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BAP1 constrains pervasive H2AK119ub1 to control the transcriptional potential of the genome [ATAC-seq]

ABSTRACT: Histone-modifying systems play fundamental roles in gene regulation and the development of multicellular organisms. Histone modifications that are enriched at gene regulatory elements have been heavily studied, but the function of modifications found more broadly throughout the genome remains poorly understood. This is exemplified by histone H2A monoubiquitylation (H2AK119ub1), which is enriched at Polycomb-repressed gene promoters but also covers the genome at lower levels. Here, using inducible genetic perturbations and quantitative genomics, we found that the BAP1 deubiquitylase plays an essential role in constraining H2AK119ub1 throughout the genome. Removal of BAP1 leads to pervasive genome-wide accumulation of H2AK119ub1, which causes widespread reductions in gene expression. We show that elevated H2AK119ub1 preferentially counteracts Ser5 phosphorylation on the C-terminal domain of RNA polymerase II at gene regulatory elements and causes reductions in transcription and transcription-associated histone modifications. Furthermore, failure to constrain pervasive H2AK119ub1 compromises Polycomb complex occupancy at a subset of Polycomb target genes, which leads to their derepression, providing a potential molecular rationale for why the BAP1 ortholog in Drosophila has been characterized as a Polycomb group gene. Together, these observations reveal that the transcriptional potential of the genome can be modulated by regulating the levels of a pervasive histone modification.

ORGANISM(S): Mus musculus Drosophila melanogaster

PROVIDER: GSE161994 | GEO | 2021/05/03

REPOSITORIES: GEO

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BAP1 constrains pervasive H2AK119ub1 to control the transcriptional potential of the genome [RNA-seq]

Project description:Histone-modifying systems play fundamental roles in gene regulation and the development of multicellular organisms. Histone modifications that are enriched at gene regulatory elements have been heavily studied, but the function of modifications found more broadly throughout the genome remains poorly understood. This is exemplified by histone H2A monoubiquitylation (H2AK119ub1), which is enriched at Polycomb-repressed gene promoters but also covers the genome at lower levels. Here, using inducible genetic perturbations and quantitative genomics, we found that the BAP1 deubiquitylase plays an essential role in constraining H2AK119ub1 throughout the genome. Removal of BAP1 leads to pervasive genome-wide accumulation of H2AK119ub1, which causes widespread reductions in gene expression. We show that elevated H2AK119ub1 preferentially counteracts Ser5 phosphorylation on the C-terminal domain of RNA polymerase II at gene regulatory elements and causes reductions in transcription and transcription-associated histone modifications. Furthermore, failure to constrain pervasive H2AK119ub1 compromises Polycomb complex occupancy at a subset of Polycomb target genes, which leads to their derepression, providing a potential molecular rationale for why the BAP1 ortholog in Drosophila has been characterized as a Polycomb group gene. Together, these observations reveal that the transcriptional potential of the genome can be modulated by regulating the levels of a pervasive histone modification.

2021-05-03 | GSE161995 | GEO

BAP1 constrains pervasive H2AK119ub1 to control the transcriptional potential of the genome [ChIP-seq]

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BAP1 activity regulates Polycomb occupancy and global chromatin condensation counteracting diffuse PCGF3/5-dependent H2AK119ub1 deposition

Project description:BAP1 is recurrently mutated or deleted in a large number of diverse cancer types, including mesothelioma, uveal melanoma and hepatocellular cholangiocarcinoma. BAP1 is the catalytic subunit of the Polycomb Repressive De-Ubiquitination complex (PR-DUB) which removes PRC1 mediated H2AK119ub1. We and others have shown that H2AK119ub1 is essential for maintaining transcriptional repression and contributes to PRC2 chromatin recruitment. However, the precise relationship between BAP1 and PRC1 remains mechanistically elusive. Using embryonic stem cells, we show that a major function of BAP1 is to restrict H2AK119ub1 deposition to target sites. This increases the stability of PcG complexes with their targets and prevents diffuse accumulation of H2AK119ub1 and H3K27me3 modifications. Loss of BAP1 results in a broad increase in H2AK119ub1 levels that are primarily dependent on PCGF3/5-PRC1 complexes with a mechanism that is reminiscent of X-chromosome inactivation. Increased genome-wide H2AK119ub1 levels titrates away PRC2 from its targets and stimulates diffuse H3K27me3 accumulation across the genome. This decreases the activity of PcG repressive machineries at physiological targets and induces a general compaction of the entire chromatin. Our findings provide evidences for a unifying model that resolves the apparent contradiction between BAP1 catalytic activity and its role in vivo, uncovering molecular vulnerabilities that could be useful for BAP1-related pathologies.

