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

Pablo Montañés-Agudo, Simona Aufiero, Eva N. Schepers, Ingeborg van der Made, Lucia Cócera-Ortega, Auriane C. Ernault, Stéphane Richard, Diederik W. D. Kuster, Vincent M. Christoffels, Yigal M. Pinto, Esther E. Creemers

Research output: Contribution to journalArticleAcademicpeer-review

10 Citations (Scopus)

Abstract

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 We generated mice with conditional deletion of QKI in cardiomyