scholarly journals Architectural Epigenetics: Mitotic Retention of Mammalian Transcriptional Regulatory Information

2010 ◽  
Vol 30 (20) ◽  
pp. 4758-4766 ◽  
Author(s):  
Sayyed K. Zaidi ◽  
Daniel W. Young ◽  
Martin Montecino ◽  
Jane B. Lian ◽  
Janet L. Stein ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Transcription Factor ◽  
Epigenetic Mechanisms ◽  
Cellular Phenotype ◽  
Transcriptional Regulatory ◽  
Regulatory Information ◽  
Cellular Identity ◽  
Epigenetic Signatures ◽  
Transcription Factor Occupancy

ABSTRACT Epigenetic regulatory information must be retained during mammalian cell division to sustain phenotype-specific and physiologically responsive gene expression in the progeny cells. Histone modifications, DNA methylation, and RNA-mediated silencing are well-defined epigenetic mechanisms that control the cellular phenotype by regulating gene expression. Recent results suggest that the mitotic retention of nuclease hypersensitivity, selective histone marks, as well as the lineage-specific transcription factor occupancy of promoter elements contribute to the epigenetic control of sustained cellular identity in progeny cells. We propose that these mitotic epigenetic signatures collectively constitute architectural epigenetics, a novel and essential mechanism that conveys regulatory information to sustain the control of phenotype and proliferation in progeny cells by bookmarking genes for activation or suppression.

Comparison of Expression and Epigenetic Profiles in Human and Mouse Erythropoiesis and Megakaryopoiesis Using a Systems Biology Model

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2383-2383
Author(s):  
Jens Lichtenberg ◽  
Elisabeth F. Heuston ◽  
Cheryl A. Keller ◽  
Ross C. Hardison ◽  
David M. Bodine
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Transcription Factor ◽  
Systems Biology ◽  
Hematopoietic Cells ◽  
Gene Body ◽  
Cell Type ◽  
Human And Mouse ◽  
Different Levels ◽  
Transcription Factor Occupancy

Abstract To date numerous datasets of gene expression and epigenetic profiles for mouse and human hematopoietic cells have been generated. While individual data sets for a particular cell type have been correlated, no approach exists to harness all expression and epigenetic profiles for the different types of hematopoietic cells. Our goal is to develop a systems biology platform to compare epigenetic profiles of hematopoietic cells towards a better understanding of epigenetic mechanisms governing hematopoiesis. To provide the necessary foundation to support systematic studies of hematopoiesis, we have developed the Systems Biology Repository (SBR, http://sbrblood.nhgri.nih.gov), a data "ranch" for organizing and analyzing transcriptome and epigenome data cells throughout differentiation. To populate SBR, we extracted, curated, annotated, and integrated all human and mouse hematopoietic datasets available through the Encyclopedia of DNA Elements (ENCODE), the Gene Expression Omnibus (GEO) and the Short Read Repository (SRR). These include genome-wide profiles of DNA methylation, histone methylation and acetylation, transcription factor occupancy (ChIPSeq), chromatin accessibility (DNaseISeq, ATACSeq, FAIRESeq), and coding as well as non-coding transcriptional profiles (RNASeq). To demonstrate the utility of SBR, we conducted three different analyses. The first was a vertical study of HistoneSeq (H3K4me1, H3K4me2, H3K4me3, and H3K27ac), DNA methylation and RNASeq profiles during mouse erythroid differentiation. We found a global decrease in DNA methylation from hematopoietic stem and progenitor cells (HSC) through common myeloid progenitors (CMP), erythroid progenitor cells (MEP) and erythroblasts (ERY; 92936 peaks in HSC to 14422 in ERY). The number of expressed genes (using a tags per million cutoff of 10) increased in erythroid progenitors (8901 in HSC to 10778 in CMP and 10670 in MEP) before decreasing in ERY (8654). 62% of histone marks delineating active enhancers (H3K27ac, H3K4me1) are present in both HSC and ERY, while 48% arise de novo during differentiation. In contrast, only 16% of active promoter specific histone marks (H3K4me2, H3K4me3) are present in both HSC and ERY. For a horizontal analysis we compared the DNA methylation, RNASeq, histone modification (H3K4me1, H3K4me2, H3K4me3, and H3K27ac) and transcription factor binding (GATA1 and NFE2) profiles of erythroblasts (ERY) and megakaryocytes (MEG). We found a similar relationship between gene expression and the histone and DNA methylation profiles in each cell type but differences between expression and in transcription factor occupancy. DNA methylation and H3K4me3 was enriched in the gene body of expressed genes (>36%) for both ERY (p ≤ 0.001) and MEG (p ≤ 0.01). In contrast DNA methylation was enriched in the upstream and downstream regions of non-coding RNA genes (p ≤ 0.001). Transcription factor occupancy was cell type specific: 79% of GATA1 sites are in ERY and 72% of NFE2 sites are in MEG. In erythroblasts, DNA methylation and GATA1 binding in the gene body are associated with gene silencing (4 fold difference, p ≤ 0.001), while in megakaryocytes, DNA methylation and NFE2 binding in the gene body are associated with gene activation (8 fold difference, p ≤ 0.001). We used the Mouse Genome Informatics homology map data to perform a cross-species comparison of the expression profiles of mouse and human multipotent progenitors (MPP), proerythroblasts and orthochromatic erythroblasts. We found a total of 5247 genes expressed at significantly different levels (p ≤ 0.001) between human and mouse MPP, while only 2010 genes were expressed at significantly similar levels (p ≤ 0.001). At the proerythroblast and orthochromatic erythroblast stages 7696 genes and 6571 genes were expressed at significantly different levels (p ≤ 0.001) between human and mouse respectively, while 2024 and 2560 genes were expressed at significantly similar levels (p ≤ 0.001). These data are consistent with previous studies showing differences in the transcriptional profiles of mouse and human hematopoietic cells. In summary, SBR provides a foundation to model the genetic and epigenetic landscape in both the mouse and human hematopoietic system, and enables functional correlations to be made between the species. As SBR is expanded to include data from patient cells, it will be possible to model epigenetic changes associated with disease. Disclosures No relevant conflicts of interest to declare.

