Epigenetics in Cardiac Fibrosis

Central Illustration. Central Roles for Epigenetic Regulators in Mediating the Fibroblast Activation and Inflammation That Culminates in Cardiac Fibrosis In response to pathological stresses such as myocardial infarction (MI) or pressure overload, epigenetic machinery is activated to promote cardiac inflammation and cardiac fibroblast proliferation, leading to cardiac fibrosis. Complex interplay between histone deacetylase (HDAC), histone acetyltransferase (HAT), lysine methyltransferase (KMT), lysine demethylase (KDM), DNA methyltransferase (DNMT), and ten-eleven translocation (TET) enzymes governs acetylation (Ac) of histones and methylation (Me) of histones and DNA that make up nucleosomes.

Figure 1. Three Mechanisms by Which Epigenetic Regulators Can Control Inflammation (A) Binding of BRD4 to acetylated p65 subunit of NF-κB leads to enhanced cyclin-dependent kinase 9 (CDK9)-mediated phosphorylation of RNA polymerase II (Pol II) and increased transcription of downstream proinflammatory genes. This provides a general mechanism by which BRD4 promotes inflammatory signaling in diverse cell types. (B) The lysine demethylases JMJD3 and UTX remove repressive H3K27 trimethylation marks at regulatory sites for proinflammatory genes in macrophages, thereby stimulating downstream target gene expression. (C) Acetylation of lysine residues in FoxP3 promotes its DNA binding and transcriptional activity, thereby leading to enhanced regulatory T cell (Treg) differentiation and anti-inflammatory function.

Figure 2. Three Mechanisms by Which Epigenetic Regulators Can Control Cardiac Fibroblast Proliferation and Myofibroblast Differentiation (A) HDACs repress expression of genes encoding the cyclin-dependent kinase inhibitors, p15 and p57, which leads to enhanced retinoblastoma (Rb) protein phosphorylation and stimulation of downstream target genes that promote cardiac fibroblast proliferation. (B) Binding of BRD4 to acetyl-histone H3K27 helps create super-enhancers (SEs), which drive expression of target genes that promote extracellular matrix (ECM) production and myofibroblast differentiation. (C) DNA methyltransferase (DNMT)-mediated methylation of DNA leads to suppression of antiproliferative genes and genes that normally repress myofibroblast differentiation.