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

Arnaud Chignon; Mickael Rosa; Marie-Chloé Boulanger; Déborah Argaud; Romain Devillers; Valentin Bon-Baret; Ghada Mkannez; Zhonglin Li; Anne Rufiange; Nathalie Gaudreault; David Gosselin; Sébastien Thériault; Yohan Bossé; Patrick Mathieu

doi:10.1016/j.isci.2021.102241

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

iScience. 2021 Feb 27;24(3):102241. doi: 10.1016/j.isci.2021.102241. eCollection 2021 Mar 19.

Affiliations

¹ 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.
² Department of Molecular Medicine, Laval University, Québec City, QC, Canada.
³ Department of Molecular Biology, Medical Biochemistry and Pathology, Laval University, Québec City, QC, Canada.

Abstract

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.

Keywords: Cell Biology; Genetics; Genomics.