Capturing the Onset of PRC2-Mediated Repressive Domain Formation

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. [Display omitted] •PRC2 nucleation at a subset of CpG islands forms spatial clusters in the nucleus•JARID2 and MTF2 increase the stability of PRC2 at its nucleation sites•Initial PRC2 activity forms H3K27me3 foci within the nucleus•After nucleation, PRC2 spreads H3K27me2/3 in cis and in far-cis via 3D contacts 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.