Genome-wide chromatin contacts of super-enhancer-associated lncRNA identify LINC01013 as a regulator of fibrosis in the aortic valve

• Published in: PLoS genetics Vol. 18; no. 1; p. e1010010
• Main Authors: Chignon, Arnaud, Argaud, Déborah, Boulanger, Marie-Chloé, Mkannez, Ghada, Bon-Baret, Valentin, Li, Zhonglin, Thériault, Sébastien, Bossé, Yohan, Mathieu, Patrick
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 18.01.2022; Public Library of Science (PLoS)
• Subjects: Aged; Algorithms; Aorta; Aortic valve; Aortic Valve - metabolism; Aortic Valve - pathology; Aortic Valve Stenosis - genetics; Aortic Valve Stenosis - metabolism; Biology and Life Sciences; Calcinosis - genetics; Calcinosis - metabolism; Cell fate; Chromatin; Chromatin - metabolism; Chromatin Immunoprecipitation Sequencing; Chromosomes; Connective tissue growth factor; Connective Tissue Growth Factor - genetics; Enhancer Elements, Genetic; Enhancers; Extracellular matrix; Female; Fibrosis; Gene expression; Genome-wide association studies; Genomes; Humans; Immunoprecipitation; Male; Medicine and Health Sciences; Middle Aged; Non-coding RNA; Ontology; Physiological aspects; Promoter Regions, Genetic; Proteins; RNA, Long Noncoding - genetics; Signal Transduction; Transcription Factors - genetics; Transforming Growth Factor beta1 - metabolism; Transforming growth factor-b1; Transposase; Up-Regulation; Canada
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1010010

Calcific aortic valve disease (CAVD) is characterized by a fibrocalcific process. The regulatory mechanisms that drive the fibrotic response in the aortic valve (AV) are poorly understood. Long noncoding RNAs derived from super-enhancers (lncRNA-SE) control gene expression and cell fate. Herein, multidimensional profiling including chromatin immunoprecipitation and sequencing, transposase-accessible chromatin sequencing, genome-wide 3D chromatin contacts of enhancer-promoter identified LINC01013 as an overexpressed lncRNA-SE during CAVD. LINC01013 is within a loop anchor, which has contact with the promoter of CCN2 (CTGF) located at ~180 kb upstream. Investigation showed that LINC01013 acts as a decoy factor for the negative transcription elongation factor E (NELF-E), whereby it controls the expression of CCN2 . LINC01013-CCN2 is part of a transforming growth factor beta 1 (TGFB1) network and exerts a control over fibrogenesis. These findings illustrate a novel mechanism whereby a dysregulated lncRNA-SE controls, through a looping process, the expression of CCN2 and fibrogenesis of the AV.