The SMAD3 signaling network in coronary artery disease risk

SMAD3 信号网络在冠状动脉疾病风险中的作用

• 批准号: 10077579
• 负责人: THOMAS QUERTERMOUS
• 金额: $ 57.6万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-15 至 2022-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10077579
• 关键词: 15q22; 1p36; Address; Affect; Alleles; Anatomy; Apolipoprotein E; Atherosclerosis; Binding; Bioinformatics; Blood Vessels; Cardiovascular Diseases; Cell Lineage; Cell Proliferation; Cell physiology; Cells; Cellular biology; ChIP-seq; Coronary; Coronary Arteriosclerosis; Coronary artery; Data; Data Set; Development; Disease; Enhancers; Etiology; Gene Expression; Gene Expression Profiling; Gene Family; Genes; Genetic; Genetic Models; Genetic Risk; Genetic Transcription; Genomic approach; Haplotypes; Human; Human Genome; In Vitro; Introns; Laboratories; Learning; Lesion; Link; MADH3 gene; Medial; Mediating; Modeling; Molecular; Mus; Pathway interactions; Pattern; Phenotype; Phosphotransferases; Process; Quantitative Trait Loci; Reporter; Research; Risk; Risk Assessment; Role; Rupture; SKI gene; Scientist; Signal Pathway; Signal Transduction; Signaling Molecule; Smooth Muscle Myocytes; Stimulus; Structure; Syndrome; Therapeutic; Tissues; Transforming Growth Factor beta; Transgenic Organisms; Variant; Vascular Diseases; Work; causal variant; cell dedifferentiation; cell type; disorder risk; epigenome; experimental study; genetic approach; genome editing; genome wide association study; genomic locus; histone modification; in vivo; innovation; interest; macrophage; molecular phenotype; mouse genetics; mouse model; programs; protective allele; public health relevance; receptor; response; single-cell RNA sequencing; therapeutic development; transcription factor; transcriptome; transcriptome sequencing; vascular stress

PROJECT SUMMARY/ABSTRACT The TGFβ signaling pathway has been extensively studied in vascular disease, but there remains considerable controversy regarding the direction and mechanism of effect for how this pathway impacts human coronary artery disease (CAD). Recent genome-wide association studies have identified several loci that harbor TGFβ family genes, including the SMAD3 gene at 15q22.33 that encodes a transcription factor critical for converting TGFβ-induced cytoplasmic signaling to gene expression changes, and ZEB2 and SKI at 2q22.3 and 1p36.33 respectively, which bind SMAD3 and modulate its transcriptional activity. Studies in this lab have employed histone modification, chromosomal accessibility, allele-specific expression, in vitro genome editing and transgenic reporter mouse studies to identify SMAD3 as the causal gene at 15q22.33. The protective allele for this gene disrupts a potent intronic enhancer in the SMAD3 gene that is associated with decreased SMAD3 expression in vascular tissues, suggesting that expression of SMAD3 in SMC promotes risk for CAD. In SMC, TGFβ signaling is known to have important differentiative and anti-proliferative roles during vascular development, but this function may be deleterious in the disease setting where SMC dedifferentiation and proliferation, “phenotypic modulation,” allows this cell type to bolster structural integrity and retard plaque rupture. A disease-promoting role for TGFβ is supported by our studies with TCF21, a CAD associated transcription factor that promotes SMC phenotypic modulation and whose protective allele confers increased expression. Taken together, these data suggest our Central Hypothesis: the TGFβ signaling molecule SMAD3, in conjunction with ZEB2 and SKI, regulates a transcriptional network that mediates the adaptive SMC phenotypic response to vascular stress, with allelic variation modulating this response contributing to CAD risk. Experiments proposed in Aim 1 in the ApoE-/- atherosclerosis mouse model will evaluate disease anatomy with SMC-specific deletion of Smad3, along with human risk and protective haplotypes created by genome editing. Lineage tracing and single cell RNA-seq will define the role of Smad3 in regulating the cellular response to disease stimuli, and molecular phenotype as lesion SMC dedifferentiate and contribute to the macrophage lineage. In Aim 2, ChIP-seq and RNA-seq studies in human coronary artery SMC will define the network of genes that are regulated by SMAD3 and investigate how expression of ZEB2 and SKI modulates the molecular composition of this network. In vitro studies in human coronary artery SMC in Aim 3 will identify the cellular and molecular processes that are mediated by SMAD3 and how these functions are modified by ZEB2 and SKI. Taken together, these studies will significantly advance our understanding of how SMAD3 and related factors ZEB2 and SKI govern the SMC phenotypic response to vascular disease, and how perturbation of their function contributes to CAD risk.

