Activity of PRC1 and Histone H2AK119 Monoubiquitination: Revising Popular Misconceptions

Cohen, Idan; Bar, Carmit; Ezhkova, Elena

doi:10.1002/bies.201900192

Cited by 51 publications

(50 citation statements)

References 120 publications

(184 reference statements)

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“…Notably, Cluster 3 promoters, which exhibited the highest level of H3K4me3 enrichment, were also slightly enriched for H2Aub (Fig. 1D, S2A), in agreement with the reported association of non-canonical PRC1 with transcription activation (Aranda et al 2015;Cohen et al 2020). Consistently, while Cluster 2 promoters are bound by both CBX7 and RYBP, which represent canonical and non-canonical PRC1 respectively, in mESCs, Cluster 3 promoters are preferentially bound by RYBP ( Fig.…”

Section: H2aub Exhibits a Similar Landscape To H3k27me3 With Broad DIsupporting

confidence: 87%

Genome-wide decoupling of H2Aub and H3K27me3 in early mouse development

Zhu

Yan

et al. 2021

Preprint

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Polycomb group (PcG) proteins are crucial chromatin regulators during development. H2Aub and H3K27me3 are catalyzed by Polycomb-repressive Complex 1 and 2 (PRC1/2) respectively, and largely overlap in the genome due to mutual recruitment of the two complexes. However, whether PRC1/H2Aub and PRC2/H3K27me3 can function independently remains obscure. Here we uncovered a genome-wide decoupling of H2Aub and H3K27me3 in preimplantation mouse embryos, at both canonical PcG targets and broad distal domains. H2Aub represses future bivalent genes without H3K27me3 but does not contribute to maintenance of H3K27me3-dependent non-canonical imprinting. Our study thus revealed their distinct and independent functions in early mammalian development.

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Section: H2aub Exhibits a Similar Landscape To H3k27me3 With Broad DIsupporting

confidence: 87%

Genome-wide decoupling of H2Aub and H3K27me3 in early mouse development

Zhu

Yan

et al. 2021

Preprint

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“…7). PCGF6 is part of the non-canonical PRC1 complex (ncPRC1) that mediates histone H2A mono-ubiquitination at K119 (H2AK119ub) (130,131). PCGF6 acts a master regulator for maintaining stem cell identity during embryonic development (132), and is known to bind to promoters of germ cell genes in developing mice (130).…”

Section: Resultsmentioning

confidence: 99%

Two transcriptionally distinct pathways drive female development in a reptile with both genetic and temperature dependent sex determination

Whiteley

Holleley

Wagner

et al. 2021

Preprint

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How temperature determines sex remains unknown. A recent hypothesis proposes that conserved cellular mechanisms (calcium and redox; CaRe status) sense temperature and identify genes and regulatory pathways likely to be involved in driving sexual development. We take advantage of the unique sex determining system of the model organism, Pogona vitticeps, to assess predictions of this hypothesis. P. vitticeps has ZZ male: ZW female sex chromosomes whose influence can be overridden in genetic males by high temperatures, causing male-to-female sex reversal. We compare a developmental transcriptome series of ZWf females and temperature sex reversed ZZf females. We demonstrate that early developmental cascades differ dramatically between genetically driven and thermally driven females, later converging to produce a common outcome (ovaries). We show that genes proposed as regulators of thermosensitive sex determination play a role in temperature sex reversal. Our study greatly advances the search for the mechanisms by which temperature determines sex.

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“…Chromatin-modifying enzymes can function at defined gene regulatory elements to support cell type-specific gene expression patterns (Atlasi and Stunnenberg 2017; Yadav et al 2018). Their recruitment to these sites often relies on DNA- and chromatin-binding activities (Smith and Shilatifard 2010), and these mechanisms underpin how PRC1 creates high-level enrichment of H2AK119ub1 at Polycomb target gene promoters to enable repression (Endoh et al 2012; Blackledge et al 2015; Fursova et al 2019; Scelfo et al 2019; Blackledge et al 2020; Tamburri et al 2020; Cohen et al 2020). In addition to this punctate pool of H2AK119ub1, we and others have recently discovered that PRC1 also places low levels of H2AK119ub1 broadly throughout the genome (Lee et al 2015; Kahn et al 2016; Fursova et al 2019).…”

Section: Discussionmentioning

confidence: 99%

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

Fursova

Turberfield

Blackledge

et al. 2020

Preprint

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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 that are found more broadly throughout the genome remains poorly understood. This is exemplified by histone H2A mono-ubiquitylation (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 discover that the BAP1 deubiquitylase plays an essential role in constraining H2AK119ub1 throughout the genome. Removal of BAP1 leads to pervasive accumulation of H2AK119ub1, which causes widespread reductions in gene expression. We show that elevated H2AK119ub1 represses gene expression by counteracting transcription initiation from gene regulatory elements, causing reductions in transcription-associated histone modifications. Furthermore, failure to constrain pervasive H2AK119ub1 compromises Polycomb complex occupancy at a subset of Polycomb target genes leading to their derepression, therefore explaining the original genetic characterisation of BAP1 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, without the need for elaborate gene-specific targeting mechanisms.

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Activity of PRC1 and Histone H2AK119 Monoubiquitination: Revising Popular Misconceptions

Cited by 51 publications

References 120 publications

Genome-wide decoupling of H2Aub and H3K27me3 in early mouse development

Genome-wide decoupling of H2Aub and H3K27me3 in early mouse development

Two transcriptionally distinct pathways drive female development in a reptile with both genetic and temperature dependent sex determination

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

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