.; Kawaoka, Yoshihiro; Roy, Sushmita

2016-01-01

Mammalian host response to pathogenic infections is controlled by a complex regulatory network connecting regulatory proteins such as transcription factors and signaling proteins to target genes. An important challenge in infectious disease research is to understand molecular similarities and differences in mammalian host response to diverse sets of pathogens. Recently, systems biology studies have produced rich collections of omic profiles measuring host response to infectious agents such as influenza viruses at multiple levels. To gain a comprehensive understanding of the regulatory network driving host response to multiple infectious agents, we integrated host transcriptomes and proteomes using a network-based approach. Our approach combines expression-based regulatory network inference, structured-sparsity based regression, and network information flow to infer putative physical regulatory programs for expression modules. We applied our approach to identify regulatory networks, modules and subnetworks that drive host response to multiple influenza infections. The inferred regulatory network and modules are significantly enriched for known pathways of immune response and implicate apoptosis, splicing, and interferon signaling processes in the differential response of viral infections of different pathogenicities. We used the learned network to prioritize regulators and study virus and time-point specific networks. RNAi-based knockdown of predicted regulators had significant impact on viral replication and include several previously unknown regulators. Taken together, our integrated analysis identified novel module level patterns that capture strain and pathogenicity-specific patterns of expression and helped identify important regulators of host response to influenza infection. PMID:27403523

A WRKY Transcription Factor Regulates Fe Translocation under Fe Deficiency.

PubMed

Yan, Jing Ying; Li, Chun Xiao; Sun, Li; Ren, Jiang Yuan; Li, Gui Xin; Ding, Zhong Jie; Zheng, Shao Jian

2016-07-01

Iron (Fe) deficiency affects plant growth and development, leading to reduction of crop yields and quality. Although the regulation of Fe uptake under Fe deficiency has been well studied in the past decade, the regulatory mechanism of Fe translocation inside the plants remains unknown. Here, we show that a WRKY transcription factor WRKY46 is involved in response to Fe deficiency. Lack of WRKY46 (wrky46-1 and wrky46-2 loss-of-function mutants) significantly affects Fe translocation from root to shoot and thus causes obvious chlorosis on the new leaves under Fe deficiency. Gene expression analysis reveals that expression of a nodulin-like gene (VACUOLAR IRON TRANSPORTER1-LIKE1 [VITL1]) is dramatically increased in wrky46-1 mutant. VITL1 expression is inhibited by Fe deficiency, while the expression of WRKY46 is induced in the root stele. Moreover, down-regulation of VITL1 expression can restore the chlorosis phenotype on wrky46-1 under Fe deficiency. Further yeast one-hybrid and chromatin immunoprecipitation experiments indicate that WRKY46 is capable of binding to the specific W-boxes present in the VITL1 promoter. In summary, our results demonstrate that WRKY46 plays an important role in the control of root-to-shoot Fe translocation under Fe deficiency condition via direct regulation of VITL1 transcript levels. © 2016 American Society of Plant Biologists. All Rights Reserved.

Capsicum annuum WRKY transcription factor d (CaWRKYd) regulates hypersensitive response and defense response upon Tobacco mosaic virus infection.

PubMed

Huh, Sung Un; Choi, La Mee; Lee, Gil-Je; Kim, Young Jin; Paek, Kyung-Hee

2012-12-01

WRKY transcription factors regulate biotic, abiotic, and developmental processes. In terms of plant defense, WRKY factors have important roles as positive and negative regulators via transcriptional regulation or protein-protein interaction. Here, we report the characterization of the gene encoding Capsicum annuum WRKY transcription factor d (CaWRKYd) isolated from microarray analysis in the Tobacco mosaic virus (TMV)-P(0)-inoculated hot pepper plants. CaWRKYd belongs to the WRKY IIa group, a very small clade in the WRKY subfamily, and WRKY IIa group has positive/negative regulatory roles in Arabidopsis and rice. CaWRKYd transcripts were induced by various plant defense-related hormone treatments and TMV-P(0) inoculation. Silencing of CaWRKYd affected TMV-P(0)-mediated hypersensitive response (HR) cell death and accumulation of TMV-P(0) coat protein in local and systemic leaves. Furthermore, expression of some pathogenesis-related (PR) genes and HR-related genes was reduced in the CaWRKYd-silenced plants compared with TRV2 vector control plants upon TMV-P(0) inoculation. CaWRKYd was confirmed to bind to the W-box. Thus CaWRKYd is a newly identified Capsicum annuum WRKY transcription factor that appears to be involved in TMV-P(0)-mediated HR cell death by regulating downstream gene expression. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

The WRKY Transcription Factor WRKY71/EXB1 Controls Shoot Branching by Transcriptionally Regulating RAX Genes in Arabidopsis

PubMed Central

Guo, Dongshu; Zhang, Jinzhe; Wang, Xinlei; Han, Xiang; Wei, Baoye; Yu, Hao; Huang, Qingpei

2015-01-01

Plant shoot branching is pivotal for developmental plasticity and crop yield. The formation of branch meristems is regulated by several key transcription factors including REGULATOR OF AXILLARY MERISTEMS1 (RAX1), RAX2, and RAX3. However, the regulatory network of shoot branching is still largely unknown. Here, we report the identification of EXCESSIVE BRANCHES1 (EXB1), which affects axillary meristem (AM) initiation and bud activity. Overexpression of EXB1 in the gain-of-function mutant exb1-D leads to severe bushy and dwarf phenotypes, which result from excessive AM initiation and elevated bud activities. EXB1 encodes the WRKY transcription factor WRKY71, which has demonstrated transactivation activities. Disruption of WRKY71/EXB1 by chimeric repressor silencing technology leads to fewer branches, indicating that EXB1 plays important roles in the control of shoot branching. We demonstrate that EXB1 controls AM initiation by positively regulating the transcription of RAX1, RAX2, and RAX3. Disruption of the RAX genes partially rescues the branching phenotype caused by EXB1 overexpression. We further show that EXB1 also regulates auxin homeostasis in control of shoot branching. Our data demonstrate that EXB1 plays pivotal roles in shoot branching by regulating both transcription of RAX genes and auxin pathways. PMID:26578700

Pharmaceutical Regulatory Framework in Ethiopia: A Critical Evaluation of Its Legal Basis and Implementation.

PubMed

Suleman, Sultan; Woliyi, Abdulkadir; Woldemichael, Kifle; Tushune, Kora; Duchateau, Luc; Degroote, Agnes; Vancauwenberghe, Roy; Bracke, Nathalie; De Spiegeleer, Bart

2016-05-01

pharmaceutical chain. An archival review, an in-depth interview of key informants and an institutions-based cross-sectional survey study were conducted during March to April 2013. The comprehensiveness of the pharmaceutical law to protect public health relative to three selected African countries (South Africa, Tanzania and Uganda) and European Union, and implementation was assessed. The study revealed that Ethiopia does have a written national drug policy upon which the Medicines Regulatory Proclamation 661/2009 is based. According to this proclamation, the Ethiopian The Food, Medicines and Healthcare Administration and Control Authority is mandated to execute the regulatory activities as per the council of ministers regulation 189/2010. The legal framework for pharmaceutical regulation of Ethiopia was founded to fulfill all the medicines regulatory functions potentially enabling to combat illegal, substandard and falsified medicines and illegal establishments. Moreover, all the key informants witnessed that the government is commited and proclamation 661/2009 is comprehensive, but they stressed the compelling need of regulatory tools for effective implementation. From the institution-based cross-sectional study, it was revealed that there exist illegal sources formedicine in the pharmaceutical market. The main reasons for their existence were regulatory factors including weak regulatory enforcement (64.5%), lack of informal market control (60.8%), weak port control (50.0%), and poor cooperation between executive bodies (39.6%); and resource constraint (27.8%), which is an institutional factor. From legislative point of view, the medicines regulatory framework in Ethiopia fulfils all regulatory functions required for effective medicines regulation. However, the existence of the legislation by its own is not a guarantee to prevent the existence of unauthorized/illegal medicine sources since this requires effective implementation of the legislation, which is in fact affected by

Updated regulation curation model at the Saccharomyces Genome Database

PubMed Central

Engel, Stacia R; Skrzypek, Marek S; Hellerstedt, Sage T; Wong, Edith D; Nash, Robert S; Weng, Shuai; Binkley, Gail; Sheppard, Travis K; Karra, Kalpana; Cherry, J Michael

2018-01-01

Abstract The Saccharomyces Genome Database (SGD) provides comprehensive, integrated biological information for the budding yeast Saccharomyces cerevisiae, along with search and analysis tools to explore these data, enabling the discovery of functional relationships between sequence and gene products in fungi and higher organisms. We have recently expanded our data model for regulation curation to address regulation at the protein level in addition to transcription, and are presenting the expanded data on the ‘Regulation’ pages at SGD. These pages include a summary describing the context under which the regulator acts, manually curated and high-throughput annotations showing the regulatory relationships for that gene and a graphical visualization of its regulatory network and connected networks. For genes whose products regulate other genes or proteins, the Regulation page includes Gene Ontology enrichment analysis of the biological processes in which those targets participate. For DNA-binding transcription factors, we also provide other information relevant to their regulatory function, such as DNA binding site motifs and protein domains. As with other data types at SGD, all regulatory relationships and accompanying data are available through YeastMine, SGD’s data warehouse based on InterMine. Database URL: http://www.yeastgenome.org PMID:29688362

Scientists versus Regulators: Precaution, Novelty & Regulatory Oversight as Predictors of Perceived Risks of Engineered Nanomaterials

PubMed Central

Beaudrie, Christian E. H.; Satterfield, Terre; Kandlikar, Milind; Harthorn, Barbara H.

2014-01-01

Engineered nanoscale materials (ENMs) present a difficult challenge for risk assessors and regulators. Continuing uncertainty about the potential risks of ENMs means that expert opinion will play an important role in the design of policies to minimize harmful implications while supporting innovation. This research aims to shed light on the views of ‘nano experts’ to understand which nanomaterials or applications are regarded as more risky than others, to characterize the differences in risk perceptions between expert groups, and to evaluate the factors that drive these perceptions. Our analysis draws from a web-survey (N = 404) of three groups of US and Canadian experts: nano-scientists and engineers, nano-environmental health and safety scientists, and regulatory scientists and decision-makers. Significant differences in risk perceptions were found across expert groups; differences found to be driven by underlying attitudes and perceptions characteristic of each group. Nano-scientists and engineers at the upstream end of the nanomaterial life cycle perceived the lowest levels of risk, while those who are responsible for assessing and regulating risks at the downstream end perceived the greatest risk. Perceived novelty of nanomaterial risks, differing preferences for regulation (i.e. the use of precaution versus voluntary or market-based approaches), and perceptions of the risk of technologies in general predicted variation in experts' judgments of nanotechnology risks. Our findings underscore the importance of involving a diverse selection of experts, particularly those with expertise at different stages along the nanomaterial lifecycle, during policy development. PMID:25222742

A prior-based integrative framework for functional transcriptional regulatory network inference

PubMed Central

Siahpirani, Alireza F.

2017-01-01

Abstract Transcriptional regulatory networks specify regulatory proteins controlling the context-specific expression levels of genes. Inference of genome-wide regulatory networks is central to understanding gene regulation, but remains an open challenge. Expression-based network inference is among the most popular methods to infer regulatory networks, however, networks inferred from such methods have low overlap with experimentally derived (e.g. ChIP-chip and transcription factor (TF) knockouts) networks. Currently we have a limited understanding of this discrepancy. To address this gap, we first develop a regulatory network inference algorithm, based on probabilistic graphical models, to integrate expression with auxiliary datasets supporting a regulatory edge. Second, we comprehensively analyze our and other state-of-the-art methods on different expression perturbation datasets. Networks inferred by integrating sequence-specific motifs with expression have substantially greater agreement with experimentally derived networks, while remaining more predictive of expression than motif-based networks. Our analysis suggests natural genetic variation as the most informative perturbation for network inference, and, identifies core TFs whose targets are predictable from expression. Multiple reasons make the identification of targets of other TFs difficult, including network architecture and insufficient variation of TF mRNA level. Finally, we demonstrate the utility of our inference algorithm to infer stress-specific regulatory networks and for regulator prioritization. PMID:27794550

Subnuclear organization and trafficking of regulatory proteins: implications for biological control and cancer.

PubMed

Stein, G S; van Wijnen, A J; Stein, J L; Lian, J B; Montecino, M; Zaidi, K; Javed, A

2000-01-01

The regulated and regulatory components that interrelate nuclear structure and function must be experimentally established. A formidable challenge is to define further the control of transcription factor targeting to acceptor sites associated with the nuclear matrix. It will be important to determine whether acceptor proteins are associated with a pre-existing core-filament structural lattice or whether a compositely organized scaffold of regulatory factors is dynamically assembled. An inclusive model for all steps in the targeting of proteins to subnuclear sites cannot yet be proposed. However, this model must account for the apparent diversity of intranuclear targeting signals. It is also important to assess the extent to which regulatory discrimination is mediated by subnuclear domain-specific trafficking signals. Furthermore, the checkpoints that monitor subnuclear distribution of regulatory factors and the sorting steps that ensure both structural and functional fidelity of nuclear domains in which replication and expression of genes occur must be biochemically and mechanistically defined. There is emerging recognition that placement of regulatory components of gene expression must be temporally and spatially coordinated to facilitate biological control. The consequences of breaches in nuclear structure-function relationships are observed in an expanding series of diseases that include cancer [Weis et al., 1994; Rogaia et al., 1997; Yano et al., 1997; Rowley, 1998; Zeng et al., 1998; McNeil et al., 1999; Tao and Levine, 1999a] and neurological disorders [Skinner et al., 1997]. As the repertoire of architecture-associated regulatory factors and cofactors expands, workers in the field are becoming increasingly confident that nuclear organization contributes significantly to control of transcription. To gain increased appreciation for the complexities of subnuclear organization and gene regulation, we must continue to characterize mechanisms that direct

The Alternative Sigma Factor SigX Controls Bacteriocin Synthesis and Competence, the Two Quorum Sensing Regulated Traits in Streptococcus mutans

PubMed Central

Reck, Michael; Tomasch, Jürgen; Wagner-Döbler, Irene

2015-01-01

Two small quorum sensing (QS) peptides regulate competence in S. mutans in a cell density dependent manner: XIP (sigX inducing peptide) and CSP (competence stimulating peptide). Depending on the environmental conditions isogenic S. mutans cells can split into a competent and non-competent subpopulation. The origin of this population heterogeneity has not been experimentally determined and it is unknown how the two QS systems are connected. We developed a toolbox of single and dual fluorescent reporter strains and systematically knocked out key genes of the competence signaling cascade in the reporter strain backgrounds. By following signal propagation on the single cell level we discovered that the master regulator of competence, the alternative sigma factor SigX, directly controls expression of the response regulator for bacteriocin synthesis ComE. Consequently, a SigX binding motif (cin-box) was identified in the promoter region of comE. Overexpressing the genetic components involved in competence development demonstrated that ComRS represents the origin of bimodality and determines the modality of the downstream regulators SigX and ComE. Moreover these analysis showed that there is no direct regulatory link between the two QS signaling cascades. Competence is induced through a hierarchical XIP signaling cascade, which has no regulatory input from the CSP cascade. CSP exclusively regulates bacteriocin synthesis. We suggest renaming it mutacin inducing peptide (MIP). Finally, using phosphomimetic comE mutants we show that unimodal bacteriocin production is controlled posttranslationally, thus solving the puzzling observation that in complex media competence is observed in a subpopulation only, while at the same time all cells produce bacteriocins. The control of both bacteriocin synthesis and competence through the alternative sigma-factor SigX suggests that S. mutans increases its genetic repertoire via QS controlled predation on neighboring species in its

Regulation of RE1 Protein Silencing Transcription Factor (REST) Expression by HIP1 Protein Interactor (HIPPI)*

PubMed Central

Datta, Moumita; Bhattacharyya, Nitai P.

