Variant PRC1 Complex-Dependent H2A Ubiquitylation Drives PRC2 Recruitment and Polycomb Domain Formation

Abstract

SummaryChromatin modifying activities inherent to polycomb repressive complexes PRC1 and PRC2 play an essential role in gene regulation, cellular differentiation, and development. However, the mechanisms by which these complexes recognize their target sites and function together to form repressive chromatin domains remain poorly understood. Recruitment of PRC1 to target sites has been proposed to occur through a hierarchical process, dependent on prior nucleation of PRC2 and placement of H3K27me3. Here, using a de novo targeting assay in mouse embryonic stem cells we unexpectedly discover that PRC1-dependent H2AK119ub1 leads to recruitment of PRC2 and H3K27me3 to effectively initiate a polycomb domain. This activity is restricted to variant PRC1 complexes, and genetic ablation experiments reveal that targeting of the variant PCGF1/PRC1 complex by KDM2B to CpG islands is required for normal polycomb domain formation and mouse development. These observations provide a surprising PRC1-dependent logic for PRC2 occupancy at target sites in vivo.

Genome-wide redistribution of H3K27me3 is linked to genotoxic stress and defective growth

“…However, the mechanisms that control Pc complexes are not fully understood. In some situations, H3K27me3-independent recruitment of PRC1 can occur, leading to subsequent PRC2 recruitment and deposition of H3K27me3 (17,18). Pc components are absent from the model yeasts Saccharomyces cerevisiae and Schizosaccharyomyces pombe, whereas PRC1 appears to be absent from all fungi (19).…”

The Polycomb Repressive Complex 1 Protein BMI1 Is Required for Constitutive Heterochromatin Formation and Silencing in Mammalian Somatic Cells

“…Histone modifications induced by the PRC2 complex (which includes EZH2, EED, and SUV12) and the PRC1 complex (which includes BMI1, RING1A, and RING1B/RNF2) allows stable silencing of gene expression in euchromatin and facultative heterochromatin (26 -28). Notably, previous recruitment models of PcG proteins through sequential histone modifications have been revised following that PRC1-variants could operate independently, and even upstreamofPRC2 (29,30).ThePRC2containshistoneH3trimeth-ylase activity at lysine 27 (H3K27 me3 ), whereas the PRC1 contains histone H2A monoubiquitin ligase activity at lysine 119 (H2A ub ) (26 -28). A number of observations have implicated these proto-oncogenes in human cancers (31)(32)(33)(34)(35)(36).…”

Au cœur d’une complexité biologique

“…Il a été établi à partir de plusieurs études montrant l'implication de PRC1 dans le recrutement de PRC2. En effet, un défaut d'expression de PRC1 entraîne une diminution de liaison de PRC2 à l'ADN, et l'adressage forcé des protéines de PRC1 à la chromatine se traduit par l'apposition de la marque H2AK119ub1 à l'origine du recrutement de PRC2 [19,20]. Des expériences de chromatographie d'affinité (ou pull down 3 ), réalisées sur des extraits nucléaires d'embryons de drosophile ou de cellules ES murines, ont révélé que les composants de PRC2 étaient, respectivement, fortement associés avec l'H2AK118ub et l'H2AK119ub.…”

“…B. Le nouveau modèle hiérarchique proposé par Blackledge et al [19] [27]. EZH2 fonctionne également comme un activateur transcriptionnel, dans les cancers de la prostate résistants à la castration [28], ou dans les lymphomes de cellules NKT (natural killer T) [29].…”