BET bromodomains mediate transcriptional pause release in heart failure

Priti Anand, Jonathan D. Brown, Charles Y. Lin, Jun Qi, Rongli Zhang, Pedro Calderon Artero, M. Amer Alaiti, Jace Bullard, Kareem Alazem, Kenneth B. Margulies, Thomas P. Cappola, Madeleine Lemieux, Jorge Plutzky, James E. Bradner, Saptarsi M. Haldar

Research output: Contribution to journalArticle

199 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)569-582
Number of pages14
JournalCell
Volume154
Issue number3
DOIs
StatePublished - Aug 1 2013

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Anand, P., Brown, J. D., Lin, C. Y., Qi, J., Zhang, R., Artero, P. C., Alaiti, M. A., Bullard, J., Alazem, K., Margulies, K. B., Cappola, T. P., Lemieux, M., Plutzky, J., Bradner, J. E., & Haldar, S. M. (2013). BET bromodomains mediate transcriptional pause release in heart failure. Cell, 154(3), 569-582. https://doi.org/10.1016/j.cell.2013.07.013