Abstract
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.
Highlights
Calcific aortic valve disease (CAVD) is the most frequent heart valve disorder [1]
By using functional assays and genomic multidimensional profiling of valve interstitial cells (VICs) and AVs (S1 Fig), we identified LINC01013, a CAVD-dysregulated long noncoding RNAs (lncRNAs)-SE within a regulatory DNA loop that controls the transcriptional process of gene enriched in the transforming growth factor (TGF) beta pathway and promotes fibrogenesis
By using GREAT, we found that the 1085 SEs were highly enriched in gene ontology (GO) for extracellular matrix organization (GO:0030198) (P = 2.01 x 10−21) (Fig 1A)
Summary
The progression of CAVD culminates in aortic valve (AV) stenosis, which can be treated by aortic valve replacement (AVR) in symptomatic patients. The identification of key underpinning processes that control the development of CAVD could lead to medical therapy to prevent the progression of CAVD. Research conducted over the last several years has underlined several molecular processes involved in the development of CAVD and has highlighted that valve interstitial cells (VICs) have a high plasticity [3]. Studies have consistently shown that the transforming growth factor (TGF) beta pathway was involved in fibrogenesis and the development of CAVD [4]. Key regulators of the TGF beta pathway that orchestrate and instruct a fibrogenic programme in the AV are still largely unknown
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