TCF21 and the environmental sensor aryl-hydrocarbon receptor cooperate to activate a pro-inflammatory gene expression program in coronary artery smooth muscle cells.
TCF21 and the environmental sensor aryl-hydrocarbon receptor cooperate to activate a pro-inflammatory gene expression program in coronary artery smooth muscle cells.
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DOI：
10.1371/journal.pgen.1006750
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发表时间：
2017-05
期刊：
影响因子：
4.5
通讯作者：
Quertermous T
中科院分区：
文献类型：
--
作者：
Kim JB;Pjanic M;Nguyen T;Miller CL;Iyer D;Liu B;Wang T;Sazonova O;Carcamo-Orive I;Matic LP;Maegdefessel L;Hedin U;Quertermous T
环境因素和遗传位点都与冠状动脉疾病（CAD）有关，然而基因-基因和基因-环境相互作用可能识别风险的分子机制，但不容易通过人类遗传方法进行研究。我们之前已经确定转录因子TCF21是6q23.2的CAD致病基因，并表征了其下游转录网络，该网络富含CAD GWAS基因。在这里，我们研究了TCF21与下游靶基因芳烃受体（AHR）相互作用的假设，AHR是一种配体激活的转录因子，介导细胞对环境污染物的反应，包括二恶英和多环芳烃（如烟草烟雾）。对人冠状动脉平滑肌细胞（HCASMC）中TCF21表达的扰动表明，TCF21促进AHR及其异源二聚化伙伴ARNT的表达，并与这些因子协同上调多种炎症下游疾病相关基因，包括IL1A、MMP1和CYP1A1。TCF21结合AHR、ARNT和下游靶基因位点，AHR-ARNT和TCF21结合位点在HCASMC开放染色质区域全基因组共定位。这些共定位区域富含与心脏代谢和慢性炎症疾病表型相关的GWAS信号。最后，研究人员发现，与TCF21类似，AHR基因在小鼠体内动脉粥样硬化病变中表达增加，并且AHR蛋白定位于人颈动脉粥样硬化病变中，与蛋白激酶相关，在先天免疫反应中起关键作用。这些数据表明，TCF21可以与AHR合作，激活炎症基因表达程序，该程序在环境刺激下加剧，并可能增加CAD的总体风险。冠心病是世界上导致死亡的主要原因。基因和环境都是疾病进展的重要危险因素，然而，基因如何调节对疾病促进环境的有害反应是未知的，也很难研究。在这里，我们发现基因TCF21的常见遗传变异可能通过调节下游基因激活对疾病环境的反应来调节冠心病的风险。我们发现一种众所周知的环境传感器——芳基烃受体（AHR）受TCF21调控，并与TCF21相互作用，从而调控冠状动脉平滑肌细胞中促炎基因的表达。我们进一步表明，众所周知的斑块动脉粥样硬化驱动因素氧化LDL可以激活AHR途径。这项工作描述了通过冠状动脉疾病的全基因组关联研究确定的基因-环境相互作用的可遗传形式，并提供了定义因果基因-基因和基因-环境相互作用的机会。
Both environmental factors and genetic loci have been associated with coronary artery disease (CAD), however gene-gene and gene-environment interactions that might identify molecular mechanisms of risk are not easily studied by human genetic approaches. We have previously identified the transcription factor TCF21 as the causal CAD gene at 6q23.2 and characterized its downstream transcriptional network that is enriched for CAD GWAS genes. Here we investigate the hypothesis that TCF21 interacts with a downstream target gene, the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor that mediates the cellular response to environmental contaminants, including dioxin and polycyclic aromatic hydrocarbons (e.g., tobacco smoke). Perturbation of TCF21 expression in human coronary artery smooth muscle cells (HCASMC) revealed that TCF21 promotes expression of AHR, its heterodimerization partner ARNT, and cooperates with these factors to upregulate a number of inflammatory downstream disease related genes including IL1A, MMP1, and CYP1A1. TCF21 was shown to bind in AHR, ARNT and downstream target gene loci, and co-localization was noted for AHR-ARNT and TCF21 binding sites genome-wide in regions of HCASMC open chromatin. These regions of co-localization were found to be enriched for GWAS signals associated with cardio-metabolic as well as chronic inflammatory disease phenotypes. Finally, we show that similar to TCF21, AHR gene expression is increased in atherosclerotic lesions in mice in vivo using laser capture microdissection, and AHR protein is localized in human carotid atherosclerotic lesions where it is associated with protein kinases with a critical role in innate immune response. These data suggest that TCF21 can cooperate with AHR to activate an inflammatory gene expression program that is exacerbated by environmental stimuli, and may contribute to the overall risk for CAD. Coronary heart disease is the leading cause of death in the world. Both genes and the environment are important risk factors for the progression of disease, however, how genes may modulate the harmful response to the disease promoting environment is unknown and difficult to study. Here, we show that a common heritable variation in the gene TCF21 may regulate coronary heart disease risk by regulating the response of downstream gene activation by the disease environment. We find that a well-known environmental sensor, aryl-hydrocarbon receptor (AHR), is regulated by TCF21 and also interacts with TCF21, resulting in regulation of pro-inflammatory gene expression in coronary artery smooth muscle cells. We further show that oxidized LDL, a well-known driver of atherosclerosis in the plaque can activate the AHR pathway. This work describes a heritable form of gene-environment interaction identified through genome wide association studies in coronary artery disease, and presents an opportunity to define causal gene-gene and gene-environment interactions.