HDAC inhibition results in widespread alteration of the histone acetylation landscape and BRD4 targeting to gene bodies.
BRD4
HDAC
bromodomain
chromatin immunoprecipitation
histone acetylation
mass spectrometry
peptide microarray
superenhancer
transcription
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
19 01 2021
19 01 2021
Historique:
received:
19
12
2018
revised:
18
09
2020
accepted:
21
12
2020
entrez:
20
1
2021
pubmed:
21
1
2021
medline:
29
1
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33472068
pii: S2211-1247(20)31627-2
doi: 10.1016/j.celrep.2020.108638
pmc: PMC7886050
mid: NIHMS1664956
pii:
doi:
Substances chimiques
BRD4 protein, human
0
Cell Cycle Proteins
0
Histone Deacetylase Inhibitors
0
Histones
0
Transcription Factors
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
108638Subventions
Organisme : NCI NIH HHS
ID : R01 CA198482
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA016086
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA166447
Pays : United States
Organisme : NIGMS NIH HHS
ID : K12 GM000678
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM126900
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM124736
Pays : United States
Informations de copyright
Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests B.D.S. is a cofounder and scientific advisory board member of EpiCypher, Inc., and a scientific advisory board member of Triangle Biotechnology, Inc. I.J.D. is a scientific advisory board member of Triangle Biotechnology, Inc.
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