Abstract
Smooth muscle cells (SMC) transition into a number of different phenotypes during atherosclerosis, including those that resemble fibroblasts and chondrocytes, and make up the majority of cells in atherosclerotic plaque. To better understand the epigenetic and transcriptional mechanisms that mediate these cell state changes, and how they relate to risk for coronary artery disease (CAD), we have investigated the causality and function of transcription factors (TFs) at genome wide associated loci. Employing in vitro CRISPR-Cas 9 genome and epigenome editing we show that complex genetic signals within a gene desert at 2q22.3 lie within novel smooth muscle long-distance enhancers for ZEB2 , a TF extensively studied in the context of epithelial mesenchymal transition (EMT) in development and cancer. Single-cell epigenetic and transcriptomic profiling demonstrated that Zeb2 regulates SMC phenotypic transition through chromatin remodeling that obviates accessibility and disrupts both Notch and TGFβ signaling, altering the epigenetic trajectory of SMC transitions. These changes resulted in an inability for transition SMC to turn off contractile programing and take on a fibroblast-like phenotype, and accelerated chondromyocyte differentiation, mirroring features of high-risk atherosclerotic plaques in human coronary arteries. Parallel epigenetic alterations are observed in human coronary artery smooth muscle cells, with ZEB binding motifs preferentially enriched for human genetic signals for coronary artery disease, affirming its role as a master epigenetic regulator of atherosclerosis pathology.
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