Polycomb repressive complex 2 (PRC2) is a histone methyltransferase that maintains the repressed state of thousands of genes during development in all metazoans. At target genes, the histone methyltransferase activity of PRC2 is stimulated through interactions between methylated histone tails to a regulatory centre in PRC2. In addition to its core subunits, PRC2 comprises multiple accessory subunits that vary in their composition during development. PRC2 binds to thousands of transcripts, and interactions with RNA inhibit the histone methyltransferase activity of PRC2. We previously showed that PRC2 binds to RNA promiscuously [1,2], with variations of affinities between target transcripts [3] that can be attributed to short repeats of consecutive guanines and G-quadruplex-forming sequences [4]. RNA proposed to serve as a decoy that prevents the recruitment of PRC2 to active genes [1], leaving open a mechanistic conundrum: how can PRC2 methylate histones within the RNA-rich environment of the nucleus?
Using crosslinking with mass-spectrometry, complemented with mutagenesis, we now identified a major RNA-interaction region within the regulatory centre of PRC2. Accordingly, upon binding of methylated histone tails to the regulatory centre of PRC2, RNA-mediated inhibition is relieved, allowing PRC2 to modify nucleosomes. Enzymatic and binding assays combined with crosslinking mass spectrometry reveal that the regulatory centre of PRC2 remains exposed and available to interact with RNA or stimulatory peptides while PRC2 is in a complex with most of its accessory subunits. Collectively, we provide a unified mechanism for RNA-mediated regulation of PRC2 throughout development.