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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE210236 | 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 (ATAC-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 | GSE210232 | GEO

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

2022-11-09 | GSE210235 | GEO

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

2022-11-09 | GSE210233 | GEO

PR-DUB preserves Polycomb repression by preventing excessive accumulation of H2Aub1, an antagonist of chromatin compaction.

Project description:The Polycomb repressive complexes PRC1, PRC2, and PR-DUB repress target genes by modifying their chromatin. In Drosophila, PRC1 compacts chromatin and monoubiquitinates histone H2A at lysine 118 (H2Aub1), whereas PR-DUB is a major H2Aub1 deubiquitinase, but how H2Aub1 levels must be balanced for Polycomb repression remains unclear. We show that in early embryos, H2Aub1 is enriched at Polycomb target genes, where it facilitates H3K27me3 deposition by PRC2 to mark genes for repression. During subsequent stages of development, H2Aub1 becomes depleted from these genes and is no longer enriched when Polycomb maintains them repressed. Accordingly, Polycomb targets remain repressed in H2Aub1-deficient animals. In PR-DUB catalytic mutants, high levels of H2Aub1 accumulate at Polycomb target genes, and Polycomb repression breaks down. These high H2Aub1 levels do not diminish Polycomb protein complex binding or H3K27 trimethylation but increase DNA accessibility. We show that H2Aub1 interferes with nucleosome stacking and chromatin fiber folding in vitro. Consistent with this, Polycomb repression defects in PR-DUB mutants are exacerbated by reducing PRC1 chromatin compaction activity, but Polycomb repression is restored if PRC1 E3 ligase activity is removed. PR-DUB therefore acts as a rheostat that removes excessive H2Aub1 that, although deposited by PRC1, antagonizes PRC1-mediated chromatin compaction.

| S-EPMC9744231 | biostudies-literature

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

Project description:PR-DUB preserves Polycomb repression by preventing excessive accumulation of H2Aub1, an antagonist of nucleosome stacking

| PRJNA864800 | ENA

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

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

| PRJNA864812 | ENA

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

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

| PRJNA864798 | ENA

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

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

| PRJNA864811 | ENA

PR-DUB safeguards Polycomb repression through H2AK119ub1 restriction.

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. Unexpectedly, the specific H2AK119 deubiquitylation complex composed by additional sex comb-like proteins and BAP1 has also been genetically characterized as Polycomb repressive deubiquitnase (PR-DUB) for unclear reasons. However, it remains a mystery whether and how PR-DUB deficiency affects chromatin states and cell fates through impaired PcG silencing. Here through a careful epigenomic analysis, we demonstrate that a bulk of H2AK119ub1 is diffusely distributed away from promoter regions and their enrichment is positively correlated with PRC1 occupancy. Upon deletion of Asxl2 in mouse embryonic stem cells (ESCs), a pervasive gain of H2AK119ub1 is coincident with increased PRC1 sampling at chromatin. Accordingly, PRC1 is significantly lost from a subset of highly occupied promoters, leading to impaired silencing of associated genes before and after lineage differentiation of Asxl2-null ESCs. Therefore, our study highlights the importance of genome-wide H2AK119ub1 restriction by PR-DUB in safeguarding robust PRC1 deposition and its roles in developmental regulation.

| S-EPMC10542648 | biostudies-literature

Histone H2A deubiquitinase activity of the Polycomb repressive complex PR-DUB.

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

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