The Polycomb repressive complex 2 (PRC2) confers transcriptional repression through histone H3 lysine 27 trimethylation (H3K27me3). Here, we examined how PRC2 is modulated by histone modifications associated with transcriptionally active chromatin. We provide the molecular basis of histone H3 N terminus recognition by the PRC2 Nurf55-Su(z)12 submodule. Binding of H3 is lost if lysine 4 in H3 is trimethylated. We find that H3K4me3 inhibits PRC2 activity in an allosteric fashion assisted by the Su(z)12 C terminus. In addition to H3K4me3, PRC2 is inhibited by H3K36me2/3 (i.e., both H3K36me2 and H3K36me3). Direct PRC2 inhibition by H3K4me3 and H3K36me2/3 active marks is conserved in humans, mouse, and fly, rendering transcriptionally active chromatin refractory to PRC2 H3K27 trimethylation. While inhibition is present in plant PRC2, it can be modulated through exchange of the Su(z)12 subunit. Inhibition by active chromatin marks, coupled to stimulation by transcriptionally repressive H3K27me3, enables PRC2 to autonomously template repressive H3K27me3 without overwriting active chromatin domains.
Bibliographical noteFunding Information:
We thank Dirk Schübeler, Antoine Peters, and Susan Gasser for helpful discussions. We thank Norman Kairies and Andrea Scrima for crystallographic support, Maja Koehn and Victoria McParland for advice on peptide synthesis and purification, and Vladimir Rybin for help with ITC measurements. We are also grateful to Ernest Laue for providing us with the plasmid for the GST-H4 construct. Funding in the laboratory of N.H.T. is provided by Association for International Cancer Research grant 10-0292 and the Novartis Research Foundation. F.W.S. gratefully acknowledges funding from the Schering Foundation and the Studienstiftung des deutschen Volkes. A.B.P., N.L.-H., and J.M. were supported by European Molecular Biology Laboratory.
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology