Dynamic chromatin targeting of BRD4 stimulates cardiac fibroblast activation
Matthew S Stratton,
Rushita A. Bagchi,
Rachel A Hirsch,
Andrew S Riching,
Marina B Felisbino,
Blake Y Enyart,
Keith A Koch,
Maria A Cavasin,
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)
Posted 28 Feb 2019
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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