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Polycomb-mediated genome architecture enables long-range spreading of H3K27 methylation [4C-seq]

ABSTRACT: Polycomb-group proteins play critical roles in gene silencing through the deposition of histone H3 lysine 27 trimethylation (H3K27me3) and chromatin compaction. This process is essential for embryonic stem cells (ESCs) pluripotency, differentiation, and development. Polycomb repressive complex 2 (PRC2) can both read and write H3K27me3, enabling processive spread of H3K27me3 on linear genome and epigenetic memory. Long-range Polycomb-associated DNA contacts have also been described, but their regulation and role in gene silencing remains unclear. Here, we develop H3K27me3 HiChIP and apply optical reconstruction of chromatin architecture to reveal long-range Polycomb-associated DNA loops that span tens to hundreds of megabases and across multiple topological associated domains in mouse ESCs and human induced pluripotent stem cells. H3K27me3 loop anchors are enriched for Polycomb nucleation points and coincide with key developmental genes, such as Hmx1, Wnt6 and Hoxa. Genetic deletion of H3K27me3 loop anchors causes spatially proximal partner chromosomal loci to break apart, and alters H3K27me3 deposition, both locally and megabases away on the same chromosome. A selective EZH2 mutant deficient in RNA binding but intact H3K27me3 enzymatic activity leads to global alteration in H3K27me3 loops, decreased spatial proximity, and failure to spread Polycomb from PRC2 nucleation points to partner loci at developmental genes. Together, these results suggest PRC2 acts as a “genomic wormhole”, using RNA binding to enhance long range chromosome folding and H3K27me3 spreading. Developmental gene loci have novel roles in Polycomb spreading, emerging as key architectural elements of the epigenome.

ORGANISM(S): Homo sapiens

PROVIDER: GSE150904 | GEO | 2022/05/13

REPOSITORIES: GEO

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Polycomb-mediated genome architecture enables long-range spreading of H3K27 methylation [RNA-Seq]

Project description:Polycomb-group proteins play critical roles in gene silencing through the deposition of histone H3 lysine 27 trimethylation (H3K27me3) and chromatin compaction. This process is essential for embryonic stem cells (ESCs) pluripotency, differentiation, and development. Polycomb repressive complex 2 (PRC2) can both read and write H3K27me3, enabling processive spread of H3K27me3 on linear genome and epigenetic memory. Long-range Polycomb-associated DNA contacts have also been described, but their regulation and role in gene silencing remains unclear. Here, we develop H3K27me3 HiChIP and apply optical reconstruction of chromatin architecture to reveal long-range Polycomb-associated DNA loops that span tens to hundreds of megabases and across multiple topological associated domains in mouse ESCs and human induced pluripotent stem cells. H3K27me3 loop anchors are enriched for Polycomb nucleation points and coincide with key developmental genes, such as Hmx1, Wnt6 and Hoxa. Genetic deletion of H3K27me3 loop anchors causes spatially proximal partner chromosomal loci to break apart, and alters H3K27me3 deposition, both locally and megabases away on the same chromosome. A selective EZH2 mutant deficient in RNA binding but intact H3K27me3 enzymatic activity leads to global alteration in H3K27me3 loops, decreased spatial proximity, and failure to spread Polycomb from PRC2 nucleation points to partner loci at developmental genes. Together, these results suggest PRC2 acts as a “genomic wormhole”, using RNA binding to enhance long range chromosome folding and H3K27me3 spreading. Developmental gene loci have novel roles in Polycomb spreading, emerging as key architectural elements of the epigenome.

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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.

2020-08-07 | PXD014290 | Pride

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

2021-09-22 | PXD020684 | Pride

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