Epigenetic Remodeling in Human Coronary Artery Smooth Muscle Cell Phenotypic Switching

Background Smooth muscle cell (SMC) dedifferentiation contributes to repair and remodeling, but also cardiovascular pathologies. To understand this plasticity, the epigenetic landscape in SMC phenotypic switching was profiled. Methods Genome-wide analyses of histone modifications (ChIP-seq), chromatin architecture (ATAC-seq), and transcriptomes (RNA-seq) were performed on human coronary artery SMCs (CASMC) treated with rapamycin (contractile phenotype) and PDGF-BB (synthetic phenotype). Results Analyses of differentially acetylated promoter regions identified ZEB and ZBT7A as novel enriched regulatory motifs. There were more changes in the enhancer epigenome than in promoters in CASMC phenotypic switching. Rapamycin-activated enhancers were associated with differentiation and TGF-β signaling pathways and were most enriched in TEAD, SRF and SMAD motifs, whereas PDGF-induced enhancers were associated with ERK signaling and migration pathways, and were most enriched in ETV4, SOX5, and FOS motifs. GATA, TEAD, and SMCA1 motifs were enriched in CASMC enhancer open chromatin compared to other cell types. Candidate enhancers with single nucleotide polymorphisms linked to cardiovascular disease were markedly enriched in active enhancers and super enhancers and showed significant activity in reporter assays. In CASMC promoters and enhancers, common regulatory motifs were often enriched in both the differentiated and dedifferentiated phenotypes, suggesting that differential cofactor binding, as occurs with SRF at CArG elements, may be a more widespread mechanism underlying phenotypic switching. Conclusions These data identify novel regulatory elements engaged in SMC phenotypic switching and provide a comprehensive profile of SMC promoters, enhancers, super enhancers, and chromatin accessibility as a significant resource for studies of CASMC phenotype. What Is New? What Question Should Be Addressed Next? ### Competing Interest Statement The authors have declared no competing interest. * hCASMC : Human coronary artery smooth muscle cells ChIP-seq : Chromatin immunoprecipitation and sequencing TSS : Transcriptional start site TGF-β : Transforming growth factor mTORC1 : Mammalian target of rapamycin complex 1 PDGF : Platelet derived growth factor SNP : Single nucleotide polymorphism