The RNA-binding protein QKI governs a muscle-specific alternative splicing program that shapes the contractile function of cardiomyocytes.
Alternative splicing
Cardiomyocytes
Quaking
RNA-binding proteins
Journal
Cardiovascular research
ISSN: 1755-3245
Titre abrégé: Cardiovasc Res
Pays: England
ID NLM: 0077427
Informations de publication
Date de publication:
22 05 2023
22 05 2023
Historique:
received:
13
05
2022
revised:
08
11
2022
accepted:
15
11
2022
medline:
24
5
2023
pubmed:
11
1
2023
entrez:
10
1
2023
Statut:
ppublish
Résumé
In the heart, splicing factors orchestrate the functional properties of cardiomyocytes by regulating the alternative splicing of multiple genes. Work in embryonic stem cells has shown that the splicing factor Quaking (QKI) regulates alternative splicing during cardiomyocyte differentiation. However, the relevance and function of QKI in adult cardiomyocytes remains unknown. In this study, we aim to identify the in vivo function of QKI in the adult mouse heart. We generated mice with conditional deletion of QKI in cardiomyocytes by the Cre-Lox system. Mice with cardiomyocyte-specific deletion of QKI died during the foetal period (E14.5), without obvious anatomical abnormalities of the heart. Adult mice with tamoxifen-inducible QKI deletion rapidly developed heart failure associated with severe disruption of sarcomeres, already 7 days after knocking out QKI. RNA sequencing revealed that QKI regulates the alternative splicing of more than 1000 genes, including sarcomere and cytoskeletal components, calcium-handling genes, and (post-)transcriptional regulators. Many of these splicing changes corresponded to the loss of muscle-specific isoforms in the heart. Forced overexpression of QKI in cultured neonatal rat ventricular myocytes directed these splicing events in the opposite direction and enhanced contractility of cardiomyocytes. Altogether, our findings show that QKI is an important regulator of the muscle-specific alternative splicing program that builds the contractile apparatus of cardiomyocytes.
Identifiants
pubmed: 36627242
pii: 6982939
doi: 10.1093/cvr/cvad007
pmc: PMC10202634
doi:
Substances chimiques
Protein Isoforms
0
RNA-Binding Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1161-1174Informations de copyright
© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.
Déclaration de conflit d'intérêts
Conflict of interest: Y.M.P. is an inventor on patents, holds minor shares (<5%), and serves as a consultant for biotech and pharmaceutical companies that develop molecules or RNA therapies that target myocardial disease (Forbion Capital, ARMGO BV, Oxitope Pharmaceuticals, Phlox Therapeutics) and received support from Roche Diagnostics. The remaining authors have no conflicts of interest to declare.
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