@article{62a4a67c106242b99ed0fd912d433e25,
title = "XBET 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.",
author = "Priti Anand and Brown, {Jonathan D.} and Lin, {Charles Y.} and Jun Qi and Rongli Zhang and Artero, {Pedro Calderon} and Alaiti, {M. Amer} and Jace Bullard and Kareem Alazem and Margulies, {Kenneth B.} and Cappola, {Thomas P.} and Madeleine Lemieux and Jorge Plutzky and Bradner, {James E.} and Haldar, {Saptarsi M.}",
note = "Funding Information: We are grateful to R. Young and P. Rahl for stimulating discussions; M. Berkeley and the late E. Fox (DFCI Microarray Core) for assistance with microarray experiments; Avery Whitlock for illustrations; and Tom Volkert, Jennifer Love, and Sumeet Gupta at the Whitehead Genome Core for assistance with genome sequencing. This research was supported by an NIH-R01 DK093821 and NIH-K08 HL086614, Individual Biomedical Research Award from The Hartwell Foundation, and the Visconsi Research Scholars Fund (S.M.H.); NIH-K08 CA128972, the Burroughs-Wellcome Fund, the Damon-Runyon Cancer Research Foundation, the Richard and Susan Smith Family Foundation, and the Next Generation Award (J.E.B.); U.S. Department of Defense (C.Y.L.); NIH-T32 HL105338 (M.A.A.); NIH-R01 HL105993 (K.B.M. and T.P.C); and NIH-K08 HL105678 (J.D.B.). Dr. Bradner is the scientific founder of Tensha Therapeutics, which is clinically translating drug-like derivatives of the JQ1 chemical probe of BET bromodomains used in this study, as cancer therapeutics. As such, the Dana-Farber Cancer Institute and Dr. Bradner have been granted minority equity in Tensha. ",
year = "2013",
month = aug,
day = "1",
doi = "10.1016/j.cell.2013.07.013",
language = "English (US)",
volume = "154",
pages = "X569--582",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "3",
}