Cross-species comparison of epigenetic poising in the mammalian germ line
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ABSTRACT:
ORGANISM(S): Bos taurus Mus musculus Gallus gallus Homo sapiens Monodelphis domestica Macaca mulatta
PROVIDER: GSE68507 | GEO | 2016/05/07
REPOSITORIES: GEO
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Project description:The histone variant H2A.Z has been implicated in nucleosome exchange, transcriptional activation and Polycomb repression. However, the relationships among these seemingly disparate functions remain obscure. We mapped H2A.Z genome-wide in mammalian ES cells and neural progenitors. H2A.Z is deposited promiscuously at promoters and enhancers, and correlates strongly with H3K4 methylation. Accordingly, H2A.Z is present at poised promoters with bivalent chromatin and at active promoters with H3K4 methylation, but is absent from stably repressed promoters that are specifically enriched for H3K27 trimethylation. We also characterized post-translational modification states of H2A.Z, including a novel species dually-modified by ubiquitination and acetylation that is enriched at bivalent chromatin. Our findings associate H2A.Z with functionally distinct genomic elements, and suggest that post-translational modifications may reconcile its contrasting locations and roles. Examination of histone variant, histone modifications and transcription machinery in 3 cell types
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Project description:Surface LE, Fields PA, Subramanian V, Behmer R, Udeshi N, Peach SE, Jaffe JD, Boyer LA. Cell Reports. 2015. Histone variant H2A.Z occupies the promoters of active and poised, bivalent genes in ESCs to regulate developmental programs, yet how it contributes to these contrasting states is poorly understood. Here, we investigate the function of H2A.Z.1 mono-ubiquitylation (H2A.Z.1ub) by mutation of the PRC1 target residues (H2A.Z.1K3R3). We show that H2A.Z.1K3R3 is properly incorporated at target promoters in murine ESCs (mESCs), however, loss of mono- ubiquitylation leads to de-repression of bivalent genes, loss of Polycomb binding, and to faulty lineage commitment. Using quantitative proteomics, we find that tandem bromodomain proteins, including the BET family member Brd2, are enriched in H2A.Z.1 chromatin. We further show that Brd2 is gained at de-repressed promoters in H2A.Z.1K3R3 mESCs whereas Brd2 inhibition restores gene silencing at these sites. Together, our study reveals an antagonistic relationship between H2A.Z.1ub and Brd2 to regulate the transcriptional balance at bivalent genes to enable proper execution of developmental programs.
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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:The histone variant H2A.Z has been implicated in nucleosome exchange, transcriptional activation and Polycomb repression. However, the relationships among these seemingly disparate functions remain obscure. We mapped H2A.Z genome-wide in mammalian ES cells and neural progenitors. H2A.Z is deposited promiscuously at promoters and enhancers, and correlates strongly with H3K4 methylation. Accordingly, H2A.Z is present at poised promoters with bivalent chromatin and at active promoters with H3K4 methylation, but is absent from stably repressed promoters that are specifically enriched for H3K27 trimethylation. We also characterized post-translational modification states of H2A.Z, including a novel species dually-modified by ubiquitination and acetylation that is enriched at bivalent chromatin. Our findings associate H2A.Z with functionally distinct genomic elements, and suggest that post-translational modifications may reconcile its contrasting locations and roles.
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Project description:Aire is an unconventional transcription factor (TF) that enhances the expression of thousands of genes in medullary thymic epithelial cells (mTECs), which promotes clonal deletion or phenotypic diversion of self-reactive T cells. The biological logic of Aire’s target specificity remains largely unknown as, unlike many TFs, it does not bind to a particular DNA-sequence motif. We implemented two orthogonal approaches to investigate Aire’s cis-regulatory mechanisms: construction of a convolutional neural network and leveraging of natural genetic variation via analysis of F1-hybrid mice. Both approaches nominated Z-DNA and Nfe2•Maf as putative positive influences on Aire’s target choices. Genome-wide mapping studies revealed that Z-DNA-forming and Nfe2l2-binding motifs were positively associated with the inherent ability of a gene’s promoter to generate DNA double-strand breaks (DSBs), and promoters showing strong DSB generation were more likely to enter a poised state with accessible chromatin and already-assembled transcriptional machinery. Consequently, Aire preferentially targeted genes with poised promoters. We propose a model whereby Z-DNA anchors the Aire-mediated transcriptional program by enhancing DSB generation and promoter poising. Beyond resolving a long-standing mechanistic conundrum, these findings suggest previously unexplored routes of manipulating T-cell tolerance.
2024-03-11 | GSE253215 | GEO
Project description:H3K4me1 distribution at promoters predicts the poised epigenetic state
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Project description:Regulatory decisions in Drosophila require Polycomb group (PcG) proteins to maintain the silent state and Trithorax group (TrxG) proteins to oppose silencing. Since PcG and TrxG are ubiquitous and lack apparent sequence specificity, a long-standing model is that targeting occurs via protein interactions; for instance, between repressors and PcG proteins. Instead, we found that Pc-repressive complex 1 (PRC1) purifies with coactivators Fs(1)h [female sterile (1) homeotic] and Enok/Br140 during embryogenesis. Fs(1)h is a TrxG member and the ortholog of BRD4, a bromodomain protein that binds to acetylated histones and is a key transcriptional coactivator in mammals. Enok and Br140, another bromodomain protein, are orthologous to subunits of a mammalian MOZ/MORF acetyltransferase complex. Here we confirm PRC1-Br140 and PRC1-Fs(1)h interactions and identify their genomic binding sites. PRC1-Br140 bind developmental genes in fly embryos, with analogous co-occupancy of PRC1 and a Br140 ortholog, BRD1, at bivalent loci in human embryonic stem (ES) cells. We propose that identification of PRC1-Br140 "bivalent complexes" in fly embryos supports and extends the bivalency model posited in mammalian cells, in which the coexistence of H3K4me3 and H3K27me3 at developmental promoters represents a poised transcriptional state. We further speculate that local competition between acetylation and deacetylation may play a critical role in the resolution of bivalent protein complexes during development.
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Project description:Background: Bivalent chromatin refers to overlapping regions containing activating histone H3 Lys4 trimethylation (H3K4me3) and inactivating H3K27me3 marks. Existence of such bivalent marks on the same nucleosome has only recently been suggested. Previous genome-wide efforts to characterize bivalent chromatin have focused primarily on individual marks to define overlapping zones of bivalency rather than mapping positions of truly bivalent mononucleosomes. Results: Here, we developed an efficacious sequential ChIP technique for examining global positioning of individual bivalent nucleosomes. Using next generation sequencing approaches we show that although individual H3K4me3 and H3K27me3 marks overlap in broad zones, bivalent nucleosomes are focally enriched in the vicinity of the transcription start site (TSS). These seem to occupy the H2A.Z nucleosome positions previously described as salt-labile nucleosomes, and are correlated with low gene expression. Although the enrichment profiles of bivalent nucleosomes show a clear dependency on CpG island content, they demonstrate a stark anti-correlation with methylation status. Conclusions: We show that regional overlap of H3K4me3 and H3K27me3 chromatin tend to be upstream to the TSS, while bivalent nucleosomes with both marks are mainly promoter proximal near the TSS of CpG island-containing genes with poised/low expression. We discuss the implications of the focal enrichment of bivalent nucleosomes around the TSS on the poised chromatin state of promoters in stem cells.
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