项目摘要/摘要 TGFββ信号传导途径已在血管疾病中进行了广泛的研究，但仍存在 关于该途径的效果方向和机理的争议很大 人类冠状动脉疾病（CAD）。 藏有TGFβ家族基因的基因座，在编码转录的15q22.33处包含SMAD3基因 将TGFβ诱导的细胞质信号转化为基因表达变化的关键因素，而Zeb2 分别在2q22.3和1p36.33处滑雪，它们结合Smad3和模块转录活性。 该实验室组蛋白修饰，染色体可及性，等位基因特异性的研究 表达，体外基因组编辑和转基因报告基因小鼠小鼠研究，以识别Smad3为因果关系 该基因基因的保护等位基因在15q22.33 与血管组织中Smad3表达降低相关的基因，表明表达 SMC中的SMAD3促进了SMC的CAD风险。 血管发育中的分化和抗散性作用，但此功能可能是有害的 在疾病的环境中，SMC脱脂和增殖“表型调节”允许这一点 细胞类型至增强结构完整性和延迟斑块ruptore。 在我们对TCF21的研究的支持下，TCF21是CAD相关的转录因子，该因子是SMC表型 调制且其保护性等位基因赋予了增加的表达 我们的中心假设：TGFββ信号传导分子SMAD3与Zeb2和Ski结合使用， 调节转录网络，该网络介导适应性SMC表型反应 血管应激，等位基因变异调节这种反应有助于CAD风险。 APOE - / - 动脉粥样硬化小鼠模型中AIM 1中支撑的经验将评估Anatome SMAD3的SMC特异性删除以及基因组创建的人类风险和保护性单倍型 编辑。 对疾病刺激的反应和分子表型，因为病变SMC分化并有助于 巨噬细胞谱系。 由SMAD3定制并研究Zeb2和Ski的表达方式的基因网络 调节该网络的分子组成。 3将确定由SMAD3介导的细胞和分子过程以及如何功能 由Zeb2和滑雪板修改。 SMAD3和相关因素Zeb2和滑雪统治SMC表型对Vascalar的反应 疾病，以及其功能的扰动如何导致CAD风险。

项目成果

Advances in Transcriptomics: Investigating Cardiovascular Disease at Unprecedented Resolution.

• DOI: 10.1161/circresaha.117.310910
• 发表时间: 2018-04-27
• 期刊: Circulation research
• 影响因子: 20.1
• 作者: Wirka RC;Pjanic M;Quertermous T
• 通讯作者: Quertermous T

Single-nucleus chromatin accessibility profiling highlights regulatory mechanisms of coronary artery disease risk.

• DOI: 10.1038/s41588-022-01069-0
• 发表时间: 2022-06
• 期刊: Nature genetics
• 影响因子: 30.8
• 作者: Turner AW;Hu SS;Mosquera JV;Ma WF;Hodonsky CJ;Wong D;Auguste G;Song Y;Sol-Church K;Farber E;Kundu S;Kundaje A;Lopez NG;Ma L;Ghosh SKB;Onengut-Gumuscu S;Ashley EA;Quertermous T;Finn AV;Leeper NJ;Kovacic JC;Björkegren JLM;Zang C;Miller CL
• 通讯作者: Miller CL

Coronary artery disease genes SMAD3 and TCF21 promote opposing interactive genetic programs that regulate smooth muscle cell differentiation and disease risk.

• DOI: 10.1371/journal.pgen.1007681
• 发表时间: 2018-10
• 期刊: PLoS genetics
• 影响因子: 4.5
• 作者: Iyer D;Zhao Q;Wirka R;Naravane A;Nguyen T;Liu B;Nagao M;Cheng P;Miller CL;Kim JB;Pjanic M;Quertermous T
• 通讯作者: Quertermous T