2011-01-01

Earlier we have shown that the proapoptotic protein HIPPI (huntingtin interacting protein 1 (HIP1) protein interactor) along with its molecular partner HIP1 could regulate transcription of the caspase-1 gene. Here we report that RE1-silencing transcription factor/neuron-restrictive silencer factor (REST/NRSF) is a new transcriptional target of HIPPI. HIPPI could bind to the promoter of REST and increased its expression in neuronal as well as non-neuronal cells. Such activation of REST down-regulated expression of REST target genes, such as brain-derived neurotrophic factor (BDNF) or proenkephalin (PENK). The ability of HIPPI to activate REST gene transcription was dependent on HIP1, the nuclear transporter of HIPPI. Using a Huntington disease cell model, we have demonstrated that feeble interaction of HIP1 with mutant huntingtin protein resulted in increased nuclear accumulation of HIPPI and HIP1, leading to higher occupancy of HIPPI at the REST promoter, triggering its transcriptional activation and consequent repression of REST target genes. This novel transcription regulatory mechanism of REST by HIPPI may contribute to the deregulation of transcription observed in the cell model of Huntington disease. PMID:21832040

Regulation of RE1 protein silencing transcription factor (REST) expression by HIP1 protein interactor (HIPPI).

PubMed

Datta, Moumita; Bhattacharyya, Nitai P

2011-09-30

Earlier we have shown that the proapoptotic protein HIPPI (huntingtin interacting protein 1 (HIP1) protein interactor) along with its molecular partner HIP1 could regulate transcription of the caspase-1 gene. Here we report that RE1-silencing transcription factor/neuron-restrictive silencer factor (REST/NRSF) is a new transcriptional target of HIPPI. HIPPI could bind to the promoter of REST and increased its expression in neuronal as well as non-neuronal cells. Such activation of REST down-regulated expression of REST target genes, such as brain-derived neurotrophic factor (BDNF) or proenkephalin (PENK). The ability of HIPPI to activate REST gene transcription was dependent on HIP1, the nuclear transporter of HIPPI. Using a Huntington disease cell model, we have demonstrated that feeble interaction of HIP1 with mutant huntingtin protein resulted in increased nuclear accumulation of HIPPI and HIP1, leading to higher occupancy of HIPPI at the REST promoter, triggering its transcriptional activation and consequent repression of REST target genes. This novel transcription regulatory mechanism of REST by HIPPI may contribute to the deregulation of transcription observed in the cell model of Huntington disease.

Regulatory divergence between parental alleles determines gene expression patterns in hybrids.

PubMed

Combes, Marie-Christine; Hueber, Yann; Dereeper, Alexis; Rialle, Stéphanie; Herrera, Juan-Carlos; Lashermes, Philippe

2015-03-29

Both hybridization and allopolyploidization generate novel phenotypes by conciliating divergent genomes and regulatory networks in the same cellular context. To understand the rewiring of gene expression in hybrids, the total expression of 21,025 genes and the allele-specific expression of over 11,000 genes were quantified in interspecific hybrids and their parental species, Coffea canephora and Coffea eugenioides using RNA-seq technology. Between parental species, cis- and trans-regulatory divergences affected around 32% and 35% of analyzed genes, respectively, with nearly 17% of them showing both. The relative importance of trans-regulatory divergences between both species could be related to their low genetic divergence and perennial habit. In hybrids, among divergently expressed genes between parental species and hybrids, 77% was expressed like one parent (expression level dominance), including 65% like C. eugenioides. Gene expression was shown to result from the expression of both alleles affected by intertwined parental trans-regulatory factors. A strong impact of C. eugenioides trans-regulatory factors on the upregulation of C. canephora alleles was revealed. The gene expression patterns appeared determined by complex combinations of cis- and trans-regulatory divergences. In particular, the observed biased expression level dominance seemed to be derived from the asymmetric effects of trans-regulatory parental factors on regulation of alleles. More generally, this study illustrates the effects of divergent trans-regulatory parental factors on the gene expression pattern in hybrids. The characteristics of the transcriptional response to hybridization appear to be determined by the compatibility of gene regulatory networks and therefore depend on genetic divergences between the parental species and their evolutionary history. © The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

Abundant raw material for cis-regulatory evolution in humans

NASA Technical Reports Server (NTRS)

Rockman, Matthew V.; Wray, Gregory A.

2002-01-01

Changes in gene expression and regulation--due in particular to the evolution of cis-regulatory DNA sequences--may underlie many evolutionary changes in phenotypes, yet little is known about the distribution of such variation in populations. We present in this study the first survey of experimentally validated functional cis-regulatory polymorphism. These data are derived from more than 140 polymorphisms involved in the regulation of 107 genes in Homo sapiens, the eukaryote species with the most available data. We find that functional cis-regulatory variation is widespread in the human genome and that the consequent variation in gene expression is twofold or greater for 63% of the genes surveyed. Transcription factor-DNA interactions are highly polymorphic, and regulatory interactions have been gained and lost within human populations. On average, humans are heterozygous at more functional cis-regulatory sites (>16,000) than at amino acid positions (<13,000), in part because of an overrepresentation among the former in multiallelic tandem repeat variation, especially (AC)(n) dinucleotide microsatellites. The role of microsatellites in gene expression variation may provide a larger store of heritable phenotypic variation, and a more rapid mutational input of such variation, than has been realized. Finally, we outline the distinctive consequences of cis-regulatory variation for the genotype-phenotype relationship, including ubiquitous epistasis and genotype-by-environment interactions, as well as underappreciated modes of pleiotropy and overdominance. Ordinary small-scale mutations contribute to pervasive variation in transcription rates and consequently to patterns of human phenotypic variation.

Rhodobase, a meta-analytical tool for reconstructing gene regulatory networks in a model photosynthetic bacterium.

PubMed

Moskvin, Oleg V; Bolotin, Dmitry; Wang, Andrew; Ivanov, Pavel S; Gomelsky, Mark

2011-02-01

We present Rhodobase, a web-based meta-analytical tool for analysis of transcriptional regulation in a model anoxygenic photosynthetic bacterium, Rhodobacter sphaeroides. The gene association meta-analysis is based on the pooled data from 100 of R. sphaeroides whole-genome DNA microarrays. Gene-centric regulatory networks were visualized using the StarNet approach (Jupiter, D.C., VanBuren, V., 2008. A visual data mining tool that facilitates reconstruction of transcription regulatory networks. PLoS ONE 3, e1717) with several modifications. We developed a means to identify and visualize operons and superoperons. We designed a framework for the cross-genome search for transcription factor binding sites that takes into account high GC-content and oligonucleotide usage profile characteristic of the R. sphaeroides genome. To facilitate reconstruction of directional relationships between co-regulated genes, we screened upstream sequences (-400 to +20bp from start codons) of all genes for putative binding sites of bacterial transcription factors using a self-optimizing search method developed here. To test performance of the meta-analysis tools and transcription factor site predictions, we reconstructed selected nodes of the R. sphaeroides transcription factor-centric regulatory matrix. The test revealed regulatory relationships that correlate well with the experimentally derived data. The database of transcriptional profile correlations, the network visualization engine and the optimized search engine for transcription factor binding sites analysis are available at http://rhodobase.org. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Genome-wide analysis of the regulatory function mediated by the small regulatory psm-mec RNA of methicillin-resistant Staphylococcus aureus.

PubMed

Cheung, Gordon Y C; Villaruz, Amer E; Joo, Hwang-Soo; Duong, Anthony C; Yeh, Anthony J; Nguyen, Thuan H; Sturdevant, Daniel E; Queck, S Y; Otto, M

2014-07-01

Several methicillin resistance (SCCmec) clusters characteristic of hospital-associated methicillin-resistant Staphylococcus aureus (MRSA) strains harbor the psm-mec locus. In addition to encoding the cytolysin, phenol-soluble modulin (PSM)-mec, this locus has been attributed gene regulatory functions. Here we employed genome-wide transcriptional profiling to define the regulatory function of the psm-mec locus. The immune evasion factor protein A emerged as the primary conserved and strongly regulated target of psm-mec, an effect we show is mediated by the psm-mec RNA. Furthermore, the psm-mec locus exerted regulatory effects that were more moderate in extent. For example, expression of PSM-mec limited expression of mecA, thereby decreasing methicillin resistance. Our study shows that the psm-mec locus has a rare dual regulatory RNA and encoded cytolysin function. Furthermore, our findings reveal a specific mechanism underscoring the recently emerging concept that S. aureus strains balance pronounced virulence and high expression of antibiotic resistance. Published by Elsevier GmbH.

Regulatory Relief for Accreditation. Position Paper

ERIC Educational Resources Information Center

Council for Higher Education Accreditation, 2017

2017-01-01

The purpose of this Council for Higher Education Accreditation Position Paper is to offer proposals for the reduction of federal regulation as this applies to accreditation, whether in law, regulation or sub-regulatory guidance, acknowledging that the major challenge is at the regulatory/subregulatory levels. This reduction is not intended nor…

Modularized Smad-regulated TGFβ signaling pathway.

PubMed

Li, Yongfeng; Wang, Minli; Carra, Claudio; Cucinotta, Francis A

2012-12-01

The transforming Growth Factor β (TGFβ) signaling pathway is a prominent regulatory signaling pathway controlling various important cellular processes. TGFβ signaling can be induced by several factors including ionizing radiation. The pathway is regulated in a negative feedback loop through promoting the nuclear import of the regulatory Smads and a subsequent expression of inhibitory Smad7, that forms ubiquitin ligase with Smurf2, targeting active TGFβ receptors for degradation. In this work, we proposed a mathematical model to study the Smad-regulated TGFβ signaling pathway. By modularization, we are able to analyze mathematically each component subsystem and recover the nonlinear dynamics of the entire network system. Meanwhile the excitability, a common feature observed in the biological systems, in the TGFβ signaling pathway is discussed and supported as well by numerical simulation, indicating the robustness of the model. Published by Elsevier Inc.

Identification of potential target genes and related regulatory transcription factors in spontaneous hairline fracture induced by hypervitaminosis A.

PubMed

Peng, Chuangang; Yang, Qi; Wei, Bo; Liu, Yong; Li, Yuxiang; Gu, Dawei; Yin, Guochao; Wang, Bo; Xu, Dehui; Zhang, Xuebing; Kong, Daliang

2017-07-01

The aim was to research the molecular changes of bone cells induced by excessive dose of vitamin A, and analyze molecular mechanism underlying spontaneous fracture. The gene expression profile of GSE29859, including 4 cortical bone marrow samples with excessive doses of Vitamin A and 4 control cortical bone marrow samples, was obtained from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DGEs) between cortical bone marrow samples and control samples were screened out and pathway enrichment analysis was undertaken. Based on the MSigDB database, the potential regulatory transcription factors (TFs) were identified. A total of 373 DEGs including 342 up- and 31 down-regulated genes were identified. These DEGs were significantly enriched in pathways of protein processing in endoplasmic reticulum, ubiquitin mediated proteolysis and glycerophospholipid metabolism. Finally, the most significant regulatory TFs were obtained, including E2F Transcription Factor 1 (E2F1), GA Binding Protein Transcription Factor (GABP), Nuclear Factor, Erythroid 2-Like 2 (NRF2) and ELK1, Member of ETS Oncogene Family (ELK1). Key TFs including E2F1, GABP, NRF2 and ELK1 and their targets genes such as Ube2d3, Uba1, Phb2 and Tomm22 may play potential key roles in spontaneous fracture induced by hypervitaminosis A. The pathways of protein processing in endoplasmic reticulum, ubiquitin mediated proteolysis and glycerophospholipid metabolism may be key mechanisms involved in spontaneous fracture induced by hypervitaminosis A. Our findings will provide new insights for the target selection in clinical application to prevent spontaneous fracture induced by hypervitaminosis A. Copyright © 2017 Elsevier Ltd. All rights reserved.

Regulatory guidance concerning the applicability of the Federal Motor Carrier Safety regulations to texting by commercial motor vehicle drivers

DOT National Transportation Integrated Search

2010-01-10

The FMCSA announces regulatory guidance concerning texting while driving a commercial motor vehicle (CMV). The guidance is applicable to all interstate drivers of CMVs subject to the Federal Motor Carrier Safety Regulations (FMCSRs).

Regulatory cross-cutting topics for fuel cycle facilities.

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

Denman, Matthew R.; Brown, Jason; Goldmann, Andrew Scott

This report overviews crosscutting regulatory topics for nuclear fuel cycle facilities for use in the Fuel Cycle Research & Development Nuclear Fuel Cycle Evaluation and Screening study. In particular, the regulatory infrastructure and analysis capability is assessed for the following topical areas: Fire Regulations (i.e., how applicable are current Nuclear Regulatory Commission (NRC) and/or International Atomic Energy Agency (IAEA) fire regulations to advance fuel cycle facilities) Consequence Assessment (i.e., how applicable are current radionuclide transportation tools to support risk-informed regulations and Level 2 and/or 3 PRA) While not addressed in detail, the following regulatory topic is also discussed: Integrated Security,more » Safeguard and Safety Requirement (i.e., how applicable are current Nuclear Regulatory Commission (NRC) regulations to future fuel cycle facilities which will likely be required to balance the sometimes conflicting Material Accountability, Security, and Safety requirements.)« less

Post-transcriptional regulatory network of epithelial-to-mesenchymal and mesenchymal-to-epithelial transitions

PubMed Central

2014-01-01

Epithelial-to-mesenchymal transition (EMT) and its reverse process, mesenchymal-to-epithelial transition (MET), play important roles in embryogenesis, stem cell biology, and cancer progression. EMT can be regulated by many signaling pathways and regulatory transcriptional networks. Furthermore, post-transcriptional regulatory networks regulate EMT; these networks include the long non-coding RNA (lncRNA) and microRNA (miRNA) families. Specifically, the miR-200 family, miR-101, miR-506, and several lncRNAs have been found to regulate EMT. Recent studies have illustrated that several lncRNAs are overexpressed in various cancers and that they can promote tumor metastasis by inducing EMT. MiRNA controls EMT by regulating EMT transcription factors or other EMT regulators, suggesting that lncRNAs and miRNA are novel therapeutic targets for the treatment of cancer. Further efforts have shown that non-coding-mediated EMT regulation is closely associated with epigenetic regulation through promoter methylation (e.g., miR-200 or miR-506) and protein regulation (e.g., SET8 via miR-502). The formation of gene fusions has also been found to promote EMT in prostate cancer. In this review, we discuss the post-transcriptional regulatory network that is involved in EMT and MET and how targeting EMT and MET may provide effective therapeutics for human disease. PMID:24598126

Quaking and PTB control overlapping splicing regulatory networks during muscle cell differentiation

PubMed Central

Hall, Megan P.; Nagel, Roland J.; Fagg, W. Samuel; Shiue, Lily; Cline, Melissa S.; Perriman, Rhonda J.; Donohue, John Paul; Ares, Manuel

2013-01-01

Alternative splicing contributes to muscle development, but a complete set of muscle-splicing factors and their combinatorial interactions are unknown. Previous work identified ACUAA (“STAR” motif) as an enriched intron sequence near muscle-specific alternative exons such as Capzb exon 9. Mass spectrometry of myoblast proteins selected by the Capzb exon 9 intron via RNA affinity chromatography identifies Quaking (QK), a protein known to regulate mRNA function through ACUAA motifs in 3′ UTRs. We find that QK promotes inclusion of Capzb exon 9 in opposition to repression by polypyrimidine tract-binding protein (PTB). QK depletion alters inclusion of 406 cassette exons whose adjacent intron sequences are also enriched in ACUAA motifs. During differentiation of myoblasts to myotubes, QK levels increase two- to threefold, suggesting a mechanism for QK-responsive exon regulation. Combined analysis of the PTB- and QK-splicing regulatory networks during myogenesis suggests that 39% of regulated exons are under the control of one or both of these splicing factors. This work provides the first evidence that QK is a global regulator of splicing during muscle development in vertebrates and shows how overlapping splicing regulatory networks contribute to gene expression programs during differentiation. PMID:23525800

Jasmonate regulates the inducer of cbf expression-C-repeat binding factor/DRE binding factor1 cascade and freezing tolerance in Arabidopsis.