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Genome-wide maps of chromatin modifications in wild-type or mutant HAP1 cells

Project description:Using ChIP-seq, we profiled several histone marks associated with active transcription (H3K4me3) or with Polycomb-mediated silencing (H2AK119ub1 and H3K27me3) in wild-type HAP1 cells and in cells mutated in BAP1, ASXL1, ASXL2, EZH2 and RING1B.

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PR-DUB safeguards Polycomb repression through restricting H2AK119ub1 [RNA-seq]

Project description:Polycomb group (PcG) proteins are critical chromatin regulators for cell fate control. The mono-ubiquitylation on histone H2AK119 (H2AK119ub1) is one of the well-recognized mechanisms for Polycomb Repressive Complex 1 (PRC1)-mediated transcription repression. However, the specific H2AK119 deubiquitylation complex composed by ASX-like proteins (ASXLs) and BAP1 has also been genetically characterized as a Polycomb Repressive complex (PR-DUB). Here we try to provide a rationale for these counterintuitive findings. Through re-examining the genomic distribution of H2AK119ub1, we find that H2AK119ub1 is non-negligibly distributed at non-promoter regions and associated with PRC1 sampling. Upon deletion of Asxl2 in mouse embryonic stem cells (ESCs), H2AK119ub1 is pervasively gained, especially at non-promoter regions, which is associated with increased RING1B occupancy. Meanwhile RING1B is significantly lost from a subset of the target promoters and thereby results in minor derepression in Asxl2-null ESCs. However notably, Asxl2 loss causes aberrant lineage differetiation, similar to PcG mutants. Therefore, our data reconcile seemingly paradoxical roles of PR-DUB on transcription repression and highlight the importance of a balanced H2AK119ub1 dynamics in developmental regulation.

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PR-DUB safeguards Polycomb repression through restricting H2AK119ub1 [ChIP-seq]

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BAP1 constrains pervasive H2AK119ub1 to control the transcriptional potential of the genome.

Project description:BAP1 constrains pervasive H2AK119ub1 to control the transcriptional potential of the genome.

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BAP1 complex promotes transcription by opposing PRC1-mediated H2A ubiquitylation

Project description:In Drosophila, a complex consisting of Calypso and ASX catalyzes H2A deubiquitination and has been reported to act as part of the Polycomb machinery in transcriptional silencing. The mammalian homologs of these proteins (BAP1 and ASXL1/2/3, respectively), are frequently mutated in various cancer types, yet their precise functions remain unclear. Using an integrative approach based on isogenic cell lines generated with CRISPR/Cas9, we uncover an unanticipated role for BAP1 in gene activation. This function requires the assembly of an enzymatically active BAP1-associated core complex (BAP1.com) containing one of the redundant ASXL proteins. We investigate the mechanism underlying BAP1.com-mediated transcriptional regulation and show that it does not participate in Polycomb-mediated silencing. Instead, our results establish that the function of BAP1.com is to safeguard transcriptionally active genes against silencing by the Polycomb Repressive Complex 1.

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Distinct dynamics and functions of H2AK119ub and H3K27me3 in mouse preimplantation embryos (RNA-Seq)

Project description:Polycomb repressive complexes 1 and 2 (PRC1/2) maintain transcriptional silencing of developmental genes largely by catalyzing mono-ubiquitination of histone H2A at lysine 119 (H2AK119ub1) and trimethylation of histone H3 at lysine 27 (H3K27me3), respectively. How Polycomb domains are reprogrammed during mammalian preimplantation development remains largely unclear. Here we show that, although H2AK119ub1 and H3K27me3 are highly colocalized in gametes, they undergo differential reprogramming dynamics following fertilization. H3K27me3 maintains thousands of maternally biased domains up to the blastocyst stage, whereas maternally biased H2AK119ub1 distribution in zygotes is largely equalized at the two-cell stage. Notably, while maternal PRC2 depletion has a limited effect on global H2AK119ub1 in early embryos, it disrupts allelic H2AK119ub1 at H3K27me3 imprinting loci including Xist. By contrast, acute H2AK119ub1 depletion in zygotes does not affect H3K27me3 imprinting maintenance, at least by the four-cell stage. Importantly, loss of H2AK119ub1, but not H3K27me3, causes premature activation of developmental genes during zygotic genome activation (ZGA) and subsequent embryonic arrest. Thus, our study reveals distinct dynamics and functions of H3K27me3 and H2AK119ub1 in mouse preimplantation embryos.

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