(A) The most notable histone acetyltransferase (HAT) in the control of cardiac fibrosis is p300, which mediates acetylation of histone tail lysine residues in enhancers and super-enhancers that control expression of profibrotic genes. p300 has a bromodomain, which mediates binding of the enzyme to acetyl-histones in chromatin. Bromodomain-containing protein 4 (BRD4) also binds acetyl-histones and initiates a profibrotic gene program by activating RNA polymerase II (RNA Pol II). (B) The small-molecule acetyl-lysine mimic JQ1 binds the bromodomains of BRD4 to displace it from chromatin, thereby attenuating profibrotic gene expression. Similarly, CBP30 inhibits the p300 bromodomain, while A-485 inhibits p300 catalytic activity. Pharmacological inhibition of histone deacetylases (HDACs) using compounds such as ITF2357/givinostat creates spurious acetyl-histone marks, resulting in mislocalization of p300 and BRD4 in the cardiac fibroblast genome, with resulting disruption of the profibrotic gene program. (C) In activated CFs, BRD4 associates with an enhancer element approximately 65 kb downstream of the gene encoding a homeobox transcription factor, Meox1. Enhancer-bound BRD4 loops to associate with the Meox1 promoter, resulting in stimulation of its expression and initiation of a profibrotic gene expression cascade.