PubMed

Hu, Yanru; Jiang, Liqun; Wang, Fang; Yu, Diqiu

2013-08-01

The inducer of cbf expression (ICE)-C-repeat binding factor/DRE binding factor1 (CBF/DREB1) transcriptional pathway plays a critical role in modulating cold stress responses in Arabidopsis thaliana. Dissecting crucial upstream regulatory signals or components of the ICE-CBF/DREB1 cascade will enhance our understanding of plant cold-tolerance mechanisms. Here, we show that jasmonate positively regulates plant responses to freezing stress in Arabidopsis. Exogenous application of jasmonate significantly enhanced plant freezing tolerance with or without cold acclimation. By contrast, blocking endogenous jasmonate biosynthesis and signaling rendered plants hypersensitive to freezing stress. Consistent with the positive role of jasmonate in freezing stress, production of endogenous jasmonate was triggered by cold treatment. In addition, cold induction of genes acting in the CBF/DREB1 signaling pathway was upregulated by jasmonate. Further investigation revealed that several jasmonate ZIM-domain (JAZ) proteins, the repressors of jasmonate signaling, physically interact with ICE1 and ICE2 transcription factors. JAZ1 and JAZ4 repress the transcriptional function of ICE1, thereby attenuating the expression of its regulon. Consistent with this, overexpression of JAZ1 or JAZ4 represses freezing stress responses of Arabidopsis. Taken together, our study provides evidence that jasmonate functions as a critical upstream signal of the ICE-CBF/DREB1 pathway to positively regulate Arabidopsis freezing tolerance.

An apple MYB transcription factor, MdMYB3, is involved in regulation of anthocyanin biosynthesis and flower development

PubMed Central

2013-01-01

Background Red coloration of fruit is an important trait in apple, and it is mainly attributed to the accumulation of anthocyanins, a class of plant flavonoid metabolites. Anthocyanin biosynthesis is genetically determined by structural and regulatory genes. Plant tissue pigmentation patterns are mainly controlled by expression profiles of regulatory genes. Among these regulatory genes are MYB transcription factors (TFs), wherein the class of two-repeats (R2R3) is deemed the largest, and these are associated with the anthocyanin biosynthesis pathway. Although three MdMYB genes, almost identical in nucleotide sequences, have been identified in apple, it is likely that there are other R2R3 MYB TFs that are present in the apple genome that are also involved in the regulation of coloration of red color pigmentation of the skin of apple fruits. Results In this study, a novel R2R3 MYB gene has been isolated and characterized in apple. This MYB gene is closely related to the Arabidopsis thaliana AtMYB3, and has been designated as MdMYB3. This TF belongs to the subgroup 4 R2R3 family of plant MYB transcription factors. This apple MdMYB3 gene is mapped onto linkage group 15 of the integrated apple genetic map. Transcripts of MdMYB3 are detected in all analyzed tissues including leaves, flowers, and fruits. However, transcripts of MdMYB3 are higher in excocarp of red-skinned apple cultivars than that in yellowish-green skinned apple cultivars. When this gene is ectopically expressed in Nicotiana tabacum cv. Petite Havana SR1, flowers of transgenic tobacco lines carrying MdMYB3 have exhibited increased pigmentation and accumulate higher levels of anthocyanins and flavonols than wild-type flowers. Overexpression of MdMYB3 has resulted in transcriptional activation of several flavonoid pathway genes, including CHS, CHI, UFGT, and FLS. Moreover, peduncles of flowers and styles of pistils of transgenic plants overexpressing MdMYB3 are longer than those of wild-type plants, thus

Non-additive interactions involving two distinct elements mediate sloppy-paired regulation by pair-rule transcription factors

PubMed Central

Prazak, Lisa; Fujioka, Miki; Gergen, J. Peter

2010-01-01

The relatively simple combinatorial rules responsible for establishing the initial metameric expression of sloppy-paired-1 (slp1) in the Drosophila blastoderm embryo make this system an attractive model for investigating the mechanism of regulation by pair rule transcription factors. This investigation of slp1 cis-regulatory architecture identifies two distinct elements, a proximal early stripe element (PESE) and a distal early stripe element (DESE) located from −3.1 kb to −2.5 kb and from −8.1 kb to −7.1 kb upstream of the slp1 promoter, respectively, that mediate this early regulation. The proximal element expresses only even-numbered stripes and mediates repression by Even-skipped (Eve) as well as by the combination of Runt and Fushi-tarazu (Ftz). A 272 basepair sub-element of PESE retains Eve-dependent repression, but is expressed throughout the even-numbered parasegments due to the loss of repression by Runt and Ftz. In contrast, the distal element expresses both odd and even-numbered stripes and also drives inappropriate expression in the anterior half of the odd-numbered parasegments due to an inability to respond to repression by Eve. Importantly, a composite reporter gene containing both early stripe elements recapitulates pair-rule gene-dependent regulation in a manner beyond what is expected from combining their individual patterns. These results indicate interactions involving distinct cis-elements contribute to the proper integration of pair-rule regulatory information. A model fully accounting for these results proposes that metameric slp1 expression is achieved through the Runt-dependent regulation of interactions between these two pair-rule response elements and the slp1 promoter. PMID:20435028

A global regulatory science agenda for vaccines.

PubMed

Elmgren, Lindsay; Li, Xuguang; Wilson, Carolyn; Ball, Robert; Wang, Junzhi; Cichutek, Klaus; Pfleiderer, Michael; Kato, Atsushi; Cavaleri, Marco; Southern, James; Jivapaisarnpong, Teeranart; Minor, Philip; Griffiths, Elwyn; Sohn, Yeowon; Wood, David

2013-04-18

The Decade of Vaccines Collaboration and development of the Global Vaccine Action Plan provides a catalyst and unique opportunity for regulators worldwide to develop and propose a global regulatory science agenda for vaccines. Regulatory oversight is critical to allow access to vaccines that are safe, effective, and of assured quality. Methods used by regulators need to constantly evolve so that scientific and technological advances are applied to address challenges such as new products and technologies, and also to provide an increased understanding of benefits and risks of existing products. Regulatory science builds on high-quality basic research, and encompasses at least two broad categories. First, there is laboratory-based regulatory science. Illustrative examples include development of correlates of immunity; or correlates of safety; or of improved product characterization and potency assays. Included in such science would be tools to standardize assays used for regulatory purposes. Second, there is science to develop regulatory processes. Illustrative examples include adaptive clinical trial designs; or tools to analyze the benefit-risk decision-making process of regulators; or novel pharmacovigilance methodologies. Included in such science would be initiatives to standardize regulatory processes (e.g., definitions of terms for adverse events [AEs] following immunization). The aim of a global regulatory science agenda is to transform current national efforts, mainly by well-resourced regulatory agencies, into a coordinated action plan to support global immunization goals. This article provides examples of how regulatory science has, in the past, contributed to improved access to vaccines, and identifies gaps that could be addressed through a global regulatory science agenda. The article also identifies challenges to implementing a regulatory science agenda and proposes strategies and actions to fill these gaps. A global regulatory science agenda will enable

A possible regulatory link between Twist 1 and PPARγ gene regulation in 3T3-L1 adipocytes.

PubMed

Ren, Rui; Chen, Zhufeng; Zhao, Xia; Sun, Tao; Zhang, Yuchao; Chen, Jie; Lu, Sumei; Ma, Wanshan

2016-11-08

Peroxisome proliferator-activated receptor γ (PPARγ) is a critical gene that regulates the function of adipocytes. Therefore, studies on the molecular regulation mechanism of PPARγ are important to understand the function of adipose tissue. Twist 1 is another important functional gene in adipose tissue, and hundreds of genes are regulated by Twist 1. The aim of this study was to investigate the regulation of Twist 1 and PPARγ expression in 3T3-L1 mature adipocytes. We induced differentiation in 3T3-L1 preadipocytes and examined alterations in Twist 1 and PPARγ expression. We used the PPARγ agonist pioglitazone and the PPARγ antagonist T0070907 to investigate the effect of PPARγ on Twist 1 expression. In addition, we utilized retroviral interference and overexpression of Twist 1 to determine the effects of Twist 1 on PPARγ expression. The expression levels of Twist 1 and PPARγ were induced during differentiation in 3T3-L1 adipocytes. Application of either a PPARγ agonist (pioglitazone) or antagonist (T0070907) influenced Twist 1 expression, with up-regulation of Twist 1 under pioglitazone (1 μM, 24 h) and down-regulation of Twist 1 under T0070907 (100 μM, 24 h) exposure. Furthermore, the retroviral interference of Twist 1 decreased the protein and mRNA expression of PPARγ, while Twist 1 overexpression had the opposite effect. There was a possible regulatory link between Twist 1 and PPARγ in 3T3-L1 mature adipocytes. This regulatory link enhanced the regulation of PPARγ and may be a functional mechanism of Twist 1 regulation of adipocyte physiology and pathology.

Genes uniquely expressed in human growth plate chondrocytes uncover a distinct regulatory network.

PubMed

Li, Bing; Balasubramanian, Karthika; Krakow, Deborah; Cohn, Daniel H

2017-12-20

Chondrogenesis is the earliest stage of skeletal development and is a highly dynamic process, integrating the activities and functions of transcription factors, cell signaling molecules and extracellular matrix proteins. The molecular mechanisms underlying chondrogenesis have been extensively studied and multiple key regulators of this process have been identified. However, a genome-wide overview of the gene regulatory network in chondrogenesis has not been achieved. In this study, employing RNA sequencing, we identified 332 protein coding genes and 34 long non-coding RNA (lncRNA) genes that are highly selectively expressed in human fetal growth plate chondrocytes. Among the protein coding genes, 32 genes were associated with 62 distinct human skeletal disorders and 153 genes were associated with skeletal defects in knockout mice, confirming their essential roles in skeletal formation. These gene products formed a comprehensive physical interaction network and participated in multiple cellular processes regulating skeletal development. The data also revealed 34 transcription factors and 11,334 distal enhancers that were uniquely active in chondrocytes, functioning as transcriptional regulators for the cartilage-selective genes. Our findings revealed a complex gene regulatory network controlling skeletal development whereby transcription factors, enhancers and lncRNAs participate in chondrogenesis by transcriptional regulation of key genes. Additionally, the cartilage-selective genes represent candidate genes for unsolved human skeletal disorders.

Nerve-dependent factors regulating transcript levels of glycogen phosphorylase in skeletal muscle.

PubMed

Matthews, C C; Carlsen, R C; Froman, B; Tait, R; Gorin, F

1998-06-01

.40% (w/v) VIN for 1 hr reduced axonal transport and decreased MGP transcript levels by 50% within 7 days, but also reduced sensory and motor nerve conduction velocities and depressed TA contractile function. 6. Myogenin, a member of a family of regulatory factors shown to influence the transcription of many muscle genes, including MGP, was used as a molecular marker for muscle inactivity. Myogenin transcript levels were increased following denervation and after treatment with TTX or 0.40% VIN but not after treatment with 0.10% VIN. 7. The results suggest that MGP transcript levels in TA are regulated predominantly by muscle activity, rather than by the delivery of neurotrophic factors. Intrinsic myogenic factors, however, also play a role in MGP expression, since denervation did not reduce MGP transcript levels below 30% of control TA. The dominant influence of activity in the regulation of MGP contrasts with the proposed regulation of oxidative enzyme expression, which appears to depend on both activity and trophic factor influences.

Alzheimer's disease master regulators analysis: search for potential molecular targets and drug repositioning candidates.

PubMed

Vargas, D M; De Bastiani, M A; Zimmer, E R; Klamt, F

2018-06-23

Alzheimer's disease (AD) is a multifactorial and complex neuropathology that involves impairment of many intricate molecular mechanisms. Despite recent advances, AD pathophysiological characterization remains incomplete, which hampers the development of effective treatments. In fact, currently, there are no effective pharmacological treatments for AD. Integrative strategies such as transcription regulatory network and master regulator analyses exemplify promising new approaches to study complex diseases and may help in the identification of potential pharmacological targets. In this study, we used transcription regulatory network and master regulator analyses on transcriptomic data of human hippocampus to identify transcription factors (TFs) that can potentially act as master regulators in AD. All expression profiles were obtained from the Gene Expression Omnibus database using the GEOquery package. A normal hippocampus transcription factor-centered regulatory network was reconstructed using the ARACNe algorithm. Master regulator analysis and two-tail gene set enrichment analysis were employed to evaluate the inferred regulatory units in AD case-control studies. Finally, we used a connectivity map adaptation to prospect new potential therapeutic interventions by drug repurposing. We identified TFs with already reported involvement in AD, such as ATF2 and PARK2, as well as possible new targets for future investigations, such as CNOT7, CSRNP2, SLC30A9, and TSC22D1. Furthermore, Connectivity Map Analysis adaptation suggested the repositioning of six FDA-approved drugs that can potentially modulate master regulator candidate regulatory units (Cefuroxime, Cyproterone, Dydrogesterone, Metrizamide, Trimethadione, and Vorinostat). Using a transcription factor-centered regulatory network reconstruction we were able to identify several potential molecular targets and six drug candidates for repositioning in AD. Our study provides further support for the use of bioinformatics

Identification of regulatory network hubs that control lipid metabolism in Chlamydomonas reinhardtii

DOE PAGES

Gargouri, Mahmoud; Park, Jeong -Jin; Holguin, F. Omar; ...

2015-05-28

Microalgae-based biofuels are promising sources of alternative energy, but improvements throughout the production process are required to establish them as economically feasible. One of the most influential improvements would be a significant increase in lipid yields, which could be achieved by altering the regulation of lipid biosynthesis and accumulation. Chlamydomonas reinhardtii accumulates oil (triacylglycerols, TAG) in response to nitrogen (N) deprivation. Although a few important regulatory genes have been identified that are involved in controlling this process, a global understanding of the larger regulatory network has not been developed. In order to uncover this network in this species, a combinedmore » omics (transcriptomic, proteomic and metabolomic) analysis was applied to cells grown in a time course experiment after a shift from N-replete to N-depleted conditions. Changes in transcript and protein levels of 414 predicted transcription factors (TFs) and transcriptional regulators (TRs) were monitored relative to other genes. The TF and TR genes were thus classified by two separate measures: up-regulated versus down-regulated and early response versus late response relative to two phases of polar lipid synthesis (before and after TAG biosynthesis initiation). Lipidomic and primary metabolite profiling generated compound accumulation levels that were integrated with the transcript dataset and TF profiling to produce a transcriptional regulatory network. In conclusion, evaluation of this proposed regulatory network led to the identification of several regulatory hubs that control many aspects of cellular metabolism, from N assimilation and metabolism, to central metabolism, photosynthesis and lipid metabolism.« less

Strategies to regulate transcription factor-mediated gene positioning and interchromosomal clustering at the nuclear periphery.

