title: BET bromodomains mediate transcriptional pause release in heart failure.
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.
authors.affiliation: 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.
authors.forename: Priti
authors.initials: P
authors.lastname: Anand
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Brown
authors.forename: Charles Y
authors.initials: CY
authors.lastname: Lin
authors.forename: Jun
authors.initials: J
authors.lastname: Qi
authors.forename: Rongli
authors.initials: R
authors.lastname: Zhang
authors.forename: Pedro Calderon
authors.initials: PC
authors.lastname: Artero
authors.forename: M Amer
authors.initials: MA
authors.lastname: Alaiti
authors.forename: Jace
authors.initials: J
authors.lastname: Bullard
authors.forename: Kareem
authors.initials: K
authors.lastname: Alazem
authors.forename: Kenneth B
authors.initials: KB
authors.lastname: Margulies
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Cappola
authors.forename: Madeleine
authors.initials: M
authors.lastname: Lemieux
authors.forename: Jorge
authors.initials: J
authors.lastname: Plutzky
authors.forename: James E
authors.initials: JE
authors.lastname: Bradner
authors.forename: Saptarsi M
authors.initials: SM
authors.lastname: Haldar
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism; D002843:Chromatin; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic; D006321:Heart; D006333:Heart Failure / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000378:metabolism; D017434:Protein Structure, Tertiary; D051381:Rats; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D014158:Transcription, Genetic; D059467:Transcriptome
chemical_list: D002843:Chromatin; D014157:Transcription Factors
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