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Polycomb erasers BAP1 and UTX are dispensable for rapid bivalent gene activation but essential for enhancer establishment [CUT&Tag]

ABSTRACT: Polycomb group (PcG) proteins safeguard cell identity by maintaining target genes in a transcriptionally repressed state through depositing two histone marks, H2A lysine-119 ubiquitination (H2AK119ub1) and H3 lysine-27 trimethylation (H3K27me3). BAP1 and UTX are thought to erase these marks during transcription activation, but their exact roles remain unclear. Here we observe a rapid loss of H2AK119ub1, followed by a reduction in H3K27me3 levels at promoters upon transcription induction, coinciding with a swift dissociation of PRCs. With an acute degradation system, we show that BAP1 and UTX are dispensable for transcription activation or the dissolution of PcG repressive marks. Instead, they promote enhancer establishment during cell fate transition independent of their eraser enzymatic activity. Therefore, our study provides novel mechanistic insights that the dissolution of PcG-marks is transcription-dependent while UTX and BAP1 primarily function as bridging factors to construct enhancers, rather than as erasers of PcG memory.

ORGANISM(S): Mus musculus

PROVIDER: GSE329243 | GEO | 2026/04/29

REPOSITORIES: GEO

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Polycomb erasers BAP1 and UTX are dispensable for rapid bivalent gene activation but essential for enhancer establishment [RNA-seq]

Project description:Polycomb group (PcG) proteins safeguard cell identity by maintaining target genes in a transcriptionally repressed state through depositing two histone marks, H2A lysine-119 ubiquitination (H2AK119ub1) and H3 lysine-27 trimethylation (H3K27me3). BAP1 and UTX are thought to erase these marks during transcription activation, but their exact roles remain unclear. Here we observe a rapid loss of H2AK119ub1, followed by a reduction in H3K27me3 levels at promoters upon transcription induction, coinciding with a swift dissociation of PRCs. With an acute degradation system, we show that BAP1 and UTX are dispensable for transcription activation or the dissolution of PcG repressive marks. Instead, they promote enhancer establishment during cell fate transition independent of their eraser enzymatic activity. Therefore, our study provides novel mechanistic insights that the dissolution of PcG-marks is transcription-dependent while UTX and BAP1 primarily function as bridging factors to construct enhancers, rather than as erasers of PcG memory.

2026-04-29 | GSE329245 | GEO

Polycomb erasers BAP1 and UTX are dispensable for rapid bivalent gene activation but essential for enhancer establishment [ChIP-seq]

2026-04-29 | GSE329244 | 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

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.

2018-11-21 | GSE110133 | GEO

H2AK119ub1 and H3K27me3 ChIP-seq in conditional knockout of Bap1

Project description:ChIP-seq of H2AK119ub1 and H3K27me3 in a conditional knockout of Bap1

2023-01-01 | GSE211544 | 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]

2023-03-31 | GSE186373 | GEO

H2AK119ub1-MLL2 counteraction underlies heritable H3K27me3 formation in oocytes [CATCH-seq and CUT&RUN]

Project description:Polycomb group (PcG) and Trithorax group (TrxG) proteins establish bivalent chromatin marked by H3K27me3, H2AK119ub1, and H3K4me3. However, how bivalent chromatin is formed in vivo in mammals is poorly understood. In mouse oocytes, it arises at thousands of promoters, including noncanonical imprinted loci whose H3K27me3 is intergenerationally inherited by early embryos. Here, we show that H3K27me3 is deposited at H3K4me3-premarked promoters in an H2AK119ub1-dependent manner during oogenesis. We find that H2AK119ub1 deficiency causes transcriptional derepression and loss of H3K27me3 proportional to preexisting H3K4me3 levels in oocytes. Importantly, concomitant deficiency of H2AK119ub1 and MLL2-mediated H3K4me3 substantially restores transcriptional silencing and H3K27me3 deposition, leading to partial restoration of noncanonical imprinting in offspring. Taken together, we propose that H2AK119ub1 antagonizes MLL2 function to repress bivalent genes during oogenesis, thereby conferring heritable H3K27me3. This study reveals how PcG and TrxG counteraction shapes the maternal epigenome for the next generation’s development.

2026-04-01 | GSE292333 | GEO

H2AK119ub1-MLL2 counteraction underlies heritable H3K27me3 formation in oocytes

2026-04-01 | GSE292237 | GEO

Histone H2AK119 Mono-Ubiquitination is Essential for Polycomb-Mediated Transcriptional Repression

Project description:The major function of Polycomb group proteins (PcG) is to maintain transcriptional repression to preserve cellular identity. This is exerted by two distinct repressive complexes, PRC1 and PRC2, that modify histones by depositing H2AK119ub1 and H3K27me3, respectively. Both complexes are essential for development and are deregulated in several types of human tumors. PRC1 and PRC2 exist in different variants and show a complex regulatory cross-talk. However, the contribution that H2AK119ub1 plays in mediating PcG repressive functions remains largely controversial. Coupling an inducible system with the expression of a fully catalytic inactive RING1B mutant, we demonstrated that H2AK119ub1 deposition is essential to maintain PcG-target genes repressed in ESC. Loss of H2AK119ub1 induced a rapid displacement of PRC2 activity and a loss of H3K27me3 deposition. This affected both PRC2.1 and PRC2.2 variants and further correlated with a strong displacement and destabilization of canonical PRC1. Finally, we find that variant PRC1 forms can sense H2AK119ub1 deposition, which contributes to their stabilization specifically at sites where this modification is highly enriched. Overall our data place H2AK119ub1 deposition as central hub that mount PcG repressive machineries to preserve cell transcriptional identit

2019-12-26 | GSE134053 | GEO

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