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PR-DUB preserves Polycomb repression by preventing excessive accumulation of H2Aub1, an antagonist of nucleosome stacking (RNA-Seq)

ABSTRACT: The Polycomb repression machinery in Drosophila comprises PRC1 that monoubiquitinates histone H2A at lysine 118 (H2Aub1) and PR-DUB, a major H2Aub1 deubiquitinase, but how H2Aub1 levels must be balanced for Polycomb repression remains enigmatic. We show that H2Aub1 is enriched at Polycomb target genes in early embryos but depleted from these genes during developmental stages when PRC1 represses their transcription. Accordingly, Polycomb targets remain repressed in H2Aub1-deficient animals. In PR-DUB catalytic mutants, high-level H2Aub1 accumulation at Polycomb targets increases chromatin accessibility, consistent with disruption of chromatin fiber folding by H2Aub1 in vitro. Consequently, PR-DUB mutants show defective Polycomb repression, while general transcription is largely unperturbed by the genome-wide, low-level H2Aub1 increase. Changes in H2Aub1 levels alter H3K27 methylation-kinetics but PRC2 nevertheless generates canonical H3K27me3 domains in PRC1 or PR-DUB catalytic mutants. PR-DUB therefore acts as a rheostat that removes excessive H2Aub1 that, though deposited by PRC1, antagonizes PRC1-mediated chromatin compaction.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE210235 | GEO | 2022/11/09

REPOSITORIES: GEO

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PR-DUB preserves Polycomb repression by preventing excessive accumulation of H2Aub1, an antagonist of nucleosome stacking (ChIP-Seq)

Project description:The Polycomb repression machinery in Drosophila comprises PRC1 that monoubiquitinates histone H2A at lysine 118 (H2Aub1) and PR-DUB, a major H2Aub1 deubiquitinase, but how H2Aub1 levels must be balanced for Polycomb repression remains enigmatic. We show that H2Aub1 is enriched at Polycomb target genes in early embryos but depleted from these genes during developmental stages when PRC1 represses their transcription. Accordingly, Polycomb targets remain repressed in H2Aub1-deficient animals. In PR-DUB catalytic mutants, high-level H2Aub1 accumulation at Polycomb targets increases chromatin accessibility, consistent with disruption of chromatin fiber folding by H2Aub1 in vitro. Consequently, PR-DUB mutants show defective Polycomb repression, while general transcription is largely unperturbed by the genome-wide, low-level H2Aub1 increase. Changes in H2Aub1 levels alter H3K27 methylation-kinetics but PRC2 nevertheless generates canonical H3K27me3 domains in PRC1 or PR-DUB catalytic mutants. PR-DUB therefore acts as a rheostat that removes excessive H2Aub1 that, though deposited by PRC1, antagonizes PRC1-mediated chromatin compaction.

2022-11-09 | GSE210233 | GEO

PR-DUB preserves Polycomb repression by preventing excessive accumulation of H2Aub1, an antagonist of nucleosome stacking (ATAC-Seq)

2022-11-09 | GSE210232 | GEO

Removal of H2Aub1 by ubiquitin-specific proteases 12 and 13 is required for stable Polycomb-mediated gene repression in Arabidopsis

Project description:Background: Stable gene repression is essential for normal growth and development. Polycomb Repressive Complexes 1 and 2 (PRC1 & PRC2) are involved in this process by establishing monoubiquitinated histone 2A (H2Aub1) and subsequent trimethylation of lysine 27 of histone 3 (H3K27me3). Previous work proposed that H2Aub1 removal by the ubiquitin-specific proteases 12 and 13 (UBP12 & UBP13) is part of the repressive PRC1&2 system, but its functional role remains elusive. Results: We show that UBP12 and UBP13 work together with PRC1, PRC2, and EMF1 to repress genes involved in stimulus response. We found that H2Aub1 is associated with responsiveness, and that it’s only indirectly repressive via PRC2 recruitment. Our analyses also revealed that PR2 targets that do not require PRC1 are pre-repressed. Lastly, we have found that removal of H2Aub1 by UBP12/13 prevents loss of H3K27me3, consistent with our finding that the H3K27me3 demethylase REF6 is enriched at H2Aub1 marked genes. Conclusions: Our data allow us to propose a model in which deposition of H2Aub1 permits recruitment of PRC2 and provides a state that allows for a rapid switch between gene activation and repression. Removal of H2Aub1 by UBP12/13 is required to achieve stable repression.

2020-05-19 | GSE131756 | GEO

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.

2023-03-31 | GSE186374 | GEO

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

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H2A monoubiquitination targeting by cohesin subunits in Arabidopsis

Project description:Histone H2A monoubiquitination (H2Aub1) function as a conserved post-translational modification in eukaryotes to maintain gene repression and ensure cellular identity. Arabidopsis H2Aub1 is catalyzed by polycomb repressive complex 1 (PRC1) contributed by AtRING1s and AtBMI1s. Because PRC1 components lack known DNA binding domains, how H2Aub1 is established at the specific genomic sites remains a topic of debate. Here we show that the cohesin subunits AtSYN4 and AtSCC3 interact with each other and AtSCC3 binds to AtBMI1s. We find that H2Aub1 levels are significantly reduced in the atsyn4 mutant or AtSCC3 RNAi knockdown plants. ChIP-seq analysis indicated that AtSYN4 and AtSCC3 tend to associate with H2Aub1 in the genome regions of transcription activation independent on H3K27me3. Finally, we show that AtSYN4 binds directly to the G-box element and targets H2Aub1to these sites. Our study thus revealed a mechanism for cohesin-mediated recruitment of AtBMI1s to specific loci to mediate H2Aub1.

2022-06-10 | GSE205736 | GEO

PRC1 catalytic activity is central to Polycomb system function. [RNA]

Project description:The Polycomb repressive system is an essential chromatin-based regulator of gene expression. Despite being extensively studied, how it selects its target genes is poorly understood and whether its histone modifying activities are required for transcriptional repression remains controversial. Here, we directly test the requirement for PRC1 catalytic activity in Polycomb system function. To achieve this, we develop a new inducible mutation system in embryonic stem cells that completely removes PRC1 catalytic activity. Using this system, we demonstrate that catalysis by PRC1 is important for Polycomb chromatin domain formation and long-range chromatin interactions. Furthermore, we show that variant PRC1 complexes with DNA-binding activities occupy target sites independently of Polycomb chromatin domain formation, providing a putative mechanism for Polycomb target site selection. Finally, we discover that Polycomb-mediated gene repression requires PRC1 catalytic activity. Together these discoveries provide compelling new evidence that PRC1 catalysis is central to Polycomb system function and gene regulation.

2020-01-08 | GSE132753 | GEO

PRC1 catalytic activity is central to Polycomb system function. [ChIP]

2020-01-08 | GSE132752 | GEO

PRC1 catalytic activity is central to Polycomb system function. [CaptureC ]

2020-01-08 | GSE132751 | GEO

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.

2021-06-27 | GSE162739 | GEO

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