Visualization of PRC2-Dinucleosome Interactions Leading to Epigenetic Repression

Abstract

Epigenetic regulation is mediated by protein complexes that couple recognition of chromatin marks to activity or recruitment of chromatin-modifying enzymes. Polycomb repressive complex 2 (PRC2), a gene silencer that methylates lysine 27 of histone H3, is stimulated upon recognition of its own catalytic product, and has been shown to be more active on dinucleosomes than H3 tails or single nucleosomes. These properties likely facilitate local H3K27me2/3 spreading causing heterochromatin formation and gene repression. Here, cryo-EM reconstructions of human PRC2 bound to dinucleosomes show how a single PRC2, interacting with nucleosomal DNA, precisely positions the H3 tails to recognize a H3K27me3 mark in one nucleosome and is stimulated to modify a neighboring nucleosome. The geometry of the PRC2-DNA interactions allow PRC2 to tolerate different dinucleosome geometries due to varying lengths of the linker DNA. Our structures are the first to illustrate how an epigenetic regulator engages with a complex chromatin substrate.