Lysine-14 acetylation of histone H3 in chromatin confers resistance to the deacetylase and demethylase activities of an epigenetic silencing complex
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.
Data availability
All data generated or analyses during this study have been deposited in Dryad.
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Data from: Lysine-14 Acetylation of Histone H3 in Chromatin Confers Resistance to the CoREST ComplexAvailable at Dryad Digital Repository under a CC0 Public Domain Dedication.
Article and author information
Author details
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
- Wilfred A van der Donk, University of Illinois at Urbana-Champaign, United States
Version history
- Received: April 3, 2018
- Accepted: June 4, 2018
- Accepted Manuscript published: June 5, 2018 (version 1)
- 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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