A transposable element into the human long noncoding RNA CARMEN is a switch for cardiac precursor cell specification.
Détails
Etat: Public
Version: Final published version
Licence: CC BY-NC 4.0
ID Serval
serval:BIB_72947E9E4C85
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
A transposable element into the human long noncoding RNA CARMEN is a switch for cardiac precursor cell specification.
Périodique
Cardiovascular research
ISSN
1755-3245 (Electronic)
ISSN-L
0008-6363
Statut éditorial
Publié
Date de publication
13/06/2023
Peer-reviewed
Oui
Volume
119
Numéro
6
Pages
1361-1376
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Publication Status: ppublish
Résumé
The major cardiac cell types composing the adult heart arise from common multipotent precursor cells. Cardiac lineage decisions are guided by extrinsic and cell-autonomous factors, including recently discovered long noncoding RNAs (lncRNAs). The human lncRNA CARMEN, which is known to dictate specification toward the cardiomyocyte (CM) and the smooth muscle cell (SMC) fates, generates a diversity of alternatively spliced isoforms.
The CARMEN locus can be manipulated to direct human primary cardiac precursor cells (CPCs) into specific cardiovascular fates. Investigating CARMEN isoform usage in differentiating CPCs represents therefore a unique opportunity to uncover isoform-specific functions in lncRNAs. Here, we identify one CARMEN isoform, CARMEN-201, to be crucial for SMC commitment. CARMEN-201 activity is encoded within an alternatively spliced exon containing a MIRc short interspersed nuclear element. This element binds the transcriptional repressor REST (RE1 Silencing Transcription Factor), targets it to cardiogenic loci, including ISL1, IRX1, IRX5, and SFRP1, and thereby blocks the CM gene program. In turn, genes regulating SMC differentiation are induced.
These data show how a critical physiological switch is wired by alternative splicing and functional transposable elements in a long noncoding RNA. They further demonstrated the crucial importance of the lncRNA isoform CARMEN-201 in SMC specification during heart development.
The CARMEN locus can be manipulated to direct human primary cardiac precursor cells (CPCs) into specific cardiovascular fates. Investigating CARMEN isoform usage in differentiating CPCs represents therefore a unique opportunity to uncover isoform-specific functions in lncRNAs. Here, we identify one CARMEN isoform, CARMEN-201, to be crucial for SMC commitment. CARMEN-201 activity is encoded within an alternatively spliced exon containing a MIRc short interspersed nuclear element. This element binds the transcriptional repressor REST (RE1 Silencing Transcription Factor), targets it to cardiogenic loci, including ISL1, IRX1, IRX5, and SFRP1, and thereby blocks the CM gene program. In turn, genes regulating SMC differentiation are induced.
These data show how a critical physiological switch is wired by alternative splicing and functional transposable elements in a long noncoding RNA. They further demonstrated the crucial importance of the lncRNA isoform CARMEN-201 in SMC specification during heart development.
Mots-clé
Humans, RNA, Long Noncoding/genetics, DNA Transposable Elements, Heart, Cell Differentiation/genetics, Protein Isoforms/genetics, Protein Isoforms/metabolism, Cardiac precursor cells, Long noncoding RNAs, Smooth muscle cells, Splicing, Transposable elements
Pubmed
Web of science
Création de la notice
27/12/2022 10:54
Dernière modification de la notice
25/01/2024 8:38