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Repression of genes by Polycomb requires that PRC2 modifies their chromatin by trimethylating lysine 27 on histone H3 (H3K27me3). At transcriptionally active genes, di- and tri-methylated H3K36 inhibit PRC2. Here, the cryo-EM structure of PRC2 on dinucleosomes reveals how binding of its catalytic subunit EZH2 to nucleosomal DNA orients the H3 N-terminus via an extended network of interactions to place H3K27 into the active site. Unmodified H3K36 occupies a critical position in the EZH2-DNA interface. Mutation of H3K36 to arginine or alanine inhibits H3K27 methylation by PRC2 on nucleosomes in vitro . Accordingly, Drosophila H3K36A and H3K36R mutants show reduced levels of H3K27me3 and defective Polycomb repression of HOX genes. The relay of interactions between EZH2, the nucleosomal DNA and the H3 N-terminus therefore creates the geometry that permits allosteric inhibition of PRC2 by methylated H3K36 in transcriptionally active chromatin., Competing Interests: KF, JB, SP, IS, KF, KS, CL, MS, CB, JM No competing interests declared, (© 2020, Finogenova et al.)

Polycomb group proteins are transcriptional repressors controlling gene expression patterns and maintaining cell type identity. The chemical modifications of histones and DNA caused by the regulated activity of chromatin-modifying enzymes such as Polycomb help establish and maintain such expression patterns. Polycomb repressive complex 2 (PRC2) is the only known methyltransferase specific for histone H3 lysine 27 (H3K27) and catalyzes its trimethylation leading to the repressive H3K27me3 mark. Structural biology has made important contributions to our understanding of the molecular mechanisms that ensure the spatiotemporal regulation of PRC2 activity and the establishment of inactive chromatin domains marked by H3K27me3. In this review, we discuss the recent structural studies that have advanced our understanding of PRC2 function, in particular the roles of intersubunit interactions in complex assembly and the regulation of methyltransferase activity, as well as the mechanism of local H3K27me3 spreading leading to repressive domains.