title: Histone methylation by PRC2 is inhibited by active chromatin marks.
abstract: 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.
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH-4058 Basel, Switzerland.
authors.forename: Frank W
authors.initials: FW
authors.lastname: Schmitges
authors.forename: Archana B
authors.initials: AB
authors.lastname: Prusty
authors.forename: Mahamadou
authors.initials: M
authors.lastname: Faty
authors.forename: Alexandra
authors.initials: A
authors.lastname: Stützer
authors.forename: Gondichatnahalli M
authors.initials: GM
authors.lastname: Lingaraju
authors.forename: Jonathan
authors.initials: J
authors.lastname: Aiwazian
authors.forename: Ragna
authors.initials: R
authors.lastname: Sack
authors.forename: Daniel
authors.initials: D
authors.lastname: Hess
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.forename: Shaolian
authors.initials: S
authors.lastname: Zhou
authors.forename: Richard D
authors.initials: RD
authors.lastname: Bunker
authors.forename: Urs
authors.initials: U
authors.lastname: Wirth
authors.forename: Tewis
authors.initials: T
authors.lastname: Bouwmeester
authors.forename: Andreas
authors.initials: A
authors.lastname: Bauer
authors.forename: Nga
authors.initials: N
authors.lastname: Ly-Hartig
authors.forename: Kehao
authors.initials: K
authors.lastname: Zhao
authors.forename: Homan
authors.initials: H
authors.lastname: Chan
authors.forename: Justin
authors.initials: J
authors.lastname: Gu
authors.forename: Heinz
authors.initials: H
authors.lastname: Gut
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Fischle
authors.forename: Jürg
authors.initials: J
authors.lastname: Müller
authors.forename: Nicolas H
authors.initials: NH
authors.lastname: Thomä
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D002843:Chromatin / Q000235:genetics / Q000378:metabolism*; D018360:Crystallography, X-Ray; D004330:Drosophila; D029721:Drosophila Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011495:Histone-Lysine N-Methyltransferase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000737:chemistry / Q000378:metabolism*; D008745:Methylation; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D063151:Polycomb Repressive Complex 2; D063146:Polycomb-Group Proteins; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D056505:Retinoblastoma-Binding Protein 4 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: C110251:Caf1-55 protein, Drosophila; D002843:Chromatin; D029721:Drosophila Proteins; D006657:Histones; D063146:Polycomb-Group Proteins; C082637:RBBP4 protein, human; D012097:Repressor Proteins; D056505:Retinoblastoma-Binding Protein 4; C543390:Su(z)12 protein, Drosophila; D011495:Histone-Lysine N-Methyltransferase; D063151:Polycomb Repressive Complex 2; D008239:Lysine