PubMed

Randise-Hinchliff, Carlo; Coukos, Robert; Sood, Varun; Sumner, Michael Chas; Zdraljevic, Stefan; Meldi Sholl, Lauren; Garvey Brickner, Donna; Ahmed, Sara; Watchmaker, Lauren; Brickner, Jason H

2016-03-14

In budding yeast, targeting of active genes to the nuclear pore complex (NPC) and interchromosomal clustering is mediated by transcription factor (TF) binding sites in the gene promoters. For example, the binding sites for the TFs Put3, Ste12, and Gcn4 are necessary and sufficient to promote positioning at the nuclear periphery and interchromosomal clustering. However, in all three cases, gene positioning and interchromosomal clustering are regulated. Under uninducing conditions, local recruitment of the Rpd3(L) histone deacetylase by transcriptional repressors blocks Put3 DNA binding. This is a general function of yeast repressors: 16 of 21 repressors blocked Put3-mediated subnuclear positioning; 11 of these required Rpd3. In contrast, Ste12-mediated gene positioning is regulated independently of DNA binding by mitogen-activated protein kinase phosphorylation of the Dig2 inhibitor, and Gcn4-dependent targeting is up-regulated by increasing Gcn4 protein levels. These different regulatory strategies provide either qualitative switch-like control or quantitative control of gene positioning over different time scales. © 2016 Randise-Hinchliff et al.

Transcriptional regulation of metabolism in disease: From transcription factors to epigenetics

PubMed Central

2018-01-01

Every cell in an individual has largely the same genomic sequence and yet cells in different tissues can present widely different phenotypes. This variation arises because each cell expresses a specific subset of genomic instructions. Control over which instructions, or genes, are expressed is largely controlled by transcriptional regulatory pathways. Each cell must assimilate a huge amount of environmental input, and thus it is of no surprise that transcription is regulated by many intertwining mechanisms. This large regulatory landscape means there are ample possibilities for problems to arise, which in a medical context means the development of disease states. Metabolism within the cell, and more broadly, affects and is affected by transcriptional regulation. Metabolism can therefore contribute to improper transcriptional programming, or pathogenic metabolism can be the result of transcriptional dysregulation. Here, we discuss the established and emerging mechanisms for controling transcription and how they affect metabolism in the context of pathogenesis. Cis- and trans-regulatory elements, microRNA and epigenetic mechanisms such as DNA and histone methylation, all have input into what genes are transcribed. Each has also been implicated in diseases such as metabolic syndrome, various forms of diabetes, and cancer. In this review, we discuss the current understanding of these areas and highlight some natural models that may inspire future therapeutics. PMID:29922517

[The Influence of the Functioning of Brain Regulatory Systems onto the Voluntary Regulation of Cognitive Performance in Children. Report 2. Neuropsychological and Electrophysiological Assessment of Brain Regulatory Functions in Children Aged 10-12 with Learning Difficulties].

PubMed

Semenova, O A; Machinskaya, R I

2015-01-01

A total number of 172 children aged 10-12 were electrophysiologically and neuropsychologically assessed in order to analyze the influence of the functioning of brain regulatory systems onto the voluntary regulation of cognitive performance during the preteen years. EEG patterns associated with the nonoptimal functioning of brain regulatory systems, particularly fronto-thalamic, limbic and fronto-striatal structures were significantly more often observed in children with learning and behavioral difficulties, as compared to the control group. Neuropsychological assessment showed that the nonoptimal functioning of different brain regulatory systems specifically affect the voluntary regulation of cognitive performance. Children with EEG patterns of fronto-thalamic nonoptimal functioning demonstrated poor voluntary regulation such as impulsiveness and difficulties in continuing the same algorithms. Children with EEG patterns of limbic nonoptimal functioning showed a less pronounced executive dysfunction manifested only in poor switching between program units within a task. Children with EEG patterns of fronto-striatal nonoptimal functioning struggled with such executive dysfunctions as motor and tactile perseverations and emotional-motivational deviations such as poor motivation and communicative skills.

Self-Regulation in Early Adolescence: Relations with Mother-Son Relationship Quality and Maternal Regulatory Support and Antagonism

ERIC Educational Resources Information Center

Moilanen, Kristin L.; Shaw, Daniel S.; Fitzpatrick, Amber

2010-01-01

The purpose of the current investigation was to examine relations among maternal regulatory support, maternal antagonism, and mother-son relationship quality in relation to boys' self-regulation during early adolescence. As part of a larger longitudinal study on 263 low-income, ethnically diverse boys, multiple informants and methods were used to…

76 FR 40150 - Semiannual Regulatory Agenda

Federal Register 2010, 2011, 2012, 2013, 2014

2011-07-07

... Commission publishes its semiannual regulatory flexibility agenda. In addition, this document includes an...) requires each agency to publish twice each year a regulatory flexibility agenda containing a brief... 12866 requires each agency to publish twice each year a regulatory agenda of regulations under...

Sucrose-induced anthocyanin accumulation in vegetative tissue of Petunia plants requires anthocyanin regulatory transcription factors.

PubMed

Ai, Trinh Ngoc; Naing, Aung Htay; Arun, Muthukrishnan; Lim, Sun-Hyung; Kim, Chang Kil

2016-11-01

The effects of three different sucrose concentrations on plant growth and anthocyanin accumulation were examined in non-transgenic (NT) and transgenic (T 2 ) specimens of the Petunia hybrida cultivar 'Mirage rose' that carried the anthocyanin regulatory transcription factors B-Peru+mPAP1 or RsMYB1. Anthocyanin accumulation was not observed in NT plants in any treatments, whereas a range of anthocyanin accumulation was observed in transgenic plants. The anthocyanin content detected in transgenic plants expressing the anthocyanin regulatory transcription factors (B-Peru+mPAP1 or RsMYB1) was higher than that in NT plants. In addition, increasing sucrose concentration strongly enhanced anthocyanin content as shown by quantitative real-time polymerase chain reaction (qRT-PCR) analysis, wherein increased concentrations of sucrose enhanced transcript levels of the transcription factors that are responsible for the induction of biosynthetic genes involved in anthocyanin synthesis; this pattern was not observed in NT plants. In addition, sucrose affected plant growth, although the effects were different between NT and transgenic plants. Taken together, the application of sucrose could enhance anthocyanin production in vegetative tissue of transgenic Petunia carrying anthocyanin regulatory transcription factors, and this study provides insights about interactive effects of sucrose and transcription factors in anthocyanin biosynthesis in the transgenic plant. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

General Aspects of Two-Component Regulatory Circuits in Bacteria: Domains, Signals and Roles.

PubMed

Padilla-Vaca, Felipe; Mondragón-Jaimes, Verónica; Franco, Bernardo

2017-01-01

All living organisms are subject to changing environments, which must be sensed in order to respond swiftly and efficiently. Two-component systems (TCS) are signal transduction regulatory circuits based typically on a membrane bound sensor kinase and a cytoplasmic response regulator, that is activated through a histidine to aspartate phosphorelay reactions. Activated response regulator acts usually as a transcription factor. The best known examples were identified in bacteria, but they are also found in fungi, algae and plants. Thus far, they are not found in mammals. Regulatory circuits coupled to two-component systems exhibit a myriad of responses to environmental stimuli such as: redox potential, pH, specific metabolites, pressure, light and more recently to specific antimicrobial peptides that activate a sensor kinase responsible for expressing virulence factors through the active response regulator. In this review we explore general aspects on two-component systems that ultimately can play a role on virulence regulation, also the intriguing domain properties of the sensor kinases that can be a potential target for antimicrobial compounds. Only a handful of sensor kinases are extensively characterized, the vast majority belong to what we call 'the dark matter of bacterial signal transduction' since no known signal, structure and biochemical properties are available. Regulatory circuits from vertebrate pathogenic organisms can explain virulence in terms of either response to environmental factors or specific niche occupancy. Hopefully, knowledge on these signal transduction systems can lead to identify novel molecules that target two-component systems, since the increase of drug resistant microorganisms is worrisome. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Physiological factors that regulate skin pigmentation

PubMed Central

Yamaguchi, Yuji; Hearing, Vincent J.

2009-01-01

More than 150 genes have been identified that affect skin color either directly or indirectly, and we review current understanding of physiological factors that regulate skin pigmentation. We focus on melanosome biogenesis, transport and transfer, melanogenic regulators in melanocytes and factors derived from keratinocytes, fibroblasts, endothelial cells, hormones, inflammatory cells and nerves. Enzymatic components of melanosomes include tyrosinase, tyrosinase-related protein 1 and dopachrome tautomerase, which depend on the functions of OA1, P, MATP, ATP7A and BLOC-1 to synthesize eumelanins and pheomelanins. The main structural component of melanosomes is Pmel17/gp100/Silv, whose sorting involves adaptor protein 1A (AP1A), AP1B, AP2 and spectrin, as well as a chaperone-like component, MART-1. During their maturation, melanosomes move from the perinuclear area toward the plasma membrane. Microtubules, dynein, kinesin, actin filaments, Rab27a, melanophilin, myosin Va and Slp2-a are involved in melanosome transport. Foxn1 and p53 up-regulate skin pigmentation via bFGF and POMC derivatives including α-MSH and ACTH, respectively. Other critical factors that affect skin pigmentation include MC1R, CREB, ASP, MITF, PAX3, SOX9/10, LEF-1/TCF, PAR-2, DKK1, SCF, HGF, GM-CSF, endothelin-1, prostaglandins, leukotrienes, thromboxanes, neurotrophins and neuropeptides. UV radiation up-regulates most factors that increase melanogenesis. Further studies will elucidate the currently unknown functions of many other pigment genes/proteins. PMID:19449448

Drug evaluation and the permissive principle: continuities and contradictions between standards and practices in antidepressant regulation.

PubMed

Abraham, John; Davis, Courtney

2009-08-01

Pharmaceuticals are not permitted on to the market unless they are granted regulatory approval. The regulatory process is, therefore, crucial in whether or not a drug is widely prescribed. Regulatory agencies have developed standards of performance that pharmaceuticals are supposed to meet before entering the market. Regulation of technologies is often discussed by reference to the precautionary principle. In contrast, this paper develops the concept of the 'permissive principle' as a way of understanding the departure of regulators' practices from standards of drug efficacy to which regulatory agencies themselves subscribe. By taking a case study of antidepressant regulation in the UK and the USA, the mechanisms of permissive regulatory practices are examined. An STS methodology of both spatial (international) and temporal comparisons of regulatory practices with regulatory standards is employed to identify the nature and extent of the permissive regulation. It is found that the permissive principle was adopted by drug regulators in the UK and the USA, but more so by the former than the latter. Evidently, permissive regulation, which favours the commercial interests of the drug manufacturer, but is contrary to the interests of patients, may penetrate to the heart of regulatory science. On the other hand, permissive regulation of specific drugs should not be regarded as an inevitable result of marketing strategies and concomitant networks deployed by powerful pharmaceutical companies, because the extent of permissive regulation may vary according to the intra-institutional normative commitments of regulators to uphold their technical standards against the commercial interests of the manufacturer. Likely sociological factors that can account for such permissive regulatory practices are 'corporate bias', secrecy and excessive regulatory trust in the pharmaceutical industry in the UK, political expediency and ideological capture in the USA, combined in both countries

The WRKY Transcription Factor WRKY71/EXB1 Controls Shoot Branching by Transcriptionally Regulating RAX Genes in Arabidopsis.

PubMed

Guo, Dongshu; Zhang, Jinzhe; Wang, Xinlei; Han, Xiang; Wei, Baoye; Wang, Jianqiao; Li, Boxun; Yu, Hao; Huang, Qingpei; Gu, Hongya; Qu, Li-Jia; Qin, Genji

2015-11-01

Plant shoot branching is pivotal for developmental plasticity and crop yield. The formation of branch meristems is regulated by several key transcription factors including REGULATOR OF AXILLARY MERISTEMS1 (RAX1), RAX2, and RAX3. However, the regulatory network of shoot branching is still largely unknown. Here, we report the identification of EXCESSIVE BRANCHES1 (EXB1), which affects axillary meristem (AM) initiation and bud activity. Overexpression of EXB1 in the gain-of-function mutant exb1-D leads to severe bushy and dwarf phenotypes, which result from excessive AM initiation and elevated bud activities. EXB1 encodes the WRKY transcription factor WRKY71, which has demonstrated transactivation activities. Disruption of WRKY71/EXB1 by chimeric repressor silencing technology leads to fewer branches, indicating that EXB1 plays important roles in the control of shoot branching. We demonstrate that EXB1 controls AM initiation by positively regulating the transcription of RAX1, RAX2, and RAX3. Disruption of the RAX genes partially rescues the branching phenotype caused by EXB1 overexpression. We further show that EXB1 also regulates auxin homeostasis in control of shoot branching. Our data demonstrate that EXB1 plays pivotal roles in shoot branching by regulating both transcription of RAX genes and auxin pathways. © 2015 American Society of Plant Biologists. All rights reserved.

In silico modeling of epigenetic-induced changes in photoreceptor cis-regulatory elements.

PubMed

Hossain, Reafa A; Dunham, Nicholas R; Enke, Raymond A; Berndsen, Christopher E

2018-01-01

DNA methylation is a well-characterized epigenetic repressor of mRNA transcription in many plant and vertebrate systems. However, the mechanism of this repression is not fully understood. The process of transcription is controlled by proteins that regulate recruitment and activity of RNA polymerase by binding to specific cis-regulatory sequences. Cone-rod homeobox (CRX) is a well-characterized mammalian transcription factor that controls photoreceptor cell-specific gene expression. Although much is known about the functions and DNA binding specificity of CRX, little is known about how DNA methylation modulates CRX binding affinity to genomic cis-regulatory elements. We used bisulfite pyrosequencing of human ocular tissues to measure DNA methylation levels of the regulatory regions of RHO , PDE6B, PAX6 , and LINE1 retrotransposon repeats. To describe the molecular mechanism of repression, we used molecular modeling to illustrate the effect of DNA methylation on human RHO regulatory sequences. In this study, we demonstrate an inverse correlation between DNA methylation in regulatory regions adjacent to the human RHO and PDE6B genes and their subsequent transcription in human ocular tissues. Docking of CRX to the DNA models shows that CRX interacts with the grooves of these sequences, suggesting changes in groove structure could regulate binding. Molecular dynamics simulations of the RHO promoter and enhancer regions show changes in the flexibility and groove width upon epigenetic modification. Models also demonstrate changes in the local dynamics of CRX binding sites within RHO regulatory sequences which may account for the repression of CRX-dependent transcription. Collectively, these data demonstrate epigenetic regulation of CRX binding sites in human retinal tissue and provide insight into the mechanism of this mode of epigenetic regulation to be tested in future experiments.

Transcriptional regulation of mammalian selenoprotein expression

PubMed Central

Stoytcheva, Zoia R.; Berry, Marla J.

