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

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, mul...

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Published inPLoS 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
LanguageEnglish
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
Online AccessGet full text
ISSN1553-7404
1553-7390
1553-7404
DOI10.1371/journal.pgen.1010010

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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.
AbstractList 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. Calcific aortic valve disease is the most common heart valve disorder characterized by a thickening of the aortic valve resulting from fibrotic and calcific processes. Because the aortic valve replacement is currently the only therapeutic option, the identification of key molecular processes that control the progression of the disease could lead to the development of novel noninvasive therapies. Growing evidence suggests that long noncoding RNAs (lncRNAs) fine tune gene expression in health and disease states. By using a multidimensional profiling including genome-wide 3D enhancer-promoter looping data, we identified LINC01013, a lncRNA, as a regulator of fibrogenesis. Specifically, we found that LINC01013 is located in a cluster of distant enhancers (super-enhancer) in aortic valve interstitial cells and has significant long-range looping with the promoter of CCN2, a gene that orchestrates fibrogenesis. We discovered that LINC01013 is acting as a decoy factor for a negative transcription elongation factor, whereby it controls the transcription of CCN2. In turn, higher expression of LINC01013 during calcific aortic valve disease promoted the expression of CCN2 and a fibrogenic program. These findings provide evidence that LINC01013 is a key regulator of fibrogenesis in CAVD.
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.
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.
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.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.
Audience Academic
Author Argaud, Déborah
Chignon, Arnaud
Mkannez, Ghada
Mathieu, Patrick
Bossé, Yohan
Li, Zhonglin
Thériault, Sébastien
Boulanger, Marie-Chloé
Bon-Baret, Valentin
AuthorAffiliation 3 Department of Molecular Medicine, Laval University, Quebec, Canada
1 Laboratory of Cardiovascular Pathobiology, Quebec Heart and Lung Institute/Research Center, Department of Surgery, Laval University, Quebec, Canada
2 Department of Molecular Biology, Medical Biochemistry and Pathology, Laval University, Quebec, Canada
Massachusetts General Hospital, Howard Hughes Medical Institute, UNITED STATES
AuthorAffiliation_xml – name: 2 Department of Molecular Biology, Medical Biochemistry and Pathology, Laval University, Quebec, Canada
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/35041643$$D View this record in MEDLINE/PubMed
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PublicationTitle PLoS genetics
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Snippet Calcific aortic valve disease (CAVD) is characterized by a fibrocalcific process. The regulatory mechanisms that drive the fibrotic response in the aortic...
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StartPage e1010010
SubjectTerms 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
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Title Genome-wide chromatin contacts of super-enhancer-associated lncRNA identify LINC01013 as a regulator of fibrosis in the aortic valve
URI https://www.ncbi.nlm.nih.gov/pubmed/35041643
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https://pubmed.ncbi.nlm.nih.gov/PMC8797204
https://doi.org/10.1371/journal.pgen.1010010
https://doaj.org/article/a52b63d858e342a38c2ef01cec081680
http://dx.doi.org/10.1371/journal.pgen.1010010
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