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Mol Cell. 2018 Jun 21;70(6):1149-1162.e5. doi: 10.1016/j.molcel.2018.05.023.

Capturing the Onset of PRC2-Mediated Repressive Domain Formation.

Author information

1
Howard Hughes Medical Institute, New York University School of Medicine, New York, NY 10016, USA; Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA.
2
Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA.
3
Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.
4
Epigenetics Program, Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
5
Department of Pathology, New York University School of Medicine, New York, NY 10016, USA; Division of Developmental Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD 20892, USA.
6
Howard Hughes Medical Institute, New York University School of Medicine, New York, NY 10016, USA; Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA. Electronic address: danny.reinberg@nyumc.org.

Abstract

Polycomb repressive complex 2 (PRC2) maintains gene silencing by catalyzing methylation of histone H3 at lysine 27 (H3K27me2/3) within chromatin. By designing a system whereby PRC2-mediated repressive domains were collapsed and then reconstructed in an inducible fashion in vivo, a two-step mechanism of H3K27me2/3 domain formation became evident. First, PRC2 is stably recruited by the actions of JARID2 and MTF2 to a limited number of spatially interacting "nucleation sites," creating H3K27me3-forming Polycomb foci within the nucleus. Second, PRC2 is allosterically activated via its binding to H3K27me3 and rapidly spreads H3K27me2/3 both in cis and in far-cis via long-range contacts. As PRC2 proceeds further from the nucleation sites, its stability on chromatin decreases such that domains of H3K27me3 remain proximal, and those of H3K27me2 distal, to the nucleation sites. This study demonstrates the principles of de novo establishment of PRC2-mediated repressive domains across the genome.

KEYWORDS:

H3K27me2/3 domains; JARID2; MTF2; Polycomb; epigenetics; nucleation; spreading

PMID:
29932905
DOI:
10.1016/j.molcel.2018.05.023
[Indexed for MEDLINE]
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