Capturing the Onset of PRC2-Mediated Repressive Domain Formation

Ozgur Oksuz, Varun Narendra, Chul Hwan Lee, Nicolas Descostes, Gary LeRoy, Ramya Raviram, Lili Blumenberg, Kelly Karch, Pedro P. Rocha, Benjamin A. Garcia, Jane A. Skok, Danny Reinberg

Research output: Contribution to journalArticlepeer-review

105 Scopus citations

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. Oksuz et al. define nucleation and spreading regions for Polycomb repressive complex 2 (PRC2), demonstrating the principle of PRC2 domain formation in mammals. They elucidate the role of genome architecture in formation of these domains and identify JARID2 and MTF2 as being crucial for full recruitment of PRC2 to chromatin.

Original languageEnglish
Pages (from-to)1149-1162.e5
JournalMolecular cell
Volume70
Issue number6
DOIs
StatePublished - Jun 21 2018

Keywords

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

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