A transposable element into the human long noncoding RNA CARMEN is a switch for cardiac precursor cell specification.

Autor:	Plaisance I; Experimental Cardiology Unit, Division of Cardiology, University of Lausanne Medical School, Lausanne, Switzerland., Chouvardas P; Department of Medical Oncology, Inselspital, University of Bern, Bern, Switzerland., Sun Y; Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia., Nemir M; Experimental Cardiology Unit, Division of Cardiology, University of Lausanne Medical School, Lausanne, Switzerland., Aghagolzadeh P; Experimental Cardiology Unit, Division of Cardiology, University of Lausanne Medical School, Lausanne, Switzerland., Aminfar F; Experimental Cardiology Unit, Division of Cardiology, University of Lausanne Medical School, Lausanne, Switzerland., Shen S; Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia., Shim WJ; Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia., Rochais F; Aix Marseille University, Marseille Medical Genetics, INSERM, U1251, Marseille, France., Johnson R; Department of Medical Oncology, Inselspital, University of Bern, Bern, Switzerland.; School of Biology and Environmental Science, University College Dublin, Dublin, Ireland., Palpant N; Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia., Pedrazzini T; Experimental Cardiology Unit, Division of Cardiology, University of Lausanne Medical School, Lausanne, Switzerland.
Jazyk:	angličtina
Zdroj:	Cardiovascular research [Cardiovasc Res] 2023 Jun 13; Vol. 119 (6), pp. 1361-1376.
DOI:	10.1093/cvr/cvac191
Abstrakt:	Aims: 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. Methods and Results: 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. Conclusions: 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. Competing Interests: Conflict of interest: T.P. is co-founder of Haya Therapeutics, Epalinges, Switzerland (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)
Databáze:	MEDLINE
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