Genome-wide profiling reveals a dual role for histone H2A monoubiquitylation at Polycomb-repressed and enhancer chromatin
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ABSTRACT:
ORGANISM(S): Caenorhabditis elegans
PROVIDER: GSE222475 | GEO | 2025/10/24
REPOSITORIES: GEO
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Project description:Histone modifications are an integral component of eukaryotic genome regulation. Polycomb Repressive Complex 1 (PRC1) is responsible for depositing histone H2A lysine 119 mono-ubiquitylation (H2AK119ub) and can work cooperatively with PRC2-mediated histone H3 lysine 27 trimethylation (H3K27me3) to maintain gene repression. However, H3K27me3-independent functions and roles in gene activation have also been described for PRC1. Thus, the extent to which Polycomb complexes and their corresponding histone modifications function together or independently is unclear. Using C. elegans as a model, we investigated the relationship between H2AK119ub and H3K27me3. Here we show that the majority of H2AK119ub and H3K27me3 enrichment across the genome in embryos is distinct, and that the bulk levels of these modifications are regulated independently. We identify many genes related to nervous system development and functionality that have H2AK119ub-enriched promoters and are misregulated in H2AK119ub-deficient mutants, including a subset of genes that are normally H3K27me3-repressed. Surprisingly, we also find an enrichment of H2AK119ub at enhancers, including enhancers proximal to genes which are both up-regulated and down-regulated following the loss of this histone modification. Together, our results indicate a dual role for H2AK119ub in the regulation of both H3K27me3-repressed and enhancer chromatin states.
2025-10-24 | GSE222473 | GEO
Project description:Histone modifications are an integral component of eukaryotic genome regulation. Polycomb Repressive Complex 1 (PRC1) is responsible for depositing histone H2A lysine 119 mono-ubiquitylation (H2AK119ub) and can work cooperatively with PRC2-mediated histone H3 lysine 27 trimethylation (H3K27me3) to maintain gene repression. However, H3K27me3-independent functions and roles in gene activation have also been described for PRC1. Thus, the extent to which Polycomb complexes and their corresponding histone modifications function together or independently is unclear. Using C. elegans as a model, we investigated the relationship between H2AK119ub and H3K27me3. Here we show that the majority of H2AK119ub and H3K27me3 enrichment across the genome in embryos is distinct, and that the bulk levels of these modifications are regulated independently. We identify many genes related to nervous system development and functionality that have H2AK119ub-enriched promoters and are misregulated in H2AK119ub-deficient mutants, including a subset of genes that are normally H3K27me3-repressed. Surprisingly, we also find an enrichment of H2AK119ub at enhancers, including enhancers proximal to genes which are both up-regulated and down-regulated following the loss of this histone modification. Together, our results indicate a dual role for H2AK119ub in the regulation of both H3K27me3-repressed and enhancer chromatin states.
2025-10-24 | GSE222472 | GEO
Project description:Genome-wide profiling reveals a dual role for histone H2A monoubiquitylation at Polycomb-repressed and enhancer chromatin
| PRJNA922168 | ENA
Project description:Genome-wide profiling reveals a dual role for histone H2A monoubiquitylation at Polycomb-repressed and enhancer chromatin [RNA-seq]
| PRJNA922175 | ENA
Project description:Genome-wide profiling reveals a dual role for histone H2A monoubiquitylation at Polycomb-repressed and enhancer chromatin [ChIP-seq]
| PRJNA922174 | ENA
Project description:Polycomb group (PcG) proteins exist in multiprotein complexes that modify chromatin to repress transcription. Drosophila PcG proteins Sex combs extra (Sce; dRing) and Posterior sex combs (Psc) are core subunits of PRC1-type complexes. The Sce:Psc module acts as an E3 ligase for monoubiquitylation of histone H2A, an activity thought to be crucial for repression by PRC1-type complexes. Here, we created an Sce knockout allele and show that depletion of Sce results in loss of H2A monoubiquitylation in developing Drosophila. Genome-wide profiling identified a set of target genes co-bound by Sce and all other PRC1 subunits. Analyses in mutants lacking individual PRC1 subunits reveals that these target genes comprise two distinct classes. Class I genes are misexpressed in mutants lacking any of the PRC1 subunits. Class II genes are only misexpressed in animals lacking the Psc-Su(z)2 and Polyhomeotic (Ph) subunits but remain stably repressed in the absence of the Sce and Polycomb (Pc) subunits. Repression of class II target genes therefore does not require Sce and H2A monoubiquitylation but might rely on the ability of Psc-Su(z)2 and Ph to inhibit nucleosome remodeling or to compact chromatin. Similarly, Sce does not provide tumor suppressor activity in larval tissues under conditions in which Psc-Su(z)2, Ph and Pc show such activity. Sce and H2A monoubiquitylation are therefore only crucial for repression of a subset of genes and processes regulated by PRC1-type complexes. Sce synergizes with the Polycomb repressive deubiquitinase (PR-DUB) complex to repress transcription at class I genes, suggesting that H2A monoubiquitylation must be appropriately balanced for their transcriptional repression.
