HDAC inhibition results in widespread alteration of the histone acetylation landscape and BRD4 targeting to gene bodies

Mariesa J Slaughter; Erin K Shanle; Abid Khan; Katrin F Chua; Tao Hong; Lisa D Boxer; C David Allis; Steven Z Josefowicz; Benjamin A Garcia; Scott B Rothbart; Brian D Strahl; Ian J Davis

doi:10.1016/j.celrep.2020.108638

HDAC inhibition results in widespread alteration of the histone acetylation landscape and BRD4 targeting to gene bodies

Cell Rep. 2021 Jan 19;34(3):108638. doi: 10.1016/j.celrep.2020.108638.

Authors

Affiliations

¹ Department of Genetics, Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
² Department of Biological and Environmental Sciences, Longwood University, Farmville, VA 23909, USA.
³ Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599, USA.
⁴ Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Geriatric Research, Education, and Clinical Center, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304, USA.
⁵ Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁶ Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY 10065, USA.
⁷ Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA.
⁸ Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁹ Center for Epigenetics, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
¹⁰ Department of Genetics, Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599, USA. Electronic address: brian_strahl@med.unc.edu.
¹¹ Department of Genetics, Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Pediatrics, University of North Carolina, Chapel Hill, NC 27514, USA. Electronic address: ian_davis@med.unc.edu.

Abstract

Histone acetylation levels are regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs) that antagonistically control the overall balance of this post-translational modification. HDAC inhibitors (HDACi) are potent agents that disrupt this balance and are used clinically to treat diseases including cancer. Despite their use, little is known about their effects on chromatin regulators, particularly those that signal through lysine acetylation. We apply quantitative genomic and proteomic approaches to demonstrate that HDACi robustly increases a low-abundance histone 4 polyacetylation state, which serves as a preferred binding substrate for several bromodomain-containing proteins, including BRD4. Increased H4 polyacetylation occurs in transcribed genes and correlates with the targeting of BRD4. Collectively, these results suggest that HDAC inhibition functions, at least in part, through expansion of a rare histone acetylation state, which then retargets lysine-acetyl readers associated with changes in gene expression, partially mimicking the effect of bromodomain inhibition.

Keywords: BRD4; HDAC; bromodomain; chromatin immunoprecipitation; histone acetylation; mass spectrometry; peptide microarray; superenhancer; transcription.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Acetylation
Cell Cycle Proteins / metabolism*
Histone Deacetylase Inhibitors / pharmacology
Histone Deacetylase Inhibitors / therapeutic use*
Histones / metabolism*
Humans
Transcription Factors / metabolism*

Substances

BRD4 protein, human
Cell Cycle Proteins
Histone Deacetylase Inhibitors
Histones
Transcription Factors

Abstract

Publication types

MeSH terms

Substances

Grants and funding