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

TitleHDAC inhibition results in widespread alteration of the histone acetylation landscape and BRD4 targeting to gene bodies.
Publication TypeJournal Article
Year of Publication2021
AuthorsSlaughter MJ, Shanle EK, Khan A, Chua KF, Hong T, Boxer LD, C Allis D, Josefowicz SZ, Garcia BA, Rothbart SB, Strahl BD, Davis IJ
JournalCell Rep
Volume34
Issue3
Pagination108638
Date Published2021 01 19
ISSN2211-1247
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.

DOI10.1016/j.celrep.2020.108638
Alternate JournalCell Rep
PubMed ID33472068
PubMed Central IDPMC7886050
Grant ListR01 CA198482 / CA / NCI NIH HHS / United States
P30 CA016086 / CA / NCI NIH HHS / United States
R01 CA166447 / CA / NCI NIH HHS / United States
K12 GM000678 / GM / NIGMS NIH HHS / United States
R35 GM126900 / GM / NIGMS NIH HHS / United States
R35 GM124736 / GM / NIGMS NIH HHS / United States
Related Faculty: 
Steven Josefowicz, Ph.D.

Pathology & Laboratory Medicine 1300 York Avenue New York, NY 10065 Phone: (212) 746-6464
Surgical Pathology: (212) 746-2700