Abstract 131: A microRNA Targets the Epigenetic Reader BRD4 to Suppress Transcription Elongation in the Heart
BRD4 is a member of the BET family of proteins, which contain tandem reader domains (bromodomains) that bind to acetylated histone tails within chromatin. We recently demonstrated that JQ1, a small molecule that prevents BRD4-chromatin interaction, potently blocks pathological cardiac hypertrophy and improves cardiac function in pre-clinical models. BRD4 functions as a nodal regulator of the transcriptional program for cardiac hypertrophy by recruiting P-TEFb to gene regulatory elements, resulting in phosphorylation of RNA polymerase II (Pol II), and subsequent transcription elongation. Here, we describe a signal-dependent mechanism for regulation of BRD4 in the heart. BRD4 protein expression is dramatically upregulated in cardiomyocytes exposed to cues for pathological, but not physiological, hypertrophy. In unstimulated cardiomyocytes, BRD4 protein expression is maintained at low levels by a microRNA, which directly targets the 3’ UTR of the BRD4 transcript, thereby preventing translation of this acetyl-lysine reader. In response to signals for hypertrophy, expression of the microRNA is down regulated through a histone deacetylase (HDAC)-dependent mechanism, resulting in robust induction of BRD4 protein synthesis. Whole genome analyses establish a crucial role for the microRNA in the control of Pol II elongation in the heart via BRD4 down regulation. These findings define a novel chromatin signaling axis that can be targeted at multiple levels (epigenetic reader, microRNA or HDAC) for the treatment of heart failure.
Author Disclosures: M.S. Stratton: None. B.S. Ferguson: None. C.Y. Lin: None. P. Anand: None. S.T. Wickers: None. P.D. Tatman: None. J.E. Bradner: None. S.M. Haldar: None. T.A. McKinsey: None.
- © 2015 by American Heart Association, Inc.