RT Journal Article
SR Electronic
T1 Dynamic chromatin targeting of BRD4 stimulates cardiac fibroblast activation
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 563445
DO 10.1101/563445
A1 Matthew S. Stratton
A1 Rushita A. Bagchi
A1 Rachel A. Hirsch
A1 Andrew S. Riching
A1 Marina B. Felisbino
A1 Blake Y. Enyart
A1 Keith A. Koch
A1 Maria A. Cavasin
A1 Michael Alexanian
A1 Kunhua Song
A1 Jun Qi
A1 Madeleine E. Lemieux
A1 Maggie P.Y. Lam
A1 Saptarsi M. Haldar
A1 Charles Y. Lin
A1 Timothy A. McKinsey
YR 2019
UL http://biorxiv.org/content/early/2019/02/28/563445.abstract
AB 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.