2009-01-01

Background Selenoproteins contain the twenty-first amino acid, selenocysteine, and are involved in cellular defenses against oxidative damage, important metabolic and developmental pathways, and responses to environmental challenges. Elucidating the mechanisms regulating selenoprotein expression at the transcriptional level is key to understanding how these mechanisms are called into play to respond to the changing environment. Methods This review summarizes published studies on transcriptional regulation of selenoprotein genes, focused primarily on genes whose encoded protein functions are at least partially understood. This is followed by in silico analysis of predicted regulatory elements in selenoprotein genes, including those in the aforementioned category as well as the genes whose functions are not known. Results Our findings reveal regulatory pathways common to many selenoprotein genes, including several involved in stress-responses. In addition, tissue-specific regulatory factors are implicated in regulating many selenoprotein genes. Conclusions These studies provide new insights into how selenoprotein genes respond to environmental and other challenges, and the roles these proteins play in allowing cells to adapt to these changes. General Significance Elucidating the regulatory mechanisms affecting selenoprotein expression is essential for understanding their roles in human diseases, and for developing diagnostic and potential therapeutic approaches to address dysregulation of members of this gene family. PMID:19465084

Social insect genomes exhibit dramatic evolution in gene composition and regulation while preserving regulatory features linked to sociality

PubMed Central

Simola, Daniel F.; Wissler, Lothar; Donahue, Greg; Waterhouse, Robert M.; Helmkampf, Martin; Roux, Julien; Nygaard, Sanne; Glastad, Karl M.; Hagen, Darren E.; Viljakainen, Lumi; Reese, Justin T.; Hunt, Brendan G.; Graur, Dan; Elhaik, Eran; Kriventseva, Evgenia V.; Wen, Jiayu; Parker, Brian J.; Cash, Elizabeth; Privman, Eyal; Childers, Christopher P.; Muñoz-Torres, Monica C.; Boomsma, Jacobus J.; Bornberg-Bauer, Erich; Currie, Cameron R.; Elsik, Christine G.; Suen, Garret; Goodisman, Michael A.D.; Keller, Laurent; Liebig, Jürgen; Rawls, Alan; Reinberg, Danny; Smith, Chris D.; Smith, Chris R.; Tsutsui, Neil; Wurm, Yannick; Zdobnov, Evgeny M.; Berger, Shelley L.; Gadau, Jürgen

2013-01-01

Genomes of eusocial insects code for dramatic examples of phenotypic plasticity and social organization. We compared the genomes of seven ants, the honeybee, and various solitary insects to examine whether eusocial lineages share distinct features of genomic organization. Each ant lineage contains ∼4000 novel genes, but only 64 of these genes are conserved among all seven ants. Many gene families have been expanded in ants, notably those involved in chemical communication (e.g., desaturases and odorant receptors). Alignment of the ant genomes revealed reduced purifying selection compared with Drosophila without significantly reduced synteny. Correspondingly, ant genomes exhibit dramatic divergence of noncoding regulatory elements; however, extant conserved regions are enriched for novel noncoding RNAs and transcription factor–binding sites. Comparison of orthologous gene promoters between eusocial and solitary species revealed significant regulatory evolution in both cis (e.g., Creb) and trans (e.g., fork head) for nearly 2000 genes, many of which exhibit phenotypic plasticity. Our results emphasize that genomic changes can occur remarkably fast in ants, because two recently diverged leaf-cutter ant species exhibit faster accumulation of species-specific genes and greater divergence in regulatory elements compared with other ants or Drosophila. Thus, while the “socio-genomes” of ants and the honeybee are broadly characterized by a pervasive pattern of divergence in gene composition and regulation, they preserve lineage-specific regulatory features linked to eusociality. We propose that changes in gene regulation played a key role in the origins of insect eusociality, whereas changes in gene composition were more relevant for lineage-specific eusocial adaptations. PMID:23636946

Jasmonate Regulates the INDUCER OF CBF EXPRESSION–C-REPEAT BINDING FACTOR/DRE BINDING FACTOR1 Cascade and Freezing Tolerance in Arabidopsis[W

PubMed Central

Hu, Yanru; Jiang, Liqun; Wang, Fang; Yu, Diqiu

2013-01-01

The INDUCER OF CBF EXPRESSION (ICE)–C-REPEAT BINDING FACTOR/DRE BINDING FACTOR1 (CBF/DREB1) transcriptional pathway plays a critical role in modulating cold stress responses in Arabidopsis thaliana. Dissecting crucial upstream regulatory signals or components of the ICE-CBF/DREB1 cascade will enhance our understanding of plant cold-tolerance mechanisms. Here, we show that jasmonate positively regulates plant responses to freezing stress in Arabidopsis. Exogenous application of jasmonate significantly enhanced plant freezing tolerance with or without cold acclimation. By contrast, blocking endogenous jasmonate biosynthesis and signaling rendered plants hypersensitive to freezing stress. Consistent with the positive role of jasmonate in freezing stress, production of endogenous jasmonate was triggered by cold treatment. In addition, cold induction of genes acting in the CBF/DREB1 signaling pathway was upregulated by jasmonate. Further investigation revealed that several JASMONATE ZIM-DOMAIN (JAZ) proteins, the repressors of jasmonate signaling, physically interact with ICE1 and ICE2 transcription factors. JAZ1 and JAZ4 repress the transcriptional function of ICE1, thereby attenuating the expression of its regulon. Consistent with this, overexpression of JAZ1 or JAZ4 represses freezing stress responses of Arabidopsis. Taken together, our study provides evidence that jasmonate functions as a critical upstream signal of the ICE-CBF/DREB1 pathway to positively regulate Arabidopsis freezing tolerance. PMID:23933884

GARP: a key receptor controlling FOXP3 in human regulatory T cells.

PubMed

Probst-Kepper, M; Geffers, R; Kröger, A; Viegas, N; Erck, C; Hecht, H-J; Lünsdorf, H; Roubin, R; Moharregh-Khiabani, D; Wagner, K; Ocklenburg, F; Jeron, A; Garritsen, H; Arstila, T P; Kekäläinen, E; Balling, R; Hauser, H; Buer, J; Weiss, S

2009-09-01

Recent evidence suggests that regulatory pathways might control sustained high levels of FOXP3 in regulatory CD4(+)CD25(hi) T (T(reg)) cells. Based on transcriptional profiling of ex vivo activated T(reg) and helper CD4(+)CD25(-) T (T(h)) cells we have identified GARP (glycoprotein-A repetitions predominant), LGALS3 (lectin, galactoside-binding, soluble, 3) and LGMN (legumain) as novel genes implicated in human T(reg) cell function, which are induced upon T-cell receptor stimulation. Retroviral overexpression of GARP in antigen-specific T(h) cells leads to an efficient and stable re-programming of an effector T cell towards a regulatory T cell, which involves up-regulation of FOXP3, LGALS3, LGMN and other T(reg)-associated markers. In contrast, overexpression of LGALS3 and LGMN enhance FOXP3 and GARP expression, but only partially induced a regulatory phenotype. Lentiviral down-regulation of GARP in T(reg) cells significantly impaired the suppressor function and was associated with down-regulation of FOXP3. Moreover, down-regulation of FOXP3 resulted in similar phenotypic changes and down-regulation of GARP. This provides compelling evidence for a GARP-FOXP3 positive feedback loop and provides a rational molecular basis for the known difference between natural and transforming growth factor-beta induced T(reg) cells as we show here that the latter do not up-regulate GARP. In summary, we have identified GARP as a key receptor controlling FOXP3 in T(reg) cells following T-cell activation in a positive feedback loop assisted by LGALS3 and LGMN, which represents a promising new system for the therapeutic manipulation of T cells in human disease.

Genome-wide regulation of light-controlled seedling morphogenesis by three families of transcription factors.

PubMed

Shi, Hui; Lyu, Mohan; Luo, Yiwen; Liu, Shoucheng; Li, Yue; He, Hang; Wei, Ning; Deng, Xing Wang; Zhong, Shangwei

2018-06-19

Three families of transcription factors have been reported to play key roles in light control of Arabidopsis seedling morphogenesis. Among them, bHLH protein PIFs and plant-specific protein EIN3/EIN3-LIKE 1 (EIN3/EIL1) accumulate in the dark to maintain skotomorphogenesis. On the other hand, HY5 and HY5 HOMOLOG (HYH), two related bZIP proteins, are stabilized in light and promote photomorphogenic development. To systemically investigate the transcriptional regulation of light-controlled seedling morphogenesis, we generated HY5 ox/ pifQein3eil1 , which contained mutations of EIN3/EIL1 and four PIF genes ( pifQein3eil1 ) and overexpression of HY5 Our results show that dark-grown HY5 ox/ pifQein3eil1 seedlings display a photomorphogenesis highly similar to that of wild-type seedlings grown in continuous light, with remarkably enhanced photomorphogenic phenotypes compared with the pifQ mutants. Consistent with the genetic evidence, transcriptome analysis indicated that PIFs, EIN3/EIL1, and HY5 are dominant transcription factors in collectively mediating a wide range of light-caused genome-wide transcriptional changes. Moreover, PIFs and EIN3/EIL1 independently control the expression of light-regulated genes such as HLS1 to cooperatively regulate apical hook formation, hypocotyl elongation, and cotyledon opening and expansion. This study illustrates a comprehensive regulatory network of transcription activities that correspond to specific morphological aspects in seedling skotomorphogenesis and photomorphogenesis.

Regulatory logic of pan-neuronal gene expression in C. elegans

PubMed Central

Stefanakis, Nikolaos; Carrera, Ines; Hobert, Oliver

2015-01-01

While neuronal cell types display an astounding degree of phenotypic diversity, most if not all neuron types share a core panel of terminal features. However, little is known about how pan-neuronal expression patterns are genetically programmed. Through an extensive analysis of the cis-regulatory control regions of a battery of pan-neuronal C.elegans genes, including genes involved in synaptic vesicle biology and neuropeptide signaling, we define a common organizational principle in the regulation of pan-neuronal genes in the form of a surprisingly complex array of seemingly redundant, parallel-acting cis-regulatory modules that direct expression to broad, overlapping domains throughout the nervous system. These parallel-acting cis-regulatory modules are responsive to a multitude of distinct trans-acting factors. Neuronal gene expression programs therefore fall into two fundamentally distinct classes. Neuron type-specific genes are generally controlled by discrete and non-redundantly acting regulatory inputs, while pan-neuronal gene expression is controlled by diverse, coincident and seemingly redundant regulatory inputs. PMID:26291158

Glucokinase regulatory proten genetic variant interacts with omega-3 PUFA to influence insulin resistance and inflammation in metabolic syndrome

USDA-ARS?s Scientific Manuscript database

Glucokinase Regulatory Protein (GCKR) plays a central role regulating both hepatic triglyceride and glucose metabolism. Fatty acids are key metabolic regulators, which interact with genetic factors and influence glucose metabolism and other metabolic traits. Omega-3 polyunsaturated fatty acids (n-3...

p38β, A novel regulatory target of Pokemon in hepatic cells.

PubMed

Chen, Zhe; Liu, Feng; Zhang, Nannan; Cao, Deliang; Liu, Min; Tan, Ying; Jiang, Yuyang

2013-06-27

Pokemon is an important proto-oncogene involved in various biological processes and cancer development, such as cell differentiation, tumorigenesis and metastasis. Pokemon is recognized as a transcription factor localized upstream of several oncogenes, regulating their expression. p38MAPKs act as key regulatory factors in cellular signaling pathways associated with inflammatory responses, cell proliferation, differentiation and survival. p38β, a member of p38MAPK family, is closely correlated with tumorigenesis, but the mechanism of activation remains unclear. In this study, we found overexpression of Pokemon promoted the growth, migration and invasion of HepG2 cells. However, a p38 inhibitor SB202190 efficiently attenuated the promoting effect of Pokemon in the HepG2 cells. Targeted expression or silencing of Pokemon changed cellular p38β protein level and phosphorylation of downstream ATF2 in the p38 signaling pathway. Both dual luciferase report assay and ChIP assay suggested that p38β is a novel regulatory target of the transcription factor Pokemon and positively regulated by Pokemon in hepatic cells.

p38β, A Novel Regulatory Target of Pokemon in Hepatic Cells

PubMed Central

Chen, Zhe; Liu, Feng; Zhang, Nannan; Cao, Deliang; Liu, Min; Tan, Ying; Jiang, Yuyang

2013-01-01

Pokemon is an important proto-oncogene involved in various biological processes and cancer development, such as cell differentiation, tumorigenesis and metastasis. Pokemon is recognized as a transcription factor localized upstream of several oncogenes, regulating their expression. p38MAPKs act as key regulatory factors in cellular signaling pathways associated with inflammatory responses, cell proliferation, differentiation and survival. p38β, a member of p38MAPK family, is closely correlated with tumorigenesis, but the mechanism of activation remains unclear. In this study, we found overexpression of Pokemon promoted the growth, migration and invasion of HepG2 cells. However, a p38 inhibitor SB202190 efficiently attenuated the promoting effect of Pokemon in the HepG2 cells. Targeted expression or silencing of Pokemon changed cellular p38β protein level and phosphorylation of downstream ATF2 in the p38 signaling pathway. Both dual luciferase report assay and ChIP assay suggested that p38β is a novel regulatory target of the transcription factor Pokemon and positively regulated by Pokemon in hepatic cells. PMID:23807508

Genome wide predictions of miRNA regulation by transcription factors.

PubMed

Ruffalo, Matthew; Bar-Joseph, Ziv

2016-09-01

Reconstructing regulatory networks from expression and interaction data is a major goal of systems biology. While much work has focused on trying to experimentally and computationally determine the set of transcription-factors (TFs) and microRNAs (miRNAs) that regulate genes in these networks, relatively little work has focused on inferring the regulation of miRNAs by TFs. Such regulation can play an important role in several biological processes including development and disease. The main challenge for predicting such interactions is the very small positive training set currently available. Another challenge is the fact that a large fraction of miRNAs are encoded within genes making it hard to determine the specific way in which they are regulated. To enable genome wide predictions of TF-miRNA interactions, we extended semi-supervised machine-learning approaches to integrate a large set of different types of data including sequence, expression, ChIP-seq and epigenetic data. As we show, the methods we develop achieve good performance on both a labeled test set, and when analyzing general co-expression networks. We next analyze mRNA and miRNA cancer expression data, demonstrating the advantage of using the predicted set of interactions for identifying more coherent and relevant modules, genes, and miRNAs. The complete set of predictions is available on the supporting website and can be used by any method that combines miRNAs, genes, and TFs. Code and full set of predictions are available from the supporting website: http://cs.cmu.edu/~mruffalo/tf-mirna/ zivbj@cs.cmu.edu Supplementary data are available at Bioinformatics online. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Endothelin-1 gene regulation

PubMed Central

Stow, Lisa R.; Jacobs, Mollie E.; Wingo, Charles S.; Cain, Brian D.

2011-01-01

Over two decades of research have demonstrated that the peptide hormone endothelin-1 (ET-1) plays multiple, complex roles in cardiovascular, neural, pulmonary, reproductive, and renal physiology. Differential and tissue-specific production of ET-1 must be tightly regulated in order to preserve these biologically diverse actions. The primary mechanism thought to control ET-1 bioavailability is the rate of transcription from the ET-1 gene (edn1). Studies conducted on a variety of cell types have identified key transcription factors that govern edn1 expression. With few exceptions, the cis-acting elements bound by these factors have been mapped in the edn1 regulatory region. Recent evidence has revealed new roles for some factors originally believed to regulate edn1 in a tissue or hormone-specific manner. In addition, other mechanisms involved in epigenetic regulation and mRNA stability have emerged as important processes for regulated edn1 expression. The goal of this review is to provide a comprehensive overview of the specific factors and signaling systems that govern edn1 activity at the molecular level.—Stow, L. R., Jacobs, M. E., Wingo, C. S., Cain, B. D. Endothelin-1 gene regulation. PMID:20837776

Alternative splicing of anciently exonized 5S rRNA regulates plant transcription factor TFIIIA

PubMed Central

Fu, Yan; Bannach, Oliver; Chen, Hao; Teune, Jan-Hendrik; Schmitz, Axel; Steger, Gerhard; Xiong, Liming; Barbazuk, W. Brad

2009-01-01

Identifying conserved alternative splicing (AS) events among evolutionarily distant species can prioritize AS events for functional characterization and help uncover relevant cis- and trans-regulatory factors. A genome-wide search for conserved cassette exon AS events in higher plants revealed the exonization of 5S ribosomal RNA (5S rRNA) within the gene of its own transcription regulator, TFIIIA (transcription factor for polymerase III A). The 5S rRNA-derived exon in TFIIIA gene exists in all representative land plant species but not in green algae and nonplant species, suggesting it is specific to land plants. TFIIIA is essential for RNA polymerase III-based transcription of 5S rRNA in eukaryotes. Integrating comparative genomics and molecular biology revealed that the conserved cassette exon derived from 5S rRNA is coupled with nonsense-mediated mRNA decay. Utilizing multiple independent Arabidopsis overexpressing TFIIIA transgenic lines under osmotic and salt stress, strong accordance between phenotypic and molecular evidence reveals the biological relevance of AS of the exonized 5S rRNA in quantitative autoregulation of TFIIIA homeostasis. Most significantly, this study provides the first evidence of ancient exaptation of 5S rRNA in plants, suggesting a novel gene regulation model mediated by the AS of an anciently exonized noncoding element. PMID:19211543

A stele-enriched gene regulatory network in the Arabidopsis root

PubMed Central

Brady, Siobhan M; Zhang, Lifang; Megraw, Molly; Martinez, Natalia J; Jiang, Eric; Yi, Charles S; Liu, Weilin; Zeng, Anna; Taylor-Teeples, Mallorie; Kim, Dahae; Ahnert, Sebastian; Ohler, Uwe; Ware, Doreen; Walhout, Albertha J M; Benfey, Philip N

2011-01-01

Tightly controlled gene expression is a hallmark of multicellular development and is accomplished by transcription factors (TFs) and microRNAs (miRNAs). Although many studies have focused on identifying downstream targets of these molecules, less is known about the factors that regulate their differential expression. We used data from high spatial resolution gene expression experiments and yeast one-hybrid (Y1H) and two-hybrid (Y2H) assays to delineate a subset of interactions occurring within a gene regulatory network (GRN) that determines tissue-specific TF and miRNA expression in plants. We find that upstream TFs are expressed in more diverse cell types than their targets and that promoters that are bound by a relatively large number of TFs correspond to key developmental regulators. The regulatory consequence of many TFs for their target was experimentally determined using genetic analysis. Remarkably, molecular phenotypes were identified for 65% of the TFs, but morphological phenotypes were associated with only 16%. This indicates that the GRN is robust, and that gene expression changes may be canalized or buffered. PMID:21245844

Heart rate variability reflects self-regulatory strength, effort, and fatigue.