Mechanisms of mammalian zinc-regulated gene expression

2008 ◽  
Vol 36 (6) ◽  
pp. 1262-1266 ◽  
Author(s):  
Kelly A. Jackson ◽  
Ruth A. Valentine ◽  
Lisa J. Coneyworth ◽  
John C. Mathers ◽  
Dianne Ford
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Transcriptional Repression ◽  
Mammalian Cells ◽  
Gene Promoter ◽  
Mrna Levels ◽  
Promoter Regions ◽  
Mrna Stabilization ◽  
Transcriptional Regulatory ◽  
Regulated Gene Expression

Mechanisms through which gene expression is regulated by zinc are central to cellular zinc homoeostasis. In this context, evidence for the involvement of zinc dyshomoeostasis in the aetiology of diseases, including Type 2 diabetes, Alzheimer's disease and cancer, highlights the importance of zinc-regulated gene expression. Mechanisms elucidated in bacteria and yeast provide examples of different possible modes of zinc-sensitive gene regulation, involving the zinc-regulated binding of transcriptional activators and repressors to gene promoter regions. A mammalian transcriptional regulatory mechanism that mediates zinc-induced transcriptional up-regulation, involving the transcription factor MTF1 (metal-response element-binding transcription factor 1), has been studied extensively. Gene responses in the opposite direction (reduced mRNA levels in response to increased zinc availability) have been observed in mammalian cells, but a specific transcriptional regulatory process responsible for such a response has yet to be identified. Examples of single zinc-sensitive transcription factors regulating gene expression in opposite directions are emerging. Although zinc-induced transcriptional repression by MTF1 is a possible explanation in some specific instances, such a mechanism cannot account for repression by zinc of all mammalian genes that show this mode of regulation, indicating the existence of as yet uncharacterized mechanisms of zinc-regulated transcription in mammalian cells. In addition, recent findings reveal a role for effects of zinc on mRNA stability in the regulation of specific zinc transporters. Our studies on the regulation of the human gene SLC30A5 (solute carrier 30A5), which codes for the zinc transporter ZnT5, have revealed that this gene provides a model system by which to study both zinc-induced transcriptional down-regulation and zinc-regulated mRNA stabilization.

scholarly journals Transcription Factor ZBED6 Mediates IGF2 Gene Expression by Regulating Promoter Activity and DNA Methylation in Myoblasts

2014 ◽  
Vol 4 (1) ◽  
Author(s):  
Yong-Zhen Huang ◽  
Liang-Zhi Zhang ◽  
Xin-Sheng Lai ◽  
Ming-Xun Li ◽  
Yu-Jia Sun ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Transcription Factor ◽  
Promoter Activity ◽  
Igf2 Gene

scholarly journals DNA Methylation Pattern in Overweight Women under an Energy-Restricted Diet Supplemented with Fish Oil

