1. Chromosomes and Gene Expression
  2. Structural Biology and Molecular Biophysics
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Structural basis for PRC2 decoding of active histone methylation marks H3K36me2/3

  1. Ksenia Finogenova
  2. Jacques Bonnet
  3. Simon Poepsel
  4. Ingmar B Schäfer
  5. Katja Finkl
  6. Katharina Schmid
  7. Claudia Litz
  8. Mike Strauss
  9. Christian Benda
  10. Jürg Müller  Is a corresponding author
  1. Max Planck Institute of Biochemistry, Germany
  2. University of California, Berkeley, United States
  3. McGill University, Canada
Research Article
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Cite this article as: eLife 2020;9:e61964 doi: 10.7554/eLife.61964

Abstract

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 trimethylated 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.

Article and author information

Author details

  1. Ksenia Finogenova

    Laboratory of Chromatin Biology, Max Planck Institute of Biochemistry, Martinsried, Germany
    Competing interests
    The authors declare that no competing interests exist.
  2. Jacques Bonnet

    Laboratory of Chromatin Biology, Max Planck Institute of Biochemistry, Martinsried, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Simon Poepsel

    California Institute for Quantitative Biology (QB3), Molecular Biophysics and Integrative Bio-Imaging Division, Lawrence Berkeley National Laboratory, University of California, Berkeley, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Ingmar B Schäfer

    Department of Structural Cell Biology, Max Planck Institute of Biochemistry, Martinsried, Germany
    Competing interests
    The authors declare that no competing interests exist.
  5. Katja Finkl

    Muscle Dynamics Group, Max Planck Institute of Biochemistry, Martinsried, Germany
    Competing interests
    The authors declare that no competing interests exist.
  6. Katharina Schmid

    Laboratory of Chromatin Biology, Max Planck Institute of Biochemistry, Martinsried, Germany
    Competing interests
    The authors declare that no competing interests exist.
  7. Claudia Litz

    Laboratory of Chromatin Biology, Max Planck Institute of Biochemistry, Martinsried, Germany
    Competing interests
    The authors declare that no competing interests exist.
  8. Mike Strauss

    Anatomy and Cell Biology, McGill University, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  9. Christian Benda

    Department of Structural Cell Biology, Max Planck Institute of Biochemistry, Martinsried, Germany
    Competing interests
    The authors declare that no competing interests exist.
  10. Jürg Müller

    Laboratory of Chromatin Biology, Max Planck Institute of Biochemistry, Martinsried, Germany
    For correspondence
    muellerj@biochem.mpg.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2391-4641

Funding

Deutsche Forschungsgemeinschaft (SFB1064)

  • Jürg Müller

Max-Planck-Gesellschaft

  • Jürg Müller

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Jerry L. Workman, Stowers Institute for Medical Research, United States

Publication history

  1. Received: August 10, 2020
  2. Accepted: November 18, 2020
  3. Accepted Manuscript published: November 19, 2020 (version 1)

Copyright

© 2020, Finogenova et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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