PubMed

Segerstrom, Suzanne C; Nes, Lise Solberg

2007-03-01

Experimental research reliably demonstrates that self-regulatory deficits are a consequence of prior self-regulatory effort. However, in naturalistic settings, although people know that they are sometimes vulnerable to saying, eating, or doing the wrong thing, they cannot accurately gauge their capacity to self-regulate at any given time. Because self-regulation and autonomic regulation colocalize in the brain, an autonomic measure, heart rate variability (HRV), could provide an index of self-regulatory strength and activity. During an experimental manipulation of self-regulation (eating carrots or cookies), HRV was elevated during high self-regulatory effort (eat carrots, resist cookies) compared with low self-regulatory effort (eat cookies, resist carrots). The experimental manipulation and higher HRV at baseline independently predicted persistence at a subsequent anagram task. HRV appears to index self-regulatory strength and effort, making it possible to study these phenomena in the field as well as the lab.

[Better medical devices regulations for better health care: enlightenment for medical devices regulatory reform in China, from experiences of the E.U. and the U.S.A].

PubMed

Sun, Qin; Yan, Liang

2006-01-01

The expansion of applications of medical devices has attracted the increased attention of government regulatory bodies around the world to the safety and effectiveness of these products. Most developed countries, such as the United States and European Union, have developed well-established regulatory systems for medical devices, which have also consistently been amended to accommodate the changing requirements of safety and the trend of globalization.The current "Regulations for the Supervision and Administration of Medical Device (China)", established in 2000, has brought about great improvements for the safety and effectiveness of products, safeguarding public health. But there are still, at present, a lot of counterfeit and poor quality devices and device-related adverse events for lack of powerful post -market and in-use regulatory controls for products. It is therefore very urgent for the Chinese government to reform its medical device administration and management. This research paper analyses and compares the different requirements and executions of medical devices regulations in the EU, the US and China, to draw some experiences of the EU and US regimes that are very useful to China's regulatory reform. It is suggested that when developing a new scheme of medical devices regulatory reform in China, two prominent aspects have to be considered by policy makers and regulators. Firstly, the global trend of medical devices regulations has to be taken into account. Secondly, the experiences learned from the EU and US systems should be applied to the Chinese regulatory reform in combination with the concrete practice of China.

Regulation of exosome release from mammary epithelial and breast cancer cells - a new regulatory pathway.

PubMed

Riches, Andrew; Campbell, Elaine; Borger, Eva; Powis, Simon

2014-03-01

Exosomes are small 50-100nm sized extracellular vesicles released from normal and tumour cells and are a source of a new intercellular communication pathway. Tumour exosomes promote tumour growth and progression. What regulates the release and homoeostatic levels of exosomes, in cancer, in body fluids remains undefined. We utilised a human mammary epithelial cell line (HMEC B42) and a breast cancer cell line derived from it (B42 clone 16) to investigate exosome production and regulation. Exosome numbers were quantified using a Nanosight LM10 and measured in culture supernatants in the absence and presence of exosomes in the medium. Concentrated suspensions of exosomes from the normal mammary epithelial cells, the breast cancer cells and bladder cancer cells were used. The interaction of exosomes with tumour cells was also investigated using fluorescently labelled exosomes. Exosome release from normal human mammary epithelial cells and breast cancer cells is regulated by the presence of exosomes, derived from their own cells, in the extracellular environment of the cells. Exosomes from normal mammary epithelial cells also inhibit exosome secretion by breast cancer cells, which occurs in a tissue specific manner. Labelled exosomes from mammary epithelial cells are internalised into the tumour cells implicating a dynamic equilibrium and suggesting a mechanism for feedback control. These data suggest a previously unknown novel feedback regulatory mechanism for controlling exosome release, which may highlight a new therapeutic approach to controlling the deleterious effects of tumour exosomes. This regulatory mechanism is likely to be generic to other tumours. Copyright © 2014 Elsevier Ltd. All rights reserved.

Trust-based environmental regulation.

PubMed

Lange, Bettina; Gouldson, Andy

2010-10-15

Within this paper, we examine the contribution that trust-based relationships can make to achieving better-and particularly more effective, efficient and equitable-environmental regulation. While levels of trust in regulators, regulatory processes and outcomes are often discussed, the influence of trust on different actors and on different measures of regulatory performance is poorly understood. Within this paper, we define trust-based environmental regulation as a specific regulatory style that involves openness and cooperation in interaction between regulated, regulators and third-party stakeholders in order to achieve environmental protection objectives. We then discuss the pros and cons of trust relationships between regulators, regulated businesses and citizens for achieving behavioural change towards greater environmental protection. To illustrate the significance of these issues, we then examine three forms of contractual regulatory style where trust relationships are critically important: responsive regulation, self-regulation and environmental agreements. Based on this analysis, we highlight the importance of trust-based relationships, and we argue that one of the greatest contributions of trust-based environmental regulation is to challenge how we think about regulation. Trust is often understood as enabling existing regulatory relationships or in the case of self-regulation as a complement to regulation. However, we argue that the real potential of trust is to open up new ways for participants in regulatory regimes to engage in collective action, to go beyond a perception of regulation as driven by the competing interests of individual actors, and thus, to open up new channels of influence for behavioural change towards greater environmental protection. Our analysis therefore has great relevance for future research and for on-going debates on the future of regulation. Copyright © 2010. Published by Elsevier B.V.

Co-regulation of Iron Metabolism and Virulence Associated Functions by Iron and XibR, a Novel Iron Binding Transcription Factor, in the Plant Pathogen Xanthomonas

PubMed Central

Pandey, Sheo Shankar; Patnana, Pradeep Kumar; Lomada, Santosh Kumar; Tomar, Archana; Chatterjee, Subhadeep

2016-01-01

Abilities of bacterial pathogens to adapt to the iron limitation present in hosts is critical to their virulence. Bacterial pathogens have evolved diverse strategies to coordinately regulate iron metabolism and virulence associated functions to maintain iron homeostasis in response to changing iron availability in the environment. In many bacteria the ferric uptake regulator (Fur) functions as transcription factor that utilize ferrous form of iron as cofactor to regulate transcription of iron metabolism and many cellular functions. However, mechanisms of fine-tuning and coordinated regulation of virulence associated function beyond iron and Fur-Fe2+ remain undefined. In this study, we show that a novel transcriptional regulator XibR (named X anthomonas iron binding regulator) of the NtrC family, is required for fine-tuning and co-coordinately regulating the expression of several iron regulated genes and virulence associated functions in phytopathogen Xanthomonas campestris pv. campestris (Xcc). Genome wide expression analysis of iron-starvation stimulon and XibR regulon, GUS assays, genetic and functional studies of xibR mutant revealed that XibR positively regulates functions involved in iron storage and uptake, chemotaxis, motility and negatively regulates siderophore production, in response to iron. Furthermore, chromatin immunoprecipitation followed by quantitative real-time PCR indicated that iron promoted binding of the XibR to the upstream regulatory sequence of operon’s involved in chemotaxis and motility. Circular dichroism spectroscopy showed that purified XibR bound ferric form of iron. Electrophoretic mobility shift assay revealed that iron positively affected the binding of XibR to the upstream regulatory sequences of the target virulence genes, an effect that was reversed by ferric iron chelator deferoxamine. Taken together, these data revealed that how XibR coordinately regulates virulence associated and iron metabolism functions in Xanthomonads in

Decoding the role of regulatory element polymorphisms in complex disease.

PubMed

Vockley, Christopher M; Barrera, Alejandro; Reddy, Timothy E

2017-04-01

Genetic variation in gene regulatory elements contributes to diverse human diseases, ranging from rare and severe developmental defects to common and complex diseases such as obesity and diabetes. Early examples of regulatory mechanisms of human diseases involve large chromosomal rearrangements that change the regulatory connections within the genome. Single nucleotide variants in regulatory elements can also contribute to disease, potentially via demonstrated associations with changes in transcription factor binding, enhancer activity, post-translational histone modifications, long-range enhancer-promoter interactions, or RNA polymerase recruitment. Establishing causality between non-coding genetic variants, gene regulation, and disease has recently become more feasible with advances in genome-editing and epigenome-editing technologies. As establishing causal regulatory mechanisms of diseases becomes routine, functional annotation of target genes is likely to emerge as a major bottleneck for translation into patient benefits. In this review, we discuss the history and recent advances in understanding the regulatory mechanisms of human disease, and new challenges likely to be encountered once establishing those mechanisms becomes rote. Copyright © 2016 Elsevier Ltd. All rights reserved.

Mouse Conjunctival Forniceal Gene Expression during Postnatal Development and Its Regulation by Krüppel-like Factor 4

PubMed Central

Gupta, Divya; Harvey, Stephen A. K.; Kaminski, Naftali

2011-01-01

Purpose. To identify the changes in postnatal mouse conjunctival forniceal gene expression and their regulation by Klf4 during the eye-opening stage when the goblet cells first appear. Methods. Laser microdissection (LMD) was used to collect conjunctival forniceal cells from postnatal (PN) day 9, PN14 and PN20 wild-type (WT), and PN14 Klf4-conditional null (Klf4CN) mice, in which goblet cells are absent, developing, present, and missing, respectively. Microarrays were used to compare gene expression among these groups. Expression of selected genes was validated by quantitative RT-PCR, and spatiotemporal expression was assessed by in situ hybridization. Results. This study identified 668, 251, 1160, and 139 transcripts that were increased and 492, 377, 1419, and 57 transcripts that were decreased between PN9 and PN14, PN14 and PN20, PN9 and PN20, and PN14 WT and Klf4CN conjunctiva, respectively. Transcripts encoding transcription factors Spdef, FoxA1, and FoxA3 that regulate goblet cell development in other mucosal epithelia, and epithelium-specific Ets (ESE) transcription factor family members were increased during conjunctival development. Components of pathways related to the mesenchymal–epithelial transition, glycoprotein biosynthesis, mucosal immunity, signaling, and endocytic and neural regulation were increased during conjunctival development. Conjunctival Klf4 target genes differed significantly from the previously identified corneal Klf4 target genes, implying tissue-dependent regulatory targets for Klf4. Conclusions. The changes in gene expression accompanying mouse conjunctival development were identified, and the role of Klf4 in this process was determined. This study provides new probes for examining conjunctival development and function and reveals that the gene regulatory network necessary for goblet cell development is conserved across different mucosal epithelia. PMID:21398290

Characterization of the Methylation Status of Pax7 and Myogenic Regulator Factors in Cell Myogenic Differentiation.

PubMed

Chao, Zhe; Zheng, Xin-Li; Sun, Rui-Ping; Liu, Hai-Long; Huang, Li-Li; Cao, Zong-Xi; Deng, Chang-Yan; Wang, Feng

2016-07-01

Epigenetic processes in the development of skeletal muscle have been appreciated for over a decade. DNA methylation is a major epigenetic modification important for regulating gene expression and suppressing spurious transcription. Up to now, the importance of epigenetic marks in the regulation of Pax7 and myogenic regulatory factors (MRFs) expression is far less explored. In the present study, semi-quantitative the real-time polymerase chain reaction (RT-PCR) analyses showed MyoD and Myf5 were expressed in activated and quiescent C2C12 cells. MyoG was expressed in a later stage of myogenesis. Pax7 was weakly expressed in differentiated C2C12 cells. To further understand the regulation of expression of these genes, the DNA methylation status of Pax7, MyoD, and Myf5 was determined by bisulfite sequencing PCR. During the C2C12 myoblasts fusion process, the changes of promoter and exon 1 methylation of Pax7, MyoD, and Myf5 genes were observed. In addition, an inverse relationship of low methylation and high expression was found. These results suggest that DNA methylation may be an important mechanism regulating Pax7 and MRFs transcription in cell myogenic differentiation.

Repeated cis-regulatory tuning of a metabolic bottleneck gene during evolution.

PubMed

Kuang, Meihua Christina; Kominek, Jacek; Alexander, William G; Cheng, Jan-Fang; Wrobel, Russell L; Hittinger, Chris Todd

2018-05-21

Repeated evolutionary events imply underlying genetic constraints that can make evolutionary mechanisms predictable. Morphological traits are thought to evolve frequently through cis-regulatory changes because these mechanisms bypass constraints in pleiotropic genes that are reused during development. In contrast, the constraints acting on metabolic traits during evolution are less well studied. Here we show how a metabolic bottleneck gene has repeatedly adopted similar cis-regulatory solutions during evolution, likely due to its pleiotropic role integrating flux from multiple metabolic pathways. Specifically, the genes encoding phosphoglucomutase activity (PGM1/PGM2), which connect GALactose catabolism to glycolysis, have gained and lost direct regulation by the transcription factor Gal4 several times during yeast evolution. Through targeted mutations of predicted Gal4-binding sites in yeast genomes, we show this galactose-mediated regulation of PGM1/2 supports vigorous growth on galactose in multiple yeast species, including Saccharomyces uvarum and Lachancea kluyveri. Furthermore, the addition of galactose-inducible PGM1 alone is sufficient to improve the growth on galactose of multiple species that lack this regulation, including Saccharomyces cerevisiae. The strong association between regulation of PGM1/2 by Gal4 even enables remarkably accurate predictions of galactose growth phenotypes between closely related species. This repeated mode of evolution suggests that this specific cis-regulatory connection is a common way that diverse yeasts can govern flux through the pathway, likely due to the constraints imposed by this pleiotropic bottleneck gene. Since metabolic pathways are highly interconnected, we argue that cis-regulatory evolution might be widespread at pleiotropic genes that control metabolic bottlenecks and intersections.

TSC1 regulates the balance between effector and regulatory T cells.

