Vascular smooth muscle cell state trajectories mediate molecular mechanisms of coronary disease risk
Year: 2026
Type: article
Abstract: Vascular smooth muscle cells (SMC) contribute to heritable coronary artery disease (CAD) risk and undergo complex cell state transitions to multiple disease related phenotypes. To investigate the genetic basis of SMC state trajectories that underlie the SMC component of CAD causality we have developed a dense timecourse single cell transcriptomic and epigenetic map of atherosclerosis in a murine disease animal model. Cellular trajectories were derived from the temporal data and probabilistic fate modeling with Waddington-Optimal Transport (WOT). We created transcription factor (TF) centered regulons mapped across the developmental timeline and through network-based prioritization with WOT predicted TFs and in silico TF perturbation, identified key drivers of cell state changes associated with EMT, vascular development, and circadian clock functions. Integration of mouse disease data with human CAD genetic findings identified transition SMC phenotypes that mediate disease risk and point to causal disease mechanisms. Parallel studies using knockout of the validated CAD gene Tcf21 revealed its impact on SMC transition cellular phenotypes and disease risk genes, due in part to a role regulating the transition of SMC precursor cells in the secondary heart field. Together, these studies characterize atherosclerosis trajectories at single cell resolution and identify genetic causal transcriptomic and epigenomic mechanisms of CAD risk.
Source: Nature Communications
Authors: Daniel Y. Li, Soumya Kundu, Paul Cheng, Wenduo Gu, Matthew D. Worssam, William R. Jackson, Quanyi Zhao, Trieu Nguyen, Amelia M. Yu, João P. Monteiro, Roxanne D. Caceres, Stanley Dale, Brian T. Palmisano, Chad S. Weldy, Markus Ramste, Ramendra Kundu, Anshul Kundaje, Robert C. Wirka, Thomas Quertermous
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Awards: The Epigenetic Regulator Prdm16 Controls Smooth Muscle Phenotypic Modulation and Atherosclerosis Risk, TCF21 is a causal coronary artery disease gene that modulates coronary smooth muscle phenotypic transition via epigenetic mechanisms, The role of TWIST1 in smooth muscle cells during atherosclerosis, G7691977247, The role of Twist1 in SMC phenotypic modulation during atherosclerosis, Predicting context-specific molecular and phenotypic effects of genetic variation through the lens of the cis-regulatory code, ADAR mediated RNA editing is a causal mechanism in coronary artery disease, Causal variant association mechanisms in TCF21 binding coronary disease loci, Adventitial Fibroblast Phenotypic Modulation in Atherosclerosis, Identifying causal gene programs for vascular disease using high throughput CRISPR genomics, Gene Regulatory Mechanisms of the Coronary Artery Disease Gene PRDM16 on Smooth Muscle Cell Phenotypic Modulation, The SMAD3 signaling network in coronary artery disease risk, Gene regulatory networks controlling smooth muscle phenotype and vasculardisease risk, Smad3-mediated gene-environment interaction and risk of tobacco-induced aneurysms, ZEB1 Mediated Coronary Artery Disease Risk in Vascular Smooth Muscle, Stanford Center for Connecting DNA Variants to Function and Phenotype
OpenAlex ID: W7138171303