Polycomb repressive complex 2 (PRC2) maintains transcriptionally silent heterochromatin by installing and spreading repressive histone methylation marks along nucleosome arrays. Despite extensive research, the mechanism by which PRC2 engages with chromatin remains incompletely understood. Here we employ single-molecule force spectroscopy and molecular dynamics simulations to dissect the interactions of PRC2 with polynucleosome substrates. Our results reveal an unexpectedly diverse repertoire of PRC2 binding configurations on chromatin. Besides interacting with bare DNA, mononucleosomes, and neighboring nucleosome pairs, PRC2 is also found to bridge non-adjacent nucleosomes, an activity associated with chromatin compaction. Furthermore, the distribution and stability of these PRC2-chromatin interaction modes are differentially modulated by accessory PRC2 cofactors, oncogenic histone mutations, and the methylation state of chromatin. Overall, this work provides a paradigm for understanding the physical basis of epigenetic maintenance mediated by Polycomb group proteins.

PRC2 bridges non-adjacent nucleosomes to establish heterochromatin