| S-EPMC3253035 | biostudies-literature
Project description:Chromatin changes within the context of DNA repair remain largely obscure. Here we show that DNA damage induces monoubiquitylation of histone H2A in the vicinity of DNA lesions. Ultraviolet (UV)-induced monoubiquitylation of H2A is dependent on functional nucleotide excision repair and occurs after incision of the damaged strand. The ubiquitin ligase Ring2 is required for the DNA damage-induced H2A ubiquitylation. UV-induced ubiquitylation of H2A is dependent on the DNA damage signaling kinase ATR (ATM- and Rad3-related) but not the related kinase ATM (ataxia telangiectasia-mutated). Although the response coincides with phosphorylation of variant histone H2AX, H2AX was not required for H2A ubiquitylation. Together our data show that monoubiquitylation of H2A forms part of the cellular response to UV damage and suggest a role of this modification in DNA repair-induced chromatin remodeling.
| S-EPMC1472908 | biostudies-literature
Project description:Histone variants help specialize chromatin regions; however, their impact on transcriptional regulation is largely unknown. Here, we determined the genome-wide localization and dynamics of Htz1, the yeast histone H2A variant. Htz1 localizes to hundreds of repressed/basal Pol II promoters and prefers TATA-less promoters. Specific Htz1 deposition requires the SWR1 complex, which largely colocalizes with Htz1. Htz1 occupancy correlates with particular histone modifications, and Htz1 deposition is partially reliant on Gcn5 (a histone acetyltransferase) and Bdf1, an SWR1 complex member that binds acetylated histones. Changes in growth conditions cause a striking redistribution of Htz1 from activated to repressed/basal promoters. Furthermore, Htz1 promotes full gene activation but does not generally impact repression. Importantly, Htz1 releases from purified chromatin in vitro under conditions where H2A and H3 remain associated. We suggest that Htz1-bearing nucleosomes are deposited at repressed/basal promoters but facilitate activation through their susceptibility to loss, thereby helping to expose promoter DNA.
| S-EPMC2788555 | biostudies-literature
Project description:Polycomb group (PcG) proteins are transcriptional repressors that control processes ranging from the maintenance of cell fate decisions and stem cell pluripotency in animals to the control of flowering time in plants. In Drosophila, genetic studies identified more than 15 different PcG proteins that are required to repress homeotic (HOX) and other developmental regulator genes in cells where they must stay inactive. Biochemical analyses established that these PcG proteins exist in distinct multiprotein complexes that bind to and modify chromatin of target genes. Among those, Polycomb repressive complex 1 (PRC1) and the related dRing-associated factors (dRAF) complex contain an E3 ligase activity for monoubiquitination of histone H2A (refs 1-4). Here we show that the uncharacterized Drosophila PcG gene calypso encodes the ubiquitin carboxy-terminal hydrolase BAP1. Biochemically purified Calypso exists in a complex with the PcG protein ASX, and this complex, named Polycomb repressive deubiquitinase (PR-DUB), is bound at PcG target genes in Drosophila. Reconstituted recombinant Drosophila and human PR-DUB complexes remove monoubiquitin from H2A but not from H2B in nucleosomes. Drosophila mutants lacking PR-DUB show a strong increase in the levels of monoubiquitinated H2A. A mutation that disrupts the catalytic activity of Calypso, or absence of the ASX subunit abolishes H2A deubiquitination in vitro and HOX gene repression in vivo. Polycomb gene silencing may thus entail a dynamic balance between H2A ubiquitination by PRC1 and dRAF, and H2A deubiquitination by PR-DUB.
| S-EPMC3182123 | biostudies-literature
Project description:It is not understood how the human T cell leukemia virus human T-lymphotropic virus-1 (HTLV-1), a retrovirus, regulates the in vivo balance between transcriptional latency and reactivation. The HTLV-1 proviral plus-strand is typically transcriptionally silent in freshly isolated peripheral blood mononuclear cells from infected individuals, but after short-term ex vivo culture, there is a strong, spontaneous burst of proviral plus-strand transcription. Here, we demonstrate that proviral reactivation in freshly isolated, naturally infected primary CD4+ T cells has 3 key attributes characteristic of an immediate-early gene. Plus-strand transcription is p38-MAPK dependent and is not inhibited by protein synthesis inhibitors. Ubiquitylation of histone H2A (H2AK119ub1), a signature of polycomb repressive complex-1 (PRC1), is enriched at the latent HTLV-1 provirus, and immediate-early proviral reactivation is associated with rapid deubiquitylation of H2A at the provirus. Inhibition of deubiquitylation by the deubiquitinase (DUB) inhibitor PR619 reverses H2AK119ub1 depletion and strongly inhibits plus-strand transcription. We conclude that the HTLV-1 proviral plus-strand is regulated with characteristics of a cellular immediate-early gene, with a PRC1-dependent bivalent promoter sensitive to p38-MAPK signaling. Finally, we compare the epigenetic signatures of p38-MAPK inhibition, DUB inhibition, and glucose deprivation at the HTLV-1 provirus, and we show that these pathways act as independent checkpoints regulating proviral reactivation from latency.
| S-EPMC6237452 | biostudies-literature