1. Biochemistry and Chemical Biology
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Lysine-14 acetylation of histone H3 in chromatin confers resistance to the deacetylase and demethylase activities of an epigenetic silencing complex

  1. Mingxuan Wu
  2. Dawn Hayward
  3. Jay H Kalin
  4. Yun Song
  5. John WR Schwabe
  6. Philip A Cole  Is a corresponding author
  1. Harvard Medical School, United States
  2. Johns Hopkins University School of Medicine, United States
  3. University of Leicester, United Kingdom
Research Article
  • Cited 13
  • Views 2,414
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Cite this article as: eLife 2018;7:e37231 doi: 10.7554/eLife.37231

Abstract

The core CoREST complex (LHC) contains histone deacetylase HDAC1 and histone demethylase LSD1 held together by the scaffold protein CoREST. Here we analyze the purified LHC with modified peptide and reconstituted semisynthetic mononucleosome substrates. LHC demethylase activity toward methyl-Lys4 in histone H3 is strongly inhibited by H3 Lys14 acetylation, and this appears to be an intrinsic property of the LSD1 subunit. Moreover, the deacetylase selectivity of LHC unexpectedly shows a marked preference for H3 acetyl-Lys9 versus acetyl-Lys14 in nucleosome substrates but this selectivity is lost with isolated acetyl-Lys H3 protein. This diminished activity of LHC to Lys-14 deacetylation in nucleosomes is not merely due to steric accessibility based on the pattern of sensitivity of the LHC enzymatic complex to hydroxamic acid-mediated inhibition. Overall, these studies have revealed how a single Lys modification can confer a composite of resistance in chromatin to a key epigenetic enzyme complex involved in gene silencing.

Article and author information

Author details

  1. Mingxuan Wu

    Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United States
    Competing interests
    No competing interests declared.
  2. Dawn Hayward

    Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    No competing interests declared.
  3. Jay H Kalin

    Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United States
    Competing interests
    No competing interests declared.
  4. Yun Song

    The Leicester Institute of Structural and Chemical Biology, University of Leicester, Leicester, United Kingdom
    Competing interests
    No competing interests declared.
  5. John WR Schwabe

    The Leicester Institute of Structural and Chemical Biology, University of Leicester, Leicester, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2865-4383
  6. Philip A Cole

    Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United States
    For correspondence
    pacole@bwh.harvard.edu
    Competing interests
    Philip A Cole, Senior editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6873-7824

Funding

National Institute of General Medical Sciences (GM62437)

  • Philip A Cole

Flight Attendant Medical Research Institute (Center of Excellence)

  • Philip A Cole

V Foundation for Cancer Research (Program Grant)

  • Philip A Cole

Wellcome Trust

  • John WR Schwabe

Wolfson Foundation

  • John WR Schwabe

Biotechnology and Biological Sciences Research Council

  • John WR Schwabe

4SC

  • John WR Schwabe

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

Reviewing Editor

  1. Wilfred A van der Donk, University of Illinois at Urbana-Champaign, United States

Publication history

  1. Received: April 3, 2018
  2. Accepted: June 4, 2018
  3. Accepted Manuscript published: June 5, 2018 (version 1)
  4. Version of Record published: June 26, 2018 (version 2)

Copyright

© 2018, Wu 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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