PT  - JOURNAL ARTICLE
AU  - Matthew S. Stratton
AU  - Rushita A. Bagchi
AU  - Rachel A. Hirsch
AU  - Andrew S. Riching
AU  - Marina B. Felisbino
AU  - Blake Y. Enyart
AU  - Keith A. Koch
AU  - Maria A. Cavasin
AU  - Michael Alexanian
AU  - Kunhua Song
AU  - Jun Qi
AU  - Madeleine E. Lemieux
AU  - Maggie P.Y. Lam
AU  - Saptarsi M. Haldar
AU  - Charles Y. Lin
AU  - Timothy A. McKinsey
TI  - Dynamic chromatin targeting of BRD4 stimulates cardiac fibroblast activation
AID  - 10.1101/563445
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 563445
4099  - http://biorxiv.org/content/early/2019/02/28/563445.short
4100  - http://biorxiv.org/content/early/2019/02/28/563445.full
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.