BET Bromodomains Mediate Transcriptional Pause Release in Heart Failure

Abstract

SUMMARY Heart failure (HF) is driven by the interplay between master regulatory transcription factors and dynamic alterations in chromatin structure. While pathologic gene transactivation in this context is known to be associated with recruitment of histone acetyl-transferases and local chromatin hyperacetylation, the role of epigenetic reader proteins in cardiac biology is unknown. We therefore undertook a first study 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 activation of canonical master regulators and effectors that are central to HF pathogenesis and relevant to the pathobiology of failing human hearts. This study implicates epigenetic readers in cardiac biology and identifies BET co-activator proteins as therapeutic targets in HF.

GC skew defines distinct RNA polymerase pause sites in CpG island promoters

“…Several recent studies suggest that enhancers may function to regulate transcription in part by modulating Pol II pausing (Krumm et al 1995;Brown et al 1996;Core and Lis 2009;Zippo et al 2009;Anand et al 2013;Liu et al 2013;Loven et al 2013). We used chromatin conformation capture (3C) to probe the relationship between enhancer-promoter looping interactions and pausing class in MCF7 cells transiently exposed to estradiol (E2).…”

“…The role of active enhancers in mediating promoter-proximal pause release is incompletely understood but has been attributed to the delivery of the P-TEFb complex to the promoter, enhancer-mediated liberation of P-TEFb complex from local HEXIM1-mediated sequestration, and, most recently, a mechanism involving competition for promoter-bound NELF complex by enhancer-derived eRNAs (Anand et al 2013;Liu et al 2013;Loven et al 2013;Schaukowitch et al 2014). It is tempting to speculate that at distally paused genes, the enhancer might bring in factors capable of resolving R-loops or other physical constraints (e.g., supercoiling).…”

“…Enhancers are cis-acting regulatory elements that control transcription from a distance through the formation of contacts between the enhancer-bound transcription factors and promoter-bound Pol II and the looping out of intervening chromatin (Kagey et al 2010b). BRD4 and components of the P-TEFb complex have been shown to colocalize with elongating (serine-2-phosphorylated) Pol II at both the promoters and enhancers of active genes, and inhibition of either suppresses not only elongation of promoter-derived mRNAs but also that of noncoding "eRNAs" arising at distal enhancers (Zhang et al 2012;Anand et al 2013;Liu et al 2013;Loven et al 2013;Kanno et al 2014). In addition, long-range chromatin looping interactions have been shown to correlate with paused Pol II during Drosophila development (Ghavi-Helm et al 2014).…”

Functions of BET proteins in erythroid gene expression

“…[12][13][14][15]58,59 Based on the results in the previous section, we tested whether BETs act in GATA1-activated transcription subsequent to the establishment of chromatin occupancy. As GATA1 occupancy might be less sensitive to BET inhibition once established, we examined the short-term effects of BET inhibition after establishment of GATA1 occupancy.…”

The Potential of Targeting Epigenetic Regulators for the Treatment of Fibrotic Cardiac Diseases

“…BRD4 activates RNA Polymerase II (Pol II) by recruiting CDK9 to gene promoters, resulting in Pol II phosphorylation and transcription elongation [12]. JQ1, a small molecule that disrupts binding of BET bromodomains to acetyl-histones, was shown to block interstitial cardiac fibrosis in mouse models of heart failure [13,14]. This was accompanied by decreased Pol II activity at pro-fibrotic genes (e.g., α-SMA, PAI-1), establishing a role for BET proteins in cardiac fi brosis [13].…”