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Dynamic chromatin targeting of BRD4 stimulates cardiac fibroblast activation

By Matthew S Stratton, Rushita A. Bagchi, Rachel A Hirsch, Andrew S Riching, Marina B Felisbino, Blake Y Enyart, Keith A Koch, Maria A Cavasin, Michael Alexanian, Kunhua Song, Jun Qi, Madeleine E Lemieux, Maggie P. Y. Lam, Saptarsi M Haldar, Charles Y Lin, Timothy A McKinsey

Posted 28 Feb 2019
bioRxiv DOI: 10.1101/563445 (published DOI: 10.1161/CIRCRESAHA.119.315125)

Small molecule inhibitors of the acetyl-histone binding protein BRD4 have been shown to block cardiac fibrosis in pre-clinical models of heart failure (HF). However, the mechanisms by which BRD4 promotes pathological myocardial fibrosis remain unclear. Here, we demonstrate that BRD4 functions as an effector of TGF-β signaling to stimulate conversion of quiescent cardiac fibroblasts into Periostin (Postn)-positive cells that express high levels of extracellular matrix. BRD4 undergoes stimulus-dependent, genome-wide redistribution in cardiac fibroblasts, becoming enriched on a subset of enhancers and super-enhancers, and leading to RNA polymerase II activation and expression of downstream target genes. Employing the SERTA domain-containing protein 4 (Sertad4) locus as a prototype, we demonstrate that dynamic chromatin targeting of BRD4 is controlled, in part, by p38 mitogen-activated protein kinase, and provide evidence of a novel function for Sertad4 in TGF-β-mediated cardiac fibroblast activation. These findings define BRD4 as a central regulator of the pro-fibrotic cell state of cardiac fibroblasts, and establish a signaling circuit for epigenetic reprogramming in HF.

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