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Cátia Lira do Amaral ◽  
Fermín I. Milagro ◽  
Rui Curi ◽  
J. Alfredo Martínez
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Weight Loss ◽  
Fish Oil ◽  
Mononuclear Cells ◽  
Energy Restriction ◽  
Dietary Factors ◽  
Epigenetic Mechanisms ◽  
Overweight Women ◽  
Fish Oil Supplementation

Dietary factors modulate gene expression and are able to alter epigenetic signatures in peripheral blood mononuclear cells (PBMC). However, there are limited studies about the effects of omega-3 polyunsaturated fatty acids (n-3 PUFA) on the epigenetic mechanisms that regulate gene expression. This research investigates the effects ofn-3-rich fish oil supplementation on DNA methylation profile of several genes whose expression has been reported to be downregulated byn-3 PUFA in PBMC:CD36,FFAR3,CD14,PDK4, andFADS1. Young overweight women were supplemented with fish oil or control in a randomized 8-week intervention trial following a balanced diet with 30% energy restriction. Fatty acid receptorCD36decreased DNA methylation at CpG +477 due to energy restriction. Hypocaloric diet-induced weight loss also reduced the methylation percentages of CpG sites located inCD14,PDK4, andFADS1. The methylation patterns of these genes were only slightly affected by the fish oil supplementation, being the most relevant to the attenuation of the weight loss-induced decrease inCD36methylation after adjusting by baseline body weight. These results suggest that then-3 PUFA-induced changes in the expression of these genes in PBMC are not mediated by DNA methylation, although other epigenetic mechanisms cannot be discarded.

DNA Methyltransferase 1 Contributes to Epigenetic Signatures and Biological Phenotype during Normal B-Cell Differentiation and Lymphomagenesis.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 685-685 ◽  
Author(s):  
Rita Shaknovich ◽  
Leandro Cerchietti ◽  
Maria E. Figueroa ◽  
Ari Melnick
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
Dna Methyltransferase ◽  
Critical Role ◽  
Epigenetic Programming ◽  
Differential Digestion ◽  
Epigenetic Signatures

Abstract Normal hematopoiesis requires incremental changes in gene expression in order to establish cellular phenotypes with specialized functions. We are particularly interested in the transcriptional and epigenetic programming of germinal center (GC) B-cells, which acquire unusual biological features normally associated with cancer. Specifically, GC B-cells (i.e. centroblasts - CB) undergo rapid DNA replication while at the same time undergoing genetic recombination, and give rise to a majority of B-cell lymphomas. We hypothesized that epigenetic programming would play a critical role in the CB stage of development, and that gene-specific and genome-wide DNA methyltransferase activity is critical for these cells. We first examined the CpG methylation levels of 24,000 gene promoters in five sets of primary human B-cells just prior to (i.e. naïve B-cells - NBC) and upon entering the GC reaction (i.e. CBs). This was achieved using the HELP (HpaII tiny fragment Enrichment by Ligation-mediated PCR) assay, which relies on differential digestion of genomic DNA by the isoschizomer enzymes HpaII and Msp. HELP is a robust and reproducible method that provides accurate and quantitative measurement of DNA methylation levels throughout the genome. Remarkably, we found that the DNA methylation profile of B-cells undergoes a significant shift as readily appreciated by hierarchical clustering. The epigenetic signatures of NBC and CB are differentiation-stage dependent and do not vary significantly between individuals. The coefficient of correlation between individuals was 0.98, as compared to the NBC vs. CB fractions 0.92–0.95. Supervised analysis demonstrated that 266 genes (P<0.001) were differentially methylated upon entry of NB-cells into the GC reaction. We further correlated the methylation status of these genes with their gene expression level. The most heavily affected pathways by differential methylation and concordant expression in naïve B-cells were the Jak/STAT and MAP3K signaling pathways, while in CBs the p38 MAPK pathway and Ikaros family of genes were most affected. Given the epigenetic reprogramming observed in CBs vs. NBCs, along with the need for maintenance of methylation during rapid replication, we predicted that DNA methyltransferase (DNMT) enzymes play a critical role in centroblasts. By performing QPCR and Western blots on isolated fractions of human tonsilar lymphocytes and anatomical localization by immunohistochemistry, we found that DNMTs have a complex temporal and combinatorial expression pattern whereby DNMT1 was the main methyltransferase detectable in centroblasts. Additionally we studied 10 DLBCL cell lines and a panel of primary DLBCL (n=176 for mRNA and 70 for protein) for DNMTs expression. Spearman Rank correlation analysis revealed that DNMT1 was preferentially highly expressed in GCB vs. ABC primary DLBCLs, as well as in BCR vs. OxPhos DLBCLs. Taken together, our data suggest that i) dynamic changes in epigenetic programming contribute to formation of GCs, ii) that DNMT1 may play both a de novo and maintenance methylation role in GC cells, iii) that DNMT1 is markedly upregulated in normal centroblasts and in DLBCLs with the BCR or GCB gene expression profiles and iv) specific therapeutic targeting of DNMT1 rather than non-specific global inhibition of DNA methylation could be a useful anti-lymphoma strategy for germinal center-derived DLBCLs.

