TCF21 and AP-1 interact through epigenetic modifications to regulate coronary artery disease gene expression [ATAC-Seq]

The majority of genetic variation associated with coronary artery disease (CAD) resides in non- coding regions that are expected to involve transcriptional and epigenetic mechanisms of gene expression. We have identified a transcriptional network downstream of the CAD associated transcription factor (TF) TCF21 and provide evidence for TCF21 colocalization and co- regulation with the activator protein-1 (AP-1) complex in disease loci. We show that TCF21 and AP-1 regulate expression of two causal CAD genes, SMAD3 and CDKN2B-AS1, in part by interactions with histone acetyltransferases and deacetylases. Genome-wide, TCF21 and AP-1 are jointly localized, regulate chromatin accessibility, and are enriched in CAD loci. These data show that the known chromatin remodeling and pioneer functions of AP-1 are a pervasive aspect of epigenetic control of transcription and thus risk in CAD associated loci, and that interaction of AP-1 with TCF21 to control epigenetic features contributes to the genetic risk in loci where they colocalize. The chromatin accessibility of human coronary artery smooth muscle cells (HCASMC) grown in serum were evaluated with shRNA of JUN, TCF21 or control knockdown.