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PMID: 23911322 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

BET bromodomains mediate transcriptional pause release in heart failure.

Cell ·Vol. 154 ·No. 3 ·2013-08-01 ·Pages 569-82

Anand P, Brown JD, Lin CY, Qi J, Zhang R, Artero PC, Alaiti MA, Bullard J, Alazem K, Margulies KB, Cappola TP, Lemieux M, Plutzky J, Bradner JE, Haldar SM

Abstract

Heart failure (HF) is driven by the interplay between regulatory transcription factors and dynamic alterations in chromatin structure. Pathologic gene transactivation in HF is associated with recruitment of histone acetyl-transferases and local chromatin hyperacetylation. We therefore assessed the role of acetyl-lysine reader proteins, or bromodomains, in HF. Using a chemical genetic approach, we establish a central role for BET family bromodomain proteins in gene control during HF pathogenesis. BET inhibition potently suppresses cardiomyocyte hypertrophy in vitro and pathologic cardiac remodeling in vivo. Integrative transcriptional and epigenomic analyses reveal that BET proteins function mechanistically as pause-release factors critical to expression of genes that are central to HF pathogenesis and relevant to the pathobiology of failing human hearts. This study implicates epigenetic readers as essential effectors of transcriptional pause release during HF pathogenesis and identifies BET coactivator proteins as therapeutic targets in the heart.

MeSH Terms
Animals Cardiomegaly/genetics,metabolism Chromatin Disease Models, Animal Epigenesis, Genetic Heart Heart Failure/drug therapy,genetics,metabolism Humans Mice Mice, Inbred C57BL Myocytes, Cardiac/metabolism Protein Structure, Tertiary Rats Transcription Factors/antagonists & inhibitors,chemistry,metabolism Transcription, Genetic Transcriptome
Chemicals
Chromatin Transcription Factors
Authors & Affiliations
15 authors, click to expand affiliations / ORCID
Anand Priti
Case Cardiovascular Research Institute, Department of Medicine, Case Western Reserve University School of Medicine, and Harrington Heart & Vascular Institute, University Hospitals Case Medical Center, Cleveland, OH 44106, USA.
Brown Jonathan D
Lin Charles Y
Qi Jun
Zhang Rongli
Artero Pedro Calderon
Alaiti M Amer
Bullard Jace
Alazem Kareem
Margulies Kenneth B
Cappola Thomas P
Lemieux Madeleine
Plutzky Jorge
Bradner James E
Haldar Saptarsi M
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Article Info
Journal
Cell
Abbr.
Cell
ISSN
1097-4172
DOI
10.1016/j.cell.2013.07.013
Published
2013-08-01
Pages
569-82
Language
English
Region
United States
NLM ID
0413066
PMCID
PMC4090947
Subset
IM
Grants
NHLBI NIH HHS · P01 HL048743 · United States
NHLBI NIH HHS · T32 HL105338 · United States
NHLBI NIH HHS · K08 HL086614 · United States
NHLBI NIH HHS · K08 HL105678 · United States
NHLBI NIH HHS · R01 HL105993 · United States
NIDDK NIH HHS · R01 DK093821 · United States
NCI NIH HHS · K08 CA128972 · United States
Databases
GEO
GSE46668, GSE48110, GSE48111, GSE48112
Corrections
CommentIn
PMID: 24080694
External Links
PubMed source DOI: 10.1016/j.cell.2013.07.013 PMC Full Text View journal details
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