Affordable Access

deepdyve-link
Publisher Website

Dynamic Chromatin Targeting of BRD4 Stimulates Cardiac Fibroblast Activation.

Authors
  • Stratton, Matthew S1, 2
  • Bagchi, Rushita A1, 2
  • Felisbino, Marina B1, 2
  • Hirsch, Rachel A3
  • Smith, Harrison E3
  • Riching, Andrew S1, 2
  • Enyart, Blake Y1, 2
  • Koch, Keith A1, 2
  • Cavasin, Maria A1, 2
  • Alexanian, Michael4
  • Song, Kunhua1, 2
  • Qi, Jun5
  • Lemieux, Madeleine E6
  • Srivastava, Deepak4
  • Lam, Maggie P Y1, 2
  • Haldar, Saptarsi M4, 7, 8
  • Lin, Charles Y3
  • McKinsey, Timothy A1, 2
  • 1 From the Department of Medicine, Division of Cardiology (M.S.S., R.A.B., M.B.F., A.S.R., B.Y.E., K.A.K., M.A.C., K.S., M.P.Y.L., T.A.M.), University of Colorado Anschutz Medical Campus, Aurora.
  • 2 Consortium for Fibrosis Research & Translation (M.S.S., R.A.B., M.B.F., A.S.R., B.Y.E., K.A.K., M.A.C., K.S., M.P.Y.L., T.A.M.), University of Colorado Anschutz Medical Campus, Aurora.
  • 3 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX (R.A.H., H.E.S., C.Y.L.).
  • 4 Gladstone Institute of Cardiovascular Disease, San Francisco, CA (M.A., D.S., S.M.H.).
  • 5 Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA (J.Q.).
  • 6 Bioinfo, Plantagenet, ON, Canada (M.E.L.). , (Canada)
  • 7 Cardiovascular Research Institute and Department of Medicine, Division of Cardiology UCSF School of Medicine, San Francisco, CA (S.M.H.).
  • 8 Cardiometabolic Disorders, Amgen, San Francisco, CA (S.M.H.).
Type
Published Article
Journal
Circulation Research
Publisher
Ovid Technologies Wolters Kluwer -American Heart Association
Publication Date
Sep 13, 2019
Volume
125
Issue
7
Pages
662–677
Identifiers
DOI: 10.1161/CIRCRESAHA.119.315125
PMID: 31409188
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Small molecule inhibitors of the acetyl-histone binding protein BRD4 have been shown to block cardiac fibrosis in preclinical models of heart failure (HF). However, since the inhibitors target BRD4 ubiquitously, it is unclear whether this chromatin reader protein functions in cell type-specific manner to control pathological myocardial fibrosis. Furthermore, the molecular mechanisms by which BRD4 stimulates the transcriptional program for cardiac fibrosis remain unknown. We sought to test the hypothesis that BRD4 functions in a cell-autonomous and signal-responsive manner to control activation of cardiac fibroblasts, which are the major extracellular matrix-producing cells of the heart. RNA-sequencing, mass spectrometry, and cell-based assays employing primary adult rat ventricular fibroblasts demonstrated that BRD4 functions as an effector of TGF-β (transforming growth factor-β) signaling to stimulate conversion of quiescent cardiac fibroblasts into Periostin (Postn)-positive cells that express high levels of extracellular matrix. These findings were confirmed in vivo through whole-transcriptome analysis of cardiac fibroblasts from mice subjected to transverse aortic constriction and treated with the small molecule BRD4 inhibitor, JQ1. Chromatin immunoprecipitation-sequencing revealed that 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 Sertad4 (SERTA domain-containing protein 4) locus as a prototype, we demonstrate that dynamic chromatin targeting of BRD4 is controlled, in part, by p38 MAPK (mitogen-activated protein kinase) and provide evidence of a critical function for Sertad4 in TGF-β-mediated cardiac fibroblast activation. These findings define BRD4 as a central regulator of the pro-fibrotic cardiac fibroblast phenotype, establish a p38-dependent signaling circuit for epigenetic reprogramming in heart failure, and uncover a novel role for Sertad4. The work provides a mechanistic foundation for the development of BRD4 inhibitors as targeted anti-fibrotic therapies for the heart.

Report this publication

Statistics

Seen <100 times