ADTRP regulates TFPI expression via transcription factor POU1F1 involved in coronary artery disease

•CAD susceptibility gene ADTRP significantly increases transcription activation of TFPI via transcription factor POU1F1.•POU1F1 interacts with the ADTRP-response element at the TFPI promoter/regulatory region.•The ADTRP-response element is required for dose-dependent transcription activation of TFPI...

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Published in:Gene 2020-08, Vol.753, p.144805-144805, Article 144805
Main Authors: Luo, Chunyan, Pook, Elisabeth, Wang, Fan, Archacki, Stephen R., Tang, Bo, Zhang, Weiyi, Hu, Jing-Shan, Yang, Jian, Leineweber, Kirsten, Bechem, Martin, Huang, Weifeng, Song, Yinhong, Cheung, Shing-Hu, Laux, Volker, Ke, Tie, Ren, Xiang, Tu, Xin, Chen, Qiuyun, Wang, Qing Kenneth, Xu, Chengqi
Format: Article
Language:English
Subjects:
ADTRP
Association
Coronary artery disease (CAD)
PhenGWA
POU1F1
TFPI
Transcription activation
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Summary:•CAD susceptibility gene ADTRP significantly increases transcription activation of TFPI via transcription factor POU1F1.•POU1F1 interacts with the ADTRP-response element at the TFPI promoter/regulatory region.•The ADTRP-response element is required for dose-dependent transcription activation of TFPI.•Genomic variants of POU1F1are significantly associated with risk of CAD.•PhenGWA identifies other phenotypic traits associated with the ADTRP-POU1F1-TFPI signaling hub. 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 phenome-wide 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.
ISSN:0378-1119
1879-0038
DOI:10.1016/j.gene.2020.144805