ADTRP regulates TFPI expression via transcription factor POU1F1 involved in coronary artery disease
ADTRP regulates TFPI expression via transcription factor POU1F1 involved in coronary artery disease
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ADTRP 通过参与冠状动脉疾病的转录因子 POU1F1 调节 TFPI 表达
DOI：
10.1016/j.gene.2020.144805
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发表时间：
2020-08-30
期刊：
影响因子：
3.5
通讯作者：
Xu, Chengqi
中科院分区：
文献类型：
--
作者：
Luo, Chunyan;Pook, Elisabeth;Xu, Chengqi
ADTRP和TFPI基因的基因组变异与冠状动脉疾病（CAD）的风险相关。ADTRP调节TFPI表达和参与动脉粥样硬化性CAD起始的内皮细胞功能。ADTRP还通过上调TFPI表达来指定原始骨髓生成和确定性造血。然而，潜在的分子机制是未知的。我们发现转录因子POU 1F 1是ADTRP调节TFPI表达的关键。荧光素酶报告分析，染色质免疫沉淀（ChIP）和电泳迁移率变动分析（EMSA）与TFPI启动子/调控区的大，小缺失的分析相结合，用于确定ADTRP调节TFPI表达的分子机制。使用病例对照关联分析和全表型关联分析（PhenGWA）评估遗传关联。ADTRP在转录水平以剂量依赖性方式调节TFPI表达。ADTRP反应元件定位于TFPI转录起始位点上游-806 bp和-756 bp之间的50 bp区域，该区域包含POU 1F 1的结合位点。POU 1F 1结合位点的缺失或POU 1F 1表达的敲低消除了ADTRP介导的TFPI转录。ChIP和EMSA证明POU 1F 1与ADTRP反应元件结合。遗传分析发现POU 1F 1变异与CAD风险之间存在显著相关性。PhenGWA鉴定了与ADTRP-POU 1F 1-TFPI轴相关的其他表型性状，如淋巴细胞计数（ADTRP）、腰围（TFPI）和站立高度（POU 1F 1）。这些数据将POU 1F 1鉴定为响应ADTRP调节TFPI转录的转录因子，并首次将POU 1F 1变体与CAD风险联系起来。
Genomic variants in both ADTRP and TFPI genes are associated with risk of coronary artery disease (CAD). ADTRP regulates TFPI expression and endothelial cell functions involved in the initiation of atherosclerotic CAD. ADTRP also specifies primitive myelopoiesis and definitive hematopoiesis by upregulating TFPI expression. However, the underlying molecular mechanism is unknown. Here we show that transcription factor POU1F1 is the key by which ADTRP regulates TFPI expression. Luciferase reporter assays, chromatin-immunoprecipitation (ChIP) and electrophoretic mobility shift assay (EMSA) in combination with analysis of large and small deletions of the TFPI promoter/regulatory region were used to identify the molecular mechanism by which ADTRP regulates TFPI expression. Genetic association was assessed using case-control association analysis and phenomewide association analysis (PhenGWA). ADTRP regulates TFPI expression at the transcription level in a dose-dependent manner. The ADTRP-response element was localized to a 50 bp region between - 806 bp and -756 bp upstream of TFPI transcription start site, which contains a binding site for POU1F1. Deletion of POU1F1-binding site or knockdown of POU1F1 expression abolished ADTRP-mediated transcription of TFPI. ChIP and EMSA demonstrated that POU1F1 binds to the ADTRP response element. Genetic analysis identified significant association between POU1F1 variants and risk of CAD. PhenGWA identified other phenotypic traits associated with the ADTRP-POU1F1-TFPI axis such as lymphocyte count (ADTRP), waist circumference (TFPI), and standing height (POU1F1). These data identify POU1F1 as a transcription factor that regulates TFPI transcription in response to ADTRP, and link POU1F1 variants to risk of CAD for the first time.