TCF21 is a causal coronary artery disease gene that modulates coronary smooth muscle phenotypic transition via epigenetic mechanisms

TCF21 是一种致病性冠状动脉疾病基因，可通过表观遗传机制调节冠状动脉平滑肌表型转变

• 批准号: 10874376
• 负责人: DANIEL YUHANG LI
• 金额: $ 6.91万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-02 至 2025-09-01
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10874376
• 关键词: ATAC-seq; Address; Anatomy; Animals; Aorta; Apolipoprotein E; Arterial Fatty Streak; Atherosclerosis; BHLH Protein; Binding; Biological Assay; Blood Vessels; Cardiometabolic Disease; Cardiovascular Pathology; Cell Lineage; Cells; Characteristics; Chromatin; Chromosome Mapping; Clinical; Computational Technique; Coronary; Coronary Arteriosclerosis; Coronary heart disease; Development; Disease; Epigenetic Process; Evaluation; Fibroblasts; Functional disorder; Gene Expression; Genes; Genetic; Genetic Transcription; Genetic study; Genome Mappings; Goals; High Fat Diet; Knock-out; Laboratories; Lesion; Lipids; Maps; Mediating; Mentors; Modeling; Molecular; Mus; Phenotype; Physicians; Proliferating; Regulator Genes; Regulatory Pathway; Research; Research Personnel; Scientist; Smooth Muscle; Smooth Muscle Myocytes; Stress; System; Therapeutic; Time; Tissues; Transgenic Organisms; Transitional Cell; Translating; Variant; Vascular Diseases; Vascular Smooth Muscle; Work; cell dedifferentiation; disorder risk; epigenomics; gene network; gene regulatory network; genome wide association study; genome-wide; genomic locus; in vivo; migration; mouse model; multiple omics; novel; overexpression; phenotypic biomarker; prevent; protective effect; response; risk variant; single cell analysis; single-cell RNA sequencing; therapeutic target; tool; transcription factor; transcriptome sequencing; transcriptomics; vascular stress

PROJECT SUMMARY More than 161 genetic loci have been associated with coronary artery disease (CAD) through the genome wide association studies (GWAS) conducted by the CARDIoGRAMplusC4D consortium. However, despite such advances in the understanding of coronary disease, therapeutic targets beyond lipid lowering therapies have yet to reach the clinical stage. At this critical juncture for discovery, there is a need for better mechanistic characterization of the genetic CAD risk loci at the single cell level to simultaneously study the genetic and epigenetic phenomena underlying disease risk. The Quertermous laboratory has previously identified TCF21 as the CAD associated gene mapped by GWAS at the 6q23.2 locus. A combination of smooth muscle cell (SMC) lineage tracing and single cell RNA sequencing has shown that Tcf21 is upregulated and promotes SMC de-differentiation, proliferation and migration into atherosclerotic plaque. TCF21 expression contributes to the phenotypic transition of SMC to the protective fibrous cap, producing fibroblast-like cells termed “fibromyocytes” (FMC). We are now studying this transitional state at multiple developmental time points with single cell transcriptomics and epigenomics in the ApoE knockout model of atherosclerosis and find wide variation in chromatin accessibility associated with the SMC-FMC transitional cell state. While loss of Tcf21 produces more than a 50% decrease in FMC, there remains a subpopulation of SMC that can contribute to FMC and the fibrous cap. The gene regulatory networks that cooperate with TCF21 to promote SMC transition, and the downstream target genes of these networks remain unknown. The central hypothesis underlying this proposal is that TCF21 exerts a protective effect toward CAD risk through its ability to promote phenotypic transition of SMC in the setting of vascular wall stress. To address this hypothesis, the applicant will study a SMC-specific model of Tcf21 over-expression in the setting of vascular disease and characterize the disease consequences of increased Tcf21 action through cutting-edge transcriptomic and epigenetic tools to simultaneously evaluate single cell gene transcription and chromatin accessibility through combined scRNAseq with scATACseq in vascular tissue. Aim 1 will examine the overall effect of increased Tcf21 expression on SMC phenotype as well as atherosclerotic plaque cellular composition and anatomy in transgenic over-expressing animals. Aim 2 will elucidate the transcriptional and epigenetic mechanisms by which Tcf21 mediates SMC de-differentiation and transition to the FMC phenotype using analysis of single cell multi-omic RNAseq and ATACseq. This study will address fundamental questions related to vascular disease pathophysiology, including: i) does TCF21 over-expression increase the SMC to FMC transition, ii) does increased SMC to FMC transition promote a more stable plaque phenotype, and iii) how does TCF21 regulate the epigenetic and transcriptional landscape to promote SMC transition to a protective FMC phenotype.

项目总结