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Activation of automethylated PRC2 by dimerization on chromatin

ABSTRACT: Polycomb Repressive Complex 2 (PRC2) trimethylates lysine 27 of histone 3 (H3K27me3). This modification transcriptionally represses chromatin and its dynamics are essential for embryonic development. PRC2 also methylates its cofactor JARID2 and both methylated H3 tail and JARID2 allosterically activate the complex. PRC2 undergoes auto-methylation of its catalytic subunit, which stimulates its activity by an unknown mechanism. We show that automethylated PRC2 forms a dimer on substrate chromatin that results in autoactivation in trans. An inactive PRC2 protomer distal to the substrate nucleosome serves as an allosteric activator of the second PRC2 protomer, which is poised to methylate H3. Functional assays support our model of allosteric activation via dimerization, suggesting a novel mechanism of PRC2 trans-autoactivation that may be important for installation of H3K27me3 into naïve chromatin.

ORGANISM(S): Mus musculus

PROVIDER: GSE234793 | GEO | 2023/11/13

REPOSITORIES: GEO

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Two distinct functional axes of positive feedback-enforced PRC2 recruitment in mouse embryonic stem cells

Project description:Polycomb Repressive Complex 2 (PRC2) plays an essential role in development by catalysing trimethylation of histone H3 lysine 27 (H3K27me3), resulting in gene repression. PRC2 consists of two sub-complexes, PRC2.1 and PRC2.2, in which the PRC2 core associates with distinct ancillary subunits such as MTF2 and JARID2, respectively. Both MTF2, present in PRC2.1, and JARID2, present in PRC2.2, play a role in core PRC2 recruitment to target genes in mouse embryonic stem cells (mESCs). However, it remains unclear how these distinct sub-complexes cooperate to establish H3K27me3 domains. Here, we combine a range of Polycomb mutant mESCs with chemical inhibition of PRC2 catalytic activity, to systematically dissect their relative contributions to PRC2 binding to target loci. We find that PRC2.1 and PRC2.2 mediate two distinct paths for recruitment, with mutually reinforced binding. Part of the cross-talk between PRC2.1 and PRC2.2 occurs via their catalytic product H3K27me3, which is bound by the PRC2 core-subunit EED, thereby mediating a positive feedback. Strikingly, removal of either JARID2 or H3K27me3 only has a minor effect on PRC2 recruitment, whereas their combined ablation largely attenuates PRC2 recruitment. This strongly suggests an unexpected redundancy between JARID2 and EED-H3K27me3-mediated recruitment of PRC2. Furthermore, we demonstrate that all core PRC2 recruitment occurs through the combined action of MTF2-mediated recruitment of PRC2.1 to DNA and PRC1-mediated recruitment of JARID2-containing PRC2.2. Both axes of binding are supported by EED-H3K27me3 positive feedback, but to a different degree. Finally, we provide evidence that PRC1 and PRC2 mutually reinforce reciprocal binding. Together, these data disentangle the interdependent and cooperative interactions between Polycomb complexes that are important to establish Polycomb repression at target sites.

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H3 K27M and EZHIP impede H3K27-methylation spreading by inhibing allosterically stimulated PRC2 [S2_ATAC]

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Polycomb repressive complex 2-dependent and -independent functions of Jarid2 in transcriptional regulation in Drosophila [ChIP-Seq]

Project description:Jarid2 was recently identified as an important component of the mammalian Polycomb Repressive Complex 2 (PRC2), where it has a major effect on PRC2 recruitment in mouse embryonic stem cells. Although Jarid2 is conserved in Drosophila, it has not previously been implicated in Polycomb (Pc) regulation. Therefore, we purified Drosophila Jarid2 and its associated proteins and find that Jarid2 associates with all of the known canonical PRC2 components, demonstrating a conserved physical interaction with PRC2 in flies and mammals. Furthermore, in vivo studies with Jarid2 mutants in flies demonstrate that among several histone modifications tested, only H3K27 methylation, the mark implemented by PRC2, was affected. Genome-wide profiling of Jarid2, Su(z)12 and H3K27me3 occupancy by ChIP-seq indicates that Jarid2 and Su(z)12 have a very similar distribution pattern on chromatin. However, Jarid2 and Su(z)12 occupancy levels at some genes are significantly different with Jarid2 being present at relatively low levels at many Pc response elements (PREs) of certain Homeobox (Hox) genes, providing a rationale for why Jarid2 was never identified in Pc screens. Gene expression analyses show that Jarid2 and E(z) (a canonical PRC2 component) are required not only for transcriptional repression but might also function in active transcription. Identification of Jarid2 as a conserved PRC2 interactor in flies provides an opportunity to begin to probe some of its novel functions in Drosophila development. Examination of Jarid2, Su(z)12, and H3K27me3 profiles in fly larvae and Su(z)12 in eye imaginal discs under wild-type and Jarid2 mutant conditions.

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Novel Form of JARID2 is Required to Regulate Differentiation in Keratinocytes.

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