Vascular smooth muscle cell state trajectories mediate molecular mechanisms of coronary disease risk [scRNA-seq and scATAC-seq]

Vascular smooth muscle cells contribute to heritable coronary artery disease risk and undergo complex transitions to multiple disease-related phenotypes. To investigate the genetic basis of these trajectories, we develop a dense timecourse single cell transcriptomic and epigenetic map of atherosclerosis in a murine disease model accompanied by high-plex in situ spatial data. Using temporal data and probabilistic fate modeling, we identify key transcription factors that drive cell state changes through a combination of network-based prioritization and in silico transcription factor perturbation. Parallel knockout studies of validated coronary artery disease gene Tcf21 uncover its molecular mechanisms in smooth muscle cell transition, due in part to a role regulating the transition of smooth muscle cells in the secondary heart field. Integrating the murine atlas with human coronary artery disease genetics pinpoint smooth muscle cell phenotypes that mediate disease risk, highlighting causal disease mechanisms. Together, these studies resolve atherosclerosis trajectories at single cell resolution and identify genetic causal transcriptomic and epigenomic mechanisms of coronary artery disease risk. Overall design: We performed single cell RNA sequencing (scRNAseq) and single-nucleus assay of transposase-accessible sequencing (scATACseq) with aortic root tissue from ApoE-/- (ApoE KO) mice to characterize the complex genetic regulatory networks that control the developmental cascade of smooth muscle cell (SMC) phenotypic transitions in the context of atherosclerotic stress