PubMed

Park, Yoon; Jin, Hyung-Seung; Lopez, Justine; Elly, Chris; Kim, Gisen; Murai, Masako; Kronenberg, Mitchell; Liu, Yun-Cai

2013-12-01

Mammalian target of rapamycin (mTOR) plays a crucial role in the control of T cell fate determination; however, the precise regulatory mechanism of the mTOR pathway is not fully understood. We found that T cell-specific deletion of the gene encoding tuberous sclerosis 1 (TSC1), an upstream negative regulator of mTOR, resulted in augmented Th1 and Th17 differentiation and led to severe intestinal inflammation in a colitis model. Conditional Tsc1 deletion in Tregs impaired their suppressive activity and expression of the Treg marker Foxp3 and resulted in increased IL-17 production under inflammatory conditions. A fate-mapping study revealed that Tsc1-null Tregs that lost Foxp3 expression gained a stronger effector-like phenotype compared with Tsc1-/- Foxp3+ Tregs. Elevated IL-17 production in Tsc1-/- Treg cells was reversed by in vivo knockdown of the mTOR target S6K1. Moreover, IL-17 production was enhanced by Treg-specific double deletion of Tsc1 and Foxo3a. Collectively, these studies suggest that TSC1 acts as an important checkpoint for maintaining immune homeostasis by regulating cell fate determination.

Physiological factors that regulate skin pigmentation.

PubMed

Yamaguchi, Yuji; Hearing, Vincent J

2009-01-01

More than 150 genes have been identified that affect skin color either directly or indirectly, and we review current understanding of physiological factors that regulate skin pigmentation. We focus on melanosome biogenesis, transport and transfer, melanogenic regulators in melanocytes, and factors derived from keratinocytes, fibroblasts, endothelial cells, hormones, inflammatory cells, and nerves. Enzymatic components of melanosomes include tyrosinase, tyrosinase-related protein 1, and dopachrome tautomerase, which depend on the functions of OA1, P, MATP, ATP7A, and BLOC-1 to synthesize eumelanins and pheomelanins. The main structural component of melanosomes is Pmel17/gp100/Silv, whose sorting involves adaptor protein 1A (AP1A), AP1B, AP2, and spectrin, as well as a chaperone-like component, MART-1. During their maturation, melanosomes move from the perinuclear area toward the plasma membrane. Microtubules, dynein, kinesin, actin filaments, Rab27a, melanophilin, myosin Va, and Slp2-a are involved in melanosome transport. Foxn1 and p53 up-regulate skin pigmentation via bFGF and POMC derivatives including alpha-MSH and ACTH, respectively. Other critical factors that affect skin pigmentation include MC1R, CREB, ASP, MITF, PAX3, SOX9/10, LEF-1/TCF, PAR-2, DKK1, SCF, HGF, GM-CSF, endothelin-1, prostaglandins, leukotrienes, thromboxanes, neurotrophins, and neuropeptides. UV radiation up-regulates most factors that increase melanogenesis. Further studies will elucidate the currently unknown functions of many other pigment genes/proteins. (c) 2009 International Union of Biochemistry and Molecular Biology, Inc.

Evolution of DNA-Binding Sites of a Floral Master Regulatory Transcription Factor

PubMed Central

Muiño, Jose M.; de Bruijn, Suzanne; Pajoro, Alice; Geuten, Koen; Vingron, Martin; Angenent, Gerco C.; Kaufmann, Kerstin

2016-01-01

Flower development is controlled by the action of key regulatory transcription factors of the MADS-domain family. The function of these factors appears to be highly conserved among species based on mutant phenotypes. However, the conservation of their downstream processes is much less well understood, mostly because the evolutionary turnover and variation of their DNA-binding sites (BSs) among plant species have not yet been experimentally determined. Here, we performed comparative ChIP (chromatin immunoprecipitation)-seq experiments of the MADS-domain transcription factor SEPALLATA3 (SEP3) in two closely related Arabidopsis species: Arabidopsis thaliana and A. lyrata which have very similar floral organ morphology. We found that BS conservation is associated with DNA sequence conservation, the presence of the CArG-box BS motif and on the relative position of the BS to its potential target gene. Differences in genome size and structure can explain that SEP3 BSs in A. lyrata can be located more distantly to their potential target genes than their counterparts in A. thaliana. In A. lyrata, we identified transposition as a mechanism to generate novel SEP3 binding locations in the genome. Comparative gene expression analysis shows that the loss/gain of BSs is associated with a change in gene expression. In summary, this study investigates the evolutionary dynamics of DNA BSs of a floral key-regulatory transcription factor and explores factors affecting this phenomenon. PMID:26429922

Enhancing gene regulatory network inference through data integration with markov random fields

DOE PAGES

Banf, Michael; Rhee, Seung Y.

2017-02-01

Here, a gene regulatory network links transcription factors to their target genes and represents a map of transcriptional regulation. Much progress has been made in deciphering gene regulatory networks computationally. However, gene regulatory network inference for most eukaryotic organisms remain challenging. To improve the accuracy of gene regulatory network inference and facilitate candidate selection for experimentation, we developed an algorithm called GRACE (Gene Regulatory network inference ACcuracy Enhancement). GRACE exploits biological a priori and heterogeneous data integration to generate high- confidence network predictions for eukaryotic organisms using Markov Random Fields in a semi-supervised fashion. GRACE uses a novel optimization schememore » to integrate regulatory evidence and biological relevance. It is particularly suited for model learning with sparse regulatory gold standard data. We show GRACE’s potential to produce high confidence regulatory networks compared to state of the art approaches using Drosophila melanogaster and Arabidopsis thaliana data. In an A. thaliana developmental gene regulatory network, GRACE recovers cell cycle related regulatory mechanisms and further hypothesizes several novel regulatory links, including a putative control mechanism of vascular structure formation due to modifications in cell proliferation.« less

Enhancing gene regulatory network inference through data integration with markov random fields

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

Banf, Michael; Rhee, Seung Y.

Here, a gene regulatory network links transcription factors to their target genes and represents a map of transcriptional regulation. Much progress has been made in deciphering gene regulatory networks computationally. However, gene regulatory network inference for most eukaryotic organisms remain challenging. To improve the accuracy of gene regulatory network inference and facilitate candidate selection for experimentation, we developed an algorithm called GRACE (Gene Regulatory network inference ACcuracy Enhancement). GRACE exploits biological a priori and heterogeneous data integration to generate high- confidence network predictions for eukaryotic organisms using Markov Random Fields in a semi-supervised fashion. GRACE uses a novel optimization schememore » to integrate regulatory evidence and biological relevance. It is particularly suited for model learning with sparse regulatory gold standard data. We show GRACE’s potential to produce high confidence regulatory networks compared to state of the art approaches using Drosophila melanogaster and Arabidopsis thaliana data. In an A. thaliana developmental gene regulatory network, GRACE recovers cell cycle related regulatory mechanisms and further hypothesizes several novel regulatory links, including a putative control mechanism of vascular structure formation due to modifications in cell proliferation.« less

Transcription factors, sucrose, and sucrose metabolic genes interact to regulate potato phenylpropanoid metabolism

PubMed Central

Payyavula, Raja S.; Navarre, Duroy A.

2013-01-01

Much remains unknown about how transcription factors and sugars regulate phenylpropanoid metabolism in tuber crops like potato (Solanum tuberosum). Based on phylogeny and protein similarity to known regulators of phenylpropanoid metabolism, 15 transcription factors were selected and their expression was compared in white, yellow, red, and purple genotypes with contrasting phenolic and anthocyanin profiles. Red and purple genotypes had increased phenylalanine ammonia lyase (PAL) enzyme activity, markedly higher levels of phenylpropanoids, and elevated expression of most phenylpropanoid structural genes, including a novel anthocyanin O-methyltransferase. The transcription factors Anthocyanin1 (StAN1), basic Helix Loop Helix1 (StbHLH1), and StWD40 were more strongly expressed in red and purple potatoes. Expression of 12 other transcription factors was not associated with phenylpropanoid content, except for StMYB12B, which showed a negative relationship. Increased expression of AN1, bHLH1, and WD40 was also associated with environmentally mediated increases in tuber phenylpropanoids. Treatment of potato plantlets with sucrose induced hydroxycinnamic acids, flavonols, anthocyanins, structural genes, AN1, bHLH1, WD40, and genes encoding the sucrose-hydrolysing enzymes SUSY1, SUSY4, and INV2. Transient expression of StAN1 in tobacco leaves induced bHLH1, structural genes, SUSY1, SUSY4, and INV1, and increased phenylpropanoid amounts. StAN1 infiltration into tobacco leaves decreased sucrose and glucose concentrations. In silico promoter analysis revealed the presence of MYB and bHLH regulatory elements on sucrolytic gene promoters and sucrose-responsive elements on the AN1 promoter. These findings reveal an interesting dynamic between AN1, sucrose, and sucrose metabolic genes in modulating potato phenylpropanoids. PMID:24098049

Signatures of combinatorial regulation in intrinsic biological noise

PubMed Central

Warmflash, Aryeh; Dinner, Aaron R.

2008-01-01

Gene expression is controlled by the action of transcription factors that bind to DNA and influence the rate at which a gene is transcribed. The quantitative mapping between the regulator concentrations and the output of the gene is known as the cis-regulatory input function (CRIF). Here, we show how the CRIF shapes the form of the joint probability distribution of molecular copy numbers of the regulators and the product of a gene. Namely, we derive a class of fluctuation-based relations that relate the moments of the distribution to the derivatives of the CRIF. These relations are useful because they enable statistics of naturally arising cell-to-cell variations in molecular copy numbers to substitute for traditional manipulations for probing regulatory mechanisms. We demonstrate that these relations can distinguish super- and subadditive gene regulatory scenarios (molecular analogs of AND and OR logic operations) in simulations that faithfully represent bacterial gene expression. Applications and extensions to other regulatory scenarios are discussed. PMID:18981421

Diverse patterns of genomic targeting by transcriptional regulators in Drosophila melanogaster.

PubMed

Slattery, Matthew; Ma, Lijia; Spokony, Rebecca F; Arthur, Robert K; Kheradpour, Pouya; Kundaje, Anshul; Nègre, Nicolas; Crofts, Alex; Ptashkin, Ryan; Zieba, Jennifer; Ostapenko, Alexander; Suchy, Sarah; Victorsen, Alec; Jameel, Nader; Grundstad, A Jason; Gao, Wenxuan; Moran, Jennifer R; Rehm, E Jay; Grossman, Robert L; Kellis, Manolis; White, Kevin P

2014-07-01

Annotation of regulatory elements and identification of the transcription-related factors (TRFs) targeting these elements are key steps in understanding how cells interpret their genetic blueprint and their environment during development, and how that process goes awry in the case of disease. One goal of the modENCODE (model organism ENCyclopedia of DNA Elements) Project is to survey a diverse sampling of TRFs, both DNA-binding and non-DNA-binding factors, to provide a framework for the subsequent study of the mechanisms by which transcriptional regulators target the genome. Here we provide an updated map of the Drosophila melanogaster regulatory genome based on the location of 84 TRFs at various stages of development. This regulatory map reveals a variety of genomic targeting patterns, including factors with strong preferences toward proximal promoter binding, factors that target intergenic and intronic DNA, and factors with distinct chromatin state preferences. The data also highlight the stringency of the Polycomb regulatory network, and show association of the Trithorax-like (Trl) protein with hotspots of DNA binding throughout development. Furthermore, the data identify more than 5800 instances in which TRFs target DNA regions with demonstrated enhancer activity. Regions of high TRF co-occupancy are more likely to be associated with open enhancers used across cell types, while lower TRF occupancy regions are associated with complex enhancers that are also regulated at the epigenetic level. Together these data serve as a resource for the research community in the continued effort to dissect transcriptional regulatory mechanisms directing Drosophila development. © 2014 Slattery et al.; Published by Cold Spring Harbor Laboratory Press.

Regulatory immune cells and functions in autoimmunity and transplantation immunology.

PubMed

Papp, Gabor; Boros, Peter; Nakken, Britt; Szodoray, Peter; Zeher, Margit

2017-05-01

In physiological circumstances, various tolerogenic mechanisms support the protection of self-structures during immune responses. However, quantitative and/or qualitative changes in regulatory immune cells and mediators can evoke auto-reactive immune responses, and upon susceptible genetic background, along with the presence of other concomitant etiological factors, autoimmune disease may develop. In transplant immunology, tolerogenic mechanisms are also critical, since the balance between of alloantigen-reactive effector cells and the regulatory immune cells will ultimately determine whether a graft is accepted or rejected. Better understanding of the immunological tolerance and the potential modulations of immune regulatory processes are crucial for developing effective therapies in autoimmune diseases as well as in organ transplantation. In this review, we focus on the novel insights regarding the impaired immune regulation and other relevant factors contributing to the development of auto-reactive and graft-reactive immune responses in autoimmune diseases and transplant rejection, respectively. We also address some promising approaches for modification of immune-regulatory processes and tolerogenic mechanisms in autoimmunity and solid organ transplantation, which may be beneficial in future therapeutic strategies. Copyright © 2017 Elsevier B.V. All rights reserved.

Regulatory T cells: mechanisms of differentiation and function.

PubMed

Josefowicz, Steven Z; Lu, Li-Fan; Rudensky, Alexander Y

2012-01-01

The immune system has evolved to mount an effective defense against pathogens and to minimize deleterious immune-mediated inflammation caused by commensal microorganisms, immune responses against self and environmental antigens, and metabolic inflammatory disorders. Regulatory T (Treg) cell-mediated suppression serves as a vital mechanism of negative regulation of immune-mediated inflammation and features prominently in autoimmune and autoinflammatory disorders, allergy, acute and chronic infections, cancer, and metabolic inflammation. The discovery that Foxp3 is the transcription factor that specifies the Treg cell lineage facilitated recent progress in understanding the biology of regulatory T cells. In this review, we discuss cellular and molecular mechanisms in the differentiation and function of these cells.

Dynamic analysis of the combinatorial regulation involving transcription factors and microRNAs in cell fate decisions.

PubMed

Yan, Fang; Liu, Haihong; Liu, Zengrong

2014-01-01

P53 and E2F1 are critical transcription factors involved in the choices between different cell fates including cell differentiation, cell cycle arrest or apoptosis. Recent experiments have shown that two families of microRNAs (miRNAs), p53-responsive miR34 (miRNA-34 a, b and c) and E2F1-inducible miR449 (miRNA-449 a, b and c) are potent inducers of these different fates and might have an important role in sensitizing cancer cells to drug treatment and tumor suppression. Identifying the mechanisms responsible for the combinatorial regulatory roles of these two transcription factors and two miRNAs is an important and challenging problem. Here, based in part on the model proposed in Tongli Zhang et al. (2007), we developed a mathematical model of the decision process and explored the combinatorial regulation between these two transcription factors and two miRNAs in response to DNA damage. By analyzing nonlinear dynamic behaviors of the model, we found that p53 exhibits pulsatile behavior. Moreover, a comparison is given to reveal the subtle differences of the cell fate decision process between regulation and deregulation of miR34 on E2F1. It predicts that miR34 plays a critical role in promoting cell cycle arrest. In addition, a computer simulation result also predicts that the miR449 is necessary for apoptosis in response to sustained DNA damage. In agreement with experimental observations, our model can account for the intricate regulatory relationship between these two transcription factors and two miRNAs in the cell fate decision process after DNA damage. These theoretical results indicate that miR34 and miR449 are effective tumor suppressors and play critical roles in cell fate decisions. The work provides a dynamic mechanism that shows how cell fate decisions are coordinated by two transcription factors and two miRNAs. This article is part of a Special Issue entitled: Computational Proteomics, Systems Biology and Clinical Implications. Guest Editor: Yudong Cai

An Arabidopsis Gene Regulatory Network for Secondary Cell Wall Synthesis

PubMed Central

Taylor-Teeples, M; Lin, L; de Lucas, M; Turco, G; Toal, TW; Gaudinier, A; Young, NF; Trabucco, GM; Veling, MT; Lamothe, R; Handakumbura, PP; Xiong, G; Wang, C; Corwin, J; Tsoukalas, A; Zhang, L; Ware, D; Pauly, M; Kliebenstein, DJ; Dehesh, K; Tagkopoulos, I; Breton, G; Pruneda-Paz, JL; Ahnert, SE; Kay, SA; Hazen, SP; Brady, SM

2014-01-01

Summary The plant cell wall is an important factor for determining cell shape, function and response to the environment. Secondary cell walls, such as those found in xylem, are composed of cellulose, hemicelluloses and lignin and account for the bulk of plant biomass. The coordination between transcriptional regulation of synthesis for each polymer is complex and vital to cell function. A regulatory hierarchy of developmental switches has been proposed, although the full complement of regulators remains unknown. Here, we present a protein-DNA network between Arabidopsis transcription factors and secondary cell wall metabolic genes with gene expression regulated by a series of feed-forward loops. This model allowed us to develop and validate new hypotheses about secondary wall gene regulation under abiotic stress. Distinct stresses are able to perturb targeted genes to potentially promote functional adaptation. These interactions will serve as a foundation for understanding the regulation of a complex, integral plant component. PMID:25533953

An Arabidopsis gene regulatory network for secondary cell wall synthesis

DOE PAGES

Taylor-Teeples, M.; Lin, L.; de Lucas, M.; ...

