The RNA-binding protein QKI governs a muscle-specific alternative splicing program that shapes the contractile function of cardiomyocytes.

Autor:	Montañés-Agudo P; Department of Experimental Cardiology, Amsterdam UMC, University of Amsterdam, Meibergdreef 15, 1105AZ Amsterdam, The Netherlands., Aufiero S; Department of Experimental Cardiology, Amsterdam UMC, University of Amsterdam, Meibergdreef 15, 1105AZ Amsterdam, The Netherlands.; Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands., Schepers EN; Department of Experimental Cardiology, Amsterdam UMC, University of Amsterdam, Meibergdreef 15, 1105AZ Amsterdam, The Netherlands., van der Made I; Department of Experimental Cardiology, Amsterdam UMC, University of Amsterdam, Meibergdreef 15, 1105AZ Amsterdam, The Netherlands., Cócera-Ortega L; Department of Experimental Cardiology, Amsterdam UMC, University of Amsterdam, Meibergdreef 15, 1105AZ Amsterdam, The Netherlands., Ernault AC; Department of Experimental Cardiology, Amsterdam UMC, University of Amsterdam, Meibergdreef 15, 1105AZ Amsterdam, The Netherlands., Richard S; Segal Cancer Center, Lady Davis Institute for Medical Research and Gerald Bronfman Department of Oncology and Departments of Biochemistry, Human Genetics and Medicine, McGill University, Montréal, QC, Canada H3T 1E2., Kuster DWD; Department of Medical Physiology, Amsterdam UMC, Vrije Universiteit Amsterdam, De Boelelaan 1117, Amsterdam, Netherlands., Christoffels VM; Department of Medical Biology, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands., Pinto YM; Department of Experimental Cardiology, Amsterdam UMC, University of Amsterdam, Meibergdreef 15, 1105AZ Amsterdam, The Netherlands., Creemers EE; Department of Experimental Cardiology, Amsterdam UMC, University of Amsterdam, Meibergdreef 15, 1105AZ Amsterdam, The Netherlands.
Jazyk:	angličtina
Zdroj:	Cardiovascular research [Cardiovasc Res] 2023 May 22; Vol. 119 (5), pp. 1161-1174.
DOI:	10.1093/cvr/cvad007
Abstrakt:	Aims: 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. Methods and Results: 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. Conclusion: Altogether, our findings show that QKI is an important regulator of the muscle-specific alternative splicing program that builds the contractile apparatus of cardiomyocytes. Competing Interests: 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. (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)
Databáze:	MEDLINE
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