Enhancer-associated aortic valve stenosis risk locus 1p21.2 alters NFATC2 binding site and promotes fibrogenesis

被引：12

作者：

Chignon, Arnaud ^{[1
]}

Rosa, Mickael ^{[1
]}

Boulanger, Marie-Chloe ^{[1
]}

Argaud, Deborah ^{[1
]}

Devillers, Romain ^{[1
]}

Bon-Baret, Valentin ^{[1
]}

Mkannez, Ghada ^{[1
]}

Li, Zhonglin ^{[1
]}

Rufiange, Anne ^{[1
]}

Gaudreault, Nathalie ^{[1
]}

Gosselin, David ^{[2
]}

Theriault, Sebastien ^{[3
]}

Bosse, Yohan ^{[2
]}

Mathieu, Patrick ^{[1
]}

机构：

[1] Laval Univ, Quebec Heart & Lung Inst, Dept Surg, Lab Cardiovasc Pathobiol,Res Ctr, 2725 Chemin Ste Foy, Quebec City, PQ G1V 4G5, Canada

[2] Laval Univ, Dept Mol Med, Quebec City, PQ, Canada

[3] Laval Univ, Dept Mol Biol Med Biochem & Pathol, Quebec City, PQ, Canada

来源：

ISCIENCE | 2021年 / 24卷 / 03期

基金：

美国国家卫生研究院; 加拿大健康研究院;

关键词：

Cell Biology; Genetics; Genomics;

D O I：

10.1016/j.isci.2021.102241

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 PALMD 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 PALMD. DNA-binding assay showed that the risk variant modified the DNA shape, which prevented the recruitment of NFATC2 and lowered the expression of PALMD. In co-expression network analysis, a module encompassing PALMD 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.

引用

页数：45

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