Coronary artery disease genes SMAD3 and TCF21 promote opposing interactive genetic programs that regulate smooth muscle cell differentiation and disease risk

• DOI: 10.1371/journal.pgen.1007681
• Publication Date: 2018-10-11T17:30:49Z
• Authors: Dharini Iyer; Quanyi Zhao; Robert Wirka; Ameay Naravane; Trieu Nguyen; Boxiang Liu; Manabu Nagao; Paul Cheng; Clint L. Miller; Juyong Brian Kim; Milos Pjanic; Thomas Quertermous
• Keywords: Chromatin immunoprecipitation

Although numerous genetic loci have been associated with coronary artery disease (CAD) genome wide association studies, efforts are needed to identify the causal genes in these and link them into fundamental signaling pathways. Recent studies investigated mechanism of CAD gene SMAD3, a central transcription factor (TF) TGFβ pathway, investigating its role smooth muscle biology. In vitro human cells (HCASMC) revealed that SMAD3 modulates cellular phenotype, promoting expression differentiation marker while inhibiting proliferation. RNA sequencing chromatin immunoprecipitation HCASMC identified downstream reside pathways which mediate vascular development atherosclerosis processes this cell type. patterns promoted by were noted opposing direction effect compared another TF, TCF21. At sites TCF21 colocalization on DNA, binding was inversely correlated binding, due part locally blocking accessibility at site. Further, able directly inhibit activation transfection reporter studies. contrast is protective toward CAD, shown be risk. We propose pro-differentiation action inhibits dedifferentiation required for expand stabilize plaque as they respond stresses, counteracting dedifferentiating activity