Dynamic chromatin targeting of BRD4 stimulates cardiac fibroblast activation

Abstract

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.

BRD4 Interacts with GATA4 to Govern Mitochondrial Homeostasis in Adult Cardiomyocytes

“…Our data show that acute BRD4 depletion in CMs of the adult mouse leads to rapid-onset systolic HF and mortality, highlighting a sharp contrast to the salubrious effects of small molecule BET BD inhibitors in treating adult mice with HF. These data are consistent with earlier transcriptomic characterization of JQ1 treated hearts and suggest that the dominant cellular targets of these compounds in the context of HF are non-CMs, such as fibroblasts and immune cells 20,49 . Further dissection of these cell compartmentand gene-specific effects in the context of HF using conditional mice for each BET allele will be a fruitful area of future study.…”

Targeting fibrosis in the Duchenne Muscular Dystrophy mice model: an uphill battle

“…Among 26 epigenetic regulators (Table 4), the only group of compounds able to reduce the fluorescence induced by TGFb1 were the members of the BRDI family: JQ1, and PFI-1 ( Figure 2G). As already demonstrated in the heart, we confirm that the BRDI family members are essential regulators of FAP differentiation into fibroblasts [34] Several transcriptional modifiers and regulators have been described as final effectors of the TGFb signaling as well as mediating its involvement in fibroblast activation and scar deposition. These include serum responsive factor (SRF) [35], C-ets-1 (ETS1) [36], and NFkB [37].…”

Apabetalone and hospitalization for heart failure in patients following an acute coronary syndrome: a prespecified analysis of the BETonMACE study

“…In those studies, apabetalone favorably modulated immune, oxidative, fibrotic, hypertrophic and vascular calcification pathways implicated in the genesis of both atherosclerosis and heart failure, as evidenced by gene and protein expression profiling in cell studies [13][14][15][16][17][18][19][20][21][22][23]. Other BET inhibitors have also been shown to reduce cardiomyocyte hypertrophy, myocardial fibrosis and apoptosis, in parallel with favorable effects on gene expression [22,[29][30][31][32]. These data from BETonMACE suggest that such cellular effects of BET inhibition may translate into clinical benefit for reducing heart failure risk.…”