2014-12-24

The plant cell wall is an important factor for determining cell shape, function and response to the environment. Secondary cell walls, such as those found in xylem, are composed of cellulose, hemicelluloses and lignin and account for the bulk of plant biomass. The coordination between transcriptional regulation of synthesis for each polymer is complex and vital to cell function. A regulatory hierarchy of developmental switches has been proposed, although the full complement of regulators remains unknown. In this paper, we present a protein–DNA network between Arabidopsis thaliana transcription factors and secondary cell wall metabolic genes with gene expression regulated bymore » a series of feed-forward loops. This model allowed us to develop and validate new hypotheses about secondary wall gene regulation under abiotic stress. Distinct stresses are able to perturb targeted genes to potentially promote functional adaptation. Finally, these interactions will serve as a foundation for understanding the regulation of a complex, integral plant component.« less

Pin1 down-regulates transforming growth factor-beta (TGF-beta) signaling by inducing degradation of Smad proteins.

PubMed

Nakano, Ayako; Koinuma, Daizo; Miyazawa, Keiji; Uchida, Takafumi; Saitoh, Masao; Kawabata, Masahiro; Hanai, Jun-ichi; Akiyama, Hirotada; Abe, Masahiro; Miyazono, Kohei; Matsumoto, Toshio; Imamura, Takeshi

2009-03-06

Transforming growth factor-beta (TGF-beta) is crucial in numerous cellular processes, such as proliferation, differentiation, migration, and apoptosis. TGF-beta signaling is transduced by intracellular Smad proteins that are regulated by the ubiquitin-proteasome system. Smad ubiquitin regulatory factor 2 (Smurf2) prevents TGF-beta and bone morphogenetic protein signaling by interacting with Smads and inducing their ubiquitin-mediated degradation. Here we identified Pin1, a peptidylprolyl cis-trans isomerase, as a novel protein binding Smads. Pin1 interacted with Smad2 and Smad3 but not Smad4; this interaction was enhanced by the phosphorylation of (S/T)P motifs in the Smad linker region. (S/T)P motif phosphorylation also enhanced the interaction of Smad2/3 with Smurf2. Pin1 reduced Smad2/3 protein levels in a manner dependent on its peptidyl-prolyl cis-trans isomerase activity. Knockdown of Pin1 increased the protein levels of endogenous Smad2/3. In addition, Pin1 both enhanced the interaction of Smurf2 with Smads and enhanced Smad ubiquitination. Pin1 inhibited TGF-beta-induced transcription and gene expression, suggesting that Pin1 negatively regulates TGF-beta signaling by down-regulating Smad2/3 protein levels via induction of Smurf2-mediated ubiquitin-proteasomal degradation.

40 CFR 94.6 - Regulatory structure.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 20 2010-07-01 2010-07-01 false Regulatory structure. 94.6 Section 94... for Compression-Ignition Marine Engines § 94.6 Regulatory structure. This section provides an overview of the regulatory structure of this part. (a) The regulations of this Part 94 are intended to control...

The influence of environmental factors on heart rate chronostructure depending on the individual characteristics of autonomic regulation. Results of long-term medical-ecological studies.

NASA Astrophysics Data System (ADS)

Isaeva, Olga; Zenchenko, Tatiana; Breus, Tamara; Chernikova, Anna; Baevsky, Roman

It was previously shown [Baevsky, Petrov, 1998] that during space flight under influence of geomagnetic disturbances there are both specific response of the autonomic regulation system in the form of vasomotor cardiovascular center activation (LF spectral components) and non-specific stress response, which depends on the actual autonomic balance [Breus, Baevsky, 2002]. Within the project "Mars-500" the parallel medical-ecological studies were conducted in 10 groups (10-16 people), that lived in different regions of the world under the influence of various environmental factors - climatic, geographic, industrial, social and other. It allowed us to obtain a sufficiently large number of variants of adaptive reactions caused by differences in external impacts. The main research method was the heart rate variability (HRV) analysis in short ECG samples (5 minutes) for assessing heart rate chronostructure and functional status of autonomic regulation. Results of studies have demonstrated that environmental loads on the regulatory mechanisms is higher in the northern and north-eastern regions of Russia - Magadan and Syktyvkar. Stress-index of regulatory systems and adaptive risk indicator is significantly higher in these groups [Baevsky, Berseneva, 2013]. The preliminary search of weather factors (atmospheric pressure, air temperature, humidity and magnetic index Kp) influence on the autonomic regulation of heart rate showed that there are no any significant changes and relationships in the entire group of participants. We have assumed that the character of adaptive responses, including responses to changing weather and geomagnetic conditions, is associated with the individual characteristics and the initial functional state of autonomic regulation. To test this hypothesis, we have identified two groups of subjects with different autonomic balance. The first group included individuals with a pronounced predominance of sympathetic regulation (n = 127), the second - with a

In silico analysis of cis-acting regulatory elements in 5' regulatory regions of sucrose transporter gene families in rice (Oryza sativa Japonica) and Arabidopsis thaliana.

PubMed

Ibraheem, Omodele; Botha, Christiaan E J; Bradley, Graeme

2010-12-01

The regulation of gene expression involves a multifarious regulatory system. Each gene contains a unique combination of cis-acting regulatory sequence elements in the 5' regulatory region that determines its temporal and spatial expression. Cis-acting regulatory elements are essential transcriptional gene regulatory units; they control many biological processes and stress responses. Thus a full understanding of the transcriptional gene regulation system will depend on successful functional analyses of cis-acting elements. Cis-acting regulatory elements present within the 5' regulatory region of the sucrose transporter gene families in rice (Oryza sativa Japonica cultivar-group) and Arabidopsis thaliana, were identified using a bioinformatics approach. The possible cis-acting regulatory elements were predicted by scanning 1.5kbp of 5' regulatory regions of the sucrose transporter genes translational start sites, using Plant CARE, PLACE and Genomatix Matinspector professional databases. Several cis-acting regulatory elements that are associated with plant development, plant hormonal regulation and stress response were identified, and were present in varying frequencies within the 1.5kbp of 5' regulatory region, among which are; A-box, RY, CAT, Pyrimidine-box, Sucrose-box, ABRE, ARF, ERE, GARE, Me-JA, ARE, DRE, GA-motif, GATA, GT-1, MYC, MYB, W-box, and I-box. This result reveals the probable cis-acting regulatory elements that possibly are involved in the expression and regulation of sucrose transporter gene families in rice and Arabidopsis thaliana during cellular development or environmental stress conditions. Copyright © 2010 Elsevier Ltd. All rights reserved.

Growth factor transgenes interactively regulate articular chondrocytes.

PubMed

Shi, Shuiliang; Mercer, Scott; Eckert, George J; Trippel, Stephen B

2013-04-01

Adult articular chondrocytes lack an effective repair response to correct damage from injury or osteoarthritis. Polypeptide growth factors that stimulate articular chondrocyte proliferation and cartilage matrix synthesis may augment this response. Gene transfer is a promising approach to delivering such factors. Multiple growth factor genes regulate these cell functions, but multiple growth factor gene transfer remains unexplored. We tested the hypothesis that multiple growth factor gene transfer selectively modulates articular chondrocyte proliferation and matrix synthesis. We tested the hypothesis by delivering combinations of the transgenes encoding insulin-like growth factor I (IGF-I), fibroblast growth factor-2 (FGF-2), transforming growth factor beta1 (TGF-β1), bone morphogenetic protein-2 (BMP-2), and bone morphogenetic protien-7 (BMP-7) to articular chondrocytes and measured changes in the production of DNA, glycosaminoglycan, and collagen. The transgenes differentially regulated all these chondrocyte activities. In concert, the transgenes interacted to generate widely divergent responses from the cells. These interactions ranged from inhibitory to synergistic. The transgene pair encoding IGF-I and FGF-2 maximized cell proliferation. The three-transgene group encoding IGF-I, BMP-2, and BMP-7 maximized matrix production and also optimized the balance between cell proliferation and matrix production. These data demonstrate an approach to articular chondrocyte regulation that may be tailored to stimulate specific cell functions, and suggest that certain growth factor gene combinations have potential value for cell-based articular cartilage repair. Copyright © 2012 Wiley Periodicals, Inc.

[Dynamic hierarchy of regulatory peptides. Structure of the induction relations of regulators as the target for therapeutic agents].

PubMed

Koroleva, S V; Miasoedov, N F

2012-01-01

Based on the database information (literature period 1970-2010 gg.) on the effects of regulatory peptides (RP) and non-peptide neurotransmitters (dopamine, serotonin, norepi-nephrine, acetylcholine) it was analyzed of possible cascade processes of endogenous regulators. It was found that the entire continuum of RP and mediators is a chaotic soup of the ordered three-level compartments. Such a dynamic functional hierarchy of endogenous regulators allows to create start-up and corrective tasks for a variety of physiological functions. Some examples of static and dynamic patterns of induction processes of RP and mediators (that regulate the states of anxiety, depression, learning and memory, feeding behavior, reproductive processes, etc.) are considered.

Facing regulatory challenges of on-line hemodiafiltration.

PubMed

Kümmerle, Wolfgang

2011-01-01

On-line hemodiafiltration (on-line HDF) is the result of a vision that triggered multifarious changes in very different areas. Driven by the idea to offer better medical treatment for renal patients, technological innovations were developed and established that also constituted new challenges in the field of regulatory affairs. The existing regulations predominantly addressed the quality and safety of those products needed to perform dialysis treatment which were supplied by industrial manufacturers. However, the complexity of treatment system required for the provision of on-line fluids demanded a holistic approach encompassing all components involved. Hence, focus was placed not only on single products, but much more on their interfacing, and the clinical infrastructure, in particular, had to undergo substantial changes. The overall understanding of the interaction between such factors, quite different in their nature, was crucial to overcome the arising regulatory obstacles. This essay describes the evolution of the on-line HDF procedure from the regulatory point of view. A simplified diagram demonstrates the path taken from the former regulatory understanding to the realization of necessary changes. That achievement was only possible through 'management of preview' and consequent promotion of technical and medical innovations as well as regulatory re-evaluations. Copyright © 2011 S. Karger AG, Basel.

Following the Footsteps of Chlamydial Gene Regulation

PubMed Central

Domman, D.; Horn, M.

2015-01-01

Regulation of gene expression ensures an organism responds to stimuli and undergoes proper development. Although the regulatory networks in bacteria have been investigated in model microorganisms, nearly nothing is known about the evolution and plasticity of these networks in obligate, intracellular bacteria. The phylum Chlamydiae contains a vast array of host-associated microbes, including several human pathogens. The Chlamydiae are unique among obligate, intracellular bacteria as they undergo a complex biphasic developmental cycle in which large swaths of genes are temporally regulated. Coupled with the low number of transcription factors, these organisms offer a model to study the evolution of regulatory networks in intracellular organisms. We provide the first comprehensive analysis exploring the diversity and evolution of regulatory networks across the phylum. We utilized a comparative genomics approach to construct predicted coregulatory networks, which unveiled genus- and family-specific regulatory motifs and architectures, most notably those of virulence-associated genes. Surprisingly, our analysis suggests that few regulatory components are conserved across the phylum, and those that are conserved are involved in the exploitation of the intracellular niche. Our study thus lends insight into a component of chlamydial evolution that has otherwise remained largely unexplored. PMID:26424812

The Streptococcus pyogenes serotype M49 Nra-Ralp3 transcriptional regulatory network and its control of virulence factor expression from the novel eno ralp3 epf sagA pathogenicity region.

PubMed

Kreikemeyer, Bernd; Nakata, Masanobu; Köller, Thomas; Hildisch, Hendrikje; Kourakos, Vassilios; Standar, Kerstin; Kawabata, Shigetada; Glocker, Michael O; Podbielski, Andreas

2007-12-01

Many Streptococcus pyogenes (group A streptococcus [GAS]) virulence factor- and transcriptional regulator-encoding genes cluster together in discrete genomic regions. Nra is a central regulator of the FCT region. Previous studies exclusively described Nra as a transcriptional repressor of adhesin and toxin genes. Here transcriptome and proteome analysis of a serotype M49 GAS strain and an isogenic Nra mutant of this strain revealed the complete Nra regulon profile. Nra is active in all growth phases tested, with the largest regulon in the transition phase. Almost exclusively, virulence factor-encoding genes are repressed by Nra; these genes include the GAS pilus operon, the capsule synthesis operon, the cytolysin-mediated translocation system genes, all Mga region core virulence genes, and genes encoding other regulators, like the Ihk/Irr system, Rgg, and two additional RofA-like protein family regulators. Surprisingly, our experiments revealed that Nra additionally acts as a positive regulator, mostly for genes encoding proteins and enzymes with metabolic functions. Epidemiological investigations revealed strong genetic linkage of one particular Nra-repressed regulator, Ralp3 (SPy0735), with a gene encoding Epf (extracellular protein factor from Streptococcus suis). In a serotype-specific fashion, this ralp3 epf gene block is integrated, most likely via transposition, into the eno sagA virulence gene block, which is present in all GAS serotypes. In GAS serotypes M1, M4, M12, M28, and M49 this novel discrete genetic region is therefore designated the eno ralp3 epf sagA (ERES) pathogenicity region. Functional experiments showed that Epf is a novel GAS plasminogen-binding protein and revealed that Ralp3 activity counteracts Nra and MsmR regulatory activity. In addition to the Mga and FCT regions, the ERES region is the third discrete chromosomal pathogenicity region. All of these regions are transcriptionally linked, adding another level of complexity to the known

The identification of transcription factors expressed in the notochord of Ciona intestinalis adds new potential players to the brachyury gene regulatory network.

PubMed

José-Edwards, Diana S; Kerner, Pierre; Kugler, Jamie E; Deng, Wei; Jiang, Di; Di Gregorio, Anna

2011-07-01

The notochord is the distinctive characteristic of chordates; however, the knowledge of the complement of transcription factors governing the development of this structure is still incomplete. Here we present the expression patterns of seven transcription factor genes detected in the notochord of the ascidian Ciona intestinalis at various stages of embryonic development. Four of these transcription factors, Fos-a, NFAT5, AFF and Klf15, have not been directly associated with the notochord in previous studies, while the others, including Spalt-like-a, Lmx-like, and STAT5/6-b, display evolutionarily conserved expression in this structure as well as in other domains. We examined the hierarchical relationships between these genes and the transcription factor Brachyury, which is necessary for notochord development in all chordates. We found that Ciona Brachyury regulates the expression of most, although not all, of these genes. These results shed light on the genetic regulatory program underlying notochord formation in Ciona and possibly other chordates. Copyright © 2011 Wiley-Liss, Inc.