Chignon Arnaud, Rosa Mickael, Boulanger Marie-Chloé, Argaud Déborah, Devillers Romain, Bon-Baret Valentin, Mkannez Ghada, Li Zhonglin, Rufiange Anne, Gaudreault Nathalie, Gosselin David, Thériault Sébastien, Bossé Yohan, Mathieu Patrick
Laboratory of Cardiovascular Pathobiology, Quebec Heart and Lung Institute/Research Center, Department of Surgery, Laval University, 2725 Chemin Ste-Foy, G1V-4G5, Québec City, QC, Canada.
Department of Molecular Medicine, Laval University, Québec City, QC, Canada.
iScience. 2021 Feb 27;24(3):102241. doi: 10.1016/j.isci.2021.102241. eCollection 2021 Mar 19.
Genome-wide association studies for calcific aortic valve stenosis (CAVS) previously reported strong signal for noncoding variants at 1p21.2. Previous study using Mendelian randomization suggested that the locus controls the expression of encoding Palmdelphin (PALMD). However, the molecular regulation at the locus and the impact of PALMD on the biology of the aortic valve is presently unknown. 3D genetic mapping and CRISPR activation identified rs6702619 as being located in a distant-acting enhancer, which controls the expression of . DNA-binding assay showed that the risk variant modified the DNA shape, which prevented the recruitment of NFATC2 and lowered the expression of . In co-expression network analysis, a module encompassing was enriched in actin-based process. Mass spectrometry and functional assessment showed that PALMD is a regulator of actin polymerization. In turn, lower level of PALMD promoted the activation of myocardin-related transcription factor and fibrosis, a key pathobiological process underpinning CAVS.
先前针对钙化性主动脉瓣狭窄（CAVS）的全基因组关联研究报告称，1p21.2处的非编码变异存在强信号。先前使用孟德尔随机化的研究表明，该基因座控制着编码棕榈酰海豚蛋白（PALMD）的表达。然而，目前尚不清楚该基因座的分子调控以及PALMD对主动脉瓣生物学的影响。三维基因图谱和CRISPR激活确定rs6702619位于一个远距离作用增强子中，该增强子控制着[此处原文缺失相关基因名称]的表达。DNA结合试验表明，风险变异改变了DNA形状，阻止了NFATC2的募集并降低了[此处原文缺失相关基因名称]的表达。在共表达网络分析中，一个包含[此处原文缺失相关基因名称]的模块在基于肌动蛋白的过程中富集。质谱分析和功能评估表明，PALMD是肌动蛋白聚合的调节因子。反过来，较低水平的PALMD促进了心肌相关转录因子的激活和纤维化，这是CAVS的一个关键病理生物学过程。
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