scholarly journals Operator Sequence Alters Gene Expression Independently of Transcription Factor Occupancy in Bacteria

Cell Reports ◽  
2012 ◽  
Vol 2 (1) ◽  
pp. 150-161 ◽  
Author(s):  
Hernan G. Garcia ◽  
Alvaro Sanchez ◽  
James Q. Boedicker ◽  
Melisa Osborne ◽  
Jeff Gelles ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Operator Sequence ◽  
Transcription Factor Occupancy

scholarly journals An epigenetic pathway approach to investigating associations between prenatal exposure to maternal mood disorder and newborn neurobehavior

2018 ◽  
Vol 30 (3) ◽  
pp. 881-890 ◽  
Author(s):  
Elisabeth Conradt ◽  
Daniel E. Adkins ◽  
Sheila E. Crowell ◽  
Catherine Monk ◽  
Michael S. Kobor
Keyword(s):  
Dna Methylation ◽  
Transcription Factor ◽  
Mood Disorder ◽  
Prenatal Exposure ◽  
Binding Sites ◽  
Association Studies ◽  
Epigenetic Mechanisms ◽  
Maternal Mood ◽  
Target Dna ◽  
Analytical Approaches

AbstractFollowing recent advances in behavioral and psychiatric epigenetics, researchers are increasingly using epigenetic methods to study prenatal exposure to maternal mood disorder and its effects on fetal and newborn neurobehavior. Despite notable progress, various methodological limitations continue to obscure our understanding of the epigenetic mechanisms underpinning prenatal exposure to maternal mood disorder on newborn neurobehavioral development. Here we detail this problem, discussing limitations of the currently dominant analytical approaches (i.e., candidate epigenetic and epigenome-wide association studies), then present a solution that retains many benefits of existing methods while minimizing their shortcomings: epigenetic pathway analysis. We argue that the application of pathway-based epigenetic approaches that target DNA methylation at transcription factor binding sites could substantially deepen our mechanistic understanding of how prenatal exposures influence newborn neurobehavior.

scholarly journals Leveraging brain cortex-derived molecular data to elucidate epigenetic and transcriptomic drivers of neurological function and disease

2018 ◽  
Author(s):  
Charlie Hatcher ◽  
Caroline L. Relton ◽  
Tom R. Gaunt ◽  
Tom G. Richardson
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Histone Acetylation ◽  
Genetic Variants ◽  
Large Scale ◽  
Genetic Variant ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Epigenetic Mechanisms ◽  
Trait Variation

AbstractIntegrative approaches which harness large-scale molecular datasets can help develop mechanistic insight into findings from genome-wide association studies (GWAS). We have performed extensive analyses to uncover transcriptional and epigenetic processes which may play a role in neurological trait variation.This was undertaken by applying Bayesian multiple-trait colocalization systematically across the genome to identify genetic variants responsible for influencing intermediate molecular phenotypes as well as neurological traits. In this analysis we leveraged high dimensional quantitative trait loci data derived from prefrontal cortex tissue (concerning gene expression, DNA methylation and histone acetylation) and GWAS findings for 5 neurological traits (Neuroticism, Schizophrenia, Educational Attainment, Insomnia and Alzheimer’s disease).There was evidence of colocalization for 118 associations suggesting that the same underlying genetic variant influenced both nearby gene expression as well as neurological trait variation. Of these, 73 associations provided evidence that the genetic variant also influenced proximal DNA methylation and/or histone acetylation. These findings support previous evidence at loci where epigenetic mechanisms may putatively mediate effects of genetic variants on traits, such as KLC1 and schizophrenia. We also uncovered evidence implicating novel loci in neurological disease susceptibility, including genes expressed predominantly in brain tissue such as MDGA1, KIRREL3 and SLC12A5.An inverse relationship between DNA methylation and gene expression was observed more than can be accounted for by chance, supporting previous findings implicating DNA methylation as a transcriptional repressor. Our study should prove valuable in helping future studies prioritise candidate genes and epigenetic mechanisms for in-depth functional follow-up analyses.

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