Histone H3K27ac separates active from poised enhancers and predicts developmental state
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE24165 | GEO | 2010/10/31
SECONDARY ACCESSION(S): PRJNA130081
REPOSITORIES: GEO
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Project description:Developmental programs are controlled by transcription factors and chromatin regulators, which maintain specific gene expression programs through epigenetic modification of the genome. These regulatory events at enhancers contribute to the specific gene expression programs that determine cell state and the potential for differentiation into new cell types. Although enhancer elements are known to be associated with certain histone modifications and transcription factors, the relationship of these modifications to gene expression and developmental state has not been clearly defined. Here we interrogate the epigenetic landscape of enhancer elements in embryonic stem cells and several adult tissues in the mouse. We find that histone H3K27ac distinguishes active enhancers from inactive/poised enhancer elements containing H3K4me1 alone. This indicates that the amount of actively used enhancers is lower than previously anticipated. Furthermore, poised enhancer networks provide clues to unrealized developmental programs. Finally, we show that enhancers are reset during nuclear reprogramming.
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Project description:This SuperSeries is composed of the following subset Series: GSE23907: Histone H3K27ac separates active from poised enhancers and predicts developmental state (gene expression data) GSE24164: ChIP-Seq of chromatin marks at distal enhancers in Mouse Embryonic Stem Cells and adult tissues. Refer to individual Series
2010-10-31 | E-GEOD-24165 | biostudies-arrayexpress
Project description:Developmental programs are controlled by transcription factors and chromatin regulators, which maintain specific gene expression programs through epigenetic modification of the genome. These regulatory events at enhancers contribute to the specific gene expression programs that determine cell state and the potential for differentiation into new cell types. While enhancer elements are known to be associated with certain histone modifications, and transcription factors, the relationship of these modifications to gene expression and developmental state has not been clearly defined. Here we interrogate the epigenetic landscape of enhancer elements in embryonic stem cells and several adult tissues in the mouse. We find that histone H3K27ac distinguishes active enhancers from inactive/poised enhancer elements, thus providing clues to current cell state and further developmental potential. Gene expression profiling was performed in mouse ES, NPC, liver, and pro-B
2010-10-31 | E-GEOD-23907 | biostudies-arrayexpress
Project description:Developmental programs are controlled by transcription factors and chromatin regulators, which maintain specific gene expression programs through epigenetic modification of the genome. These regulatory events at enhancers contribute to the specific gene expression programs that determine cell state and the potential for differentiation into new cell types. While enhancer elements are known to be associated with certain histone modifications, and transcription factors, the relationship of these modifications to gene expression and developmental state has not been clearly defined. Here we interrogate the epigenetic landscape of enhancer elements in embryonic stem cells and several adult tissues in the mouse. We find that histone H3K27ac distinguishes active enhancers from inactive/poised enhancer elements, thus providing clues to current cell state and further developmental potential.
2010-10-31 | GSE23907 | GEO
Project description:Chromatin features are widely used for genome-scale mapping of enhancers. However, discriminating active enhancers from other cis-regulatory elements, predicting enhancer strength and identifying their target genes is challenging. Here we establish histone H2B N-terminus multisite lysine acetylation (H2BNTac) as a signature of active enhancers. H2BNTac prominently marks candidate active enhancers and a subset of promoters and discriminates them from ubiquitously active promoters. Two mechanisms underlie the distinct H2BNTac specificity: (1) unlike H3K27ac, H2BNTac is specifically catalyzed by CBP/p300; (2) H2A-H2B, but not H3-H4, are rapidly exchanged through transcription-induced nucleosome remodeling. H2BNTac-positive candidate enhancers show a high validation rate in orthogonal enhancer activity assays and a vast majority of endogenously active enhancers are marked by H2BNTac and H3K27ac. Notably, H2BNTac intensity predicts enhancer strength and outperforms current state-of-the-art models in predicting CBP/p300 target genes. These findings have broad implications for generating fine-grained enhancer maps and modeling CBP/p300-dependent gene regulation.
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Project description:Epigenetics, especially histone marks, functions beyond the DNA sequences to regulate gene expression. Depletion of NSD1, which catalyzes H3K36me2, leads to both up- and down-regulation of gene expression, indicating NSD1 is associated with both active and repressed gene expression. It's known that NSD1 regulates the deposition and expansion of H3K27me3, a repressive mark for gene expression, to keep active gene transcription. However, how NSD1 functions to repress gene expression is largely unknown. Here, we find that, when NSD1 is knocked out in mouse embryonic stem cells (mESCs), H3K27ac increases correlatively with the decrease of H3K36me2 at active enhancers, which is associated with mesoderm differentiation genes, leading to elevated gene expression. Mechanistically, NSD1 recruits HDAC1, the deacetylase of H3K27ac, to chromatin. Moreover, HDAC1 knockout (KO) recapitulates the increase of H3K27ac at active enhancers as the NSD1 depletion. Together, we propose that NSD1 deposits H3K36me2 and recruits HDAC1 at active enhancers to serve as a 'safeguard', preventing further activation of active enhancer-associated genes.
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Project description:BCL6 is crucial for B-cell activation and lymphomagenesis. We used integrative genomics to explore BCL6 mechanism in normal and malignant B-cells. Surprisingly, BCL6 assembled distinct complexes at enhancers vs. promoters. At enhancers BCL6 preferentially recruited SMRT, which mediated H3K27 deacetylation through HDAC3, antagonized p300 activity and repressed transcription, but without decommissioning enhancers. This provides a biochemical basis for toggling enhancers from the active to poised state. Virtually all SMRT was bound with BCL6 suggesting that in B-cells BCL6 uniquely sequesters SMRT from other factors. In promoters BCL6 preferentially recruited BCOR, but most potently repressed promoters where it formed a distinctive ternary complex with SMRT and BCOR. Promoter repression was associated with decreased H3K36me3, H3K79me2 and Pol II elongation, linking BCL6 to transcriptional pausing. We identified the binding patterns of BCL6, SMRT, NCOR and BCOR corepressors in normal germinal center B cells and a DLBCL cell line (OCI-Ly1) using ChIP-seq. Additionally we treated lymphoma cells with siRNA against BCL6 and a non-targeted siRNA (NT control) and performed RNA-seq to identify the genes bound and repressed by BCL6. RNA-seq experiments were performed at 24h and 48h after siRNA treatments. Additional biological triplicate RNA-seq experiments were performed at 48h after BCL6 knockdown. Furthermore, a series of histone mark ChIP-seq and RNA polymerase ChIP-seq (total, Ser5-P and Ser2-P) were preformed to capture the chromatin states associated with the formation of BCL6 corepressor complexes.
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Project description:Post-translational modifications on histone tails are closely correlated to transcriptional states. One such modification is monomethylation on lysine 4 of histone 3(H3K4me1), a mark that has been linked to enhancers. Identifying regions enriched for H3K4me1 and depleted in H3K4me3, or regions enriched for both H3K4me1 and H3K27ac, has proven to be a feasible enhancer discovery method. At the same time, not all H3K4me1-enriched regions correspond to enhancers. H3K4me1 marks also exist at promoters, which implies that the H3K4me1 modification may have a context-dependent role in regulating transcription. We report distinct patterns of H3K4me1 that predict transcriptional regulatory states at promoters in germ cells and ESCs. We examined ChIP-seq data for H3K4me1, H3K4me3, H3K27me3, and H3K27ac in mouse and human male germ cells, and found that H3K4me1 peak density around the transcription start sites (TSS) exhibits either a broad bimodal profile or a narrower unimodal profile centered at the TSS. We then examined the position of the H3K4me1 marks relative to H3K4me3, and found that unimodal H3K4me1 directly at the TSS predicts a poised (H3K4me1/H3K27me3 bivalent) state of chromatin, while bimodal H3K4me1 flanking the TSS predicts an active state. We conclude that unimodal H3K4me1 centered on the TSS is a characteristic feature of the poised epigenetic state in ESCs and germ cells. Note: H3K4me1 and H3K27ac data are included in this GEO accession; H3K4me3 and H3K27me3 were released in GSE68507.
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Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
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Project description:Chromatin features are widely used for genome-scale mapping of enhancers. However, discriminating active enhancers from other cis-regulatory elements, predicting enhancer strength, and identifying their target genes remains challenging. Here we establish histone H2B N-terminus multisite lysine acetylation (H2BNTac) as a genuine signature of active enhancers. H2BNTac prominently marks candidate active enhancers and a subset of promoters and discriminates them from ubiquitously active promoters. Two mechanisms afford the distinct H2BNTac specificity. (1) Unlike H3K27ac, H2BNTac is specifically catalyzed by CBP/p300. (2) H2A-H2B, but not H3-H4, are rapidly exchanged through transcription-induced nucleosome remodeling. H2BNTac-positive candidate enhancers show a high validation rate in orthogonal enhancer activity assays, and a vast majority of endogenously active enhancers are marked by H2BNTac and H3K27ac. Notably, H2BNTac intensity predicts enhancer strength and outperforms the current state-of-the-art models in predicting CBP/p300 target genes. These findings have broad implications for generating fine-grained enhancer maps and modeling CBP/p300-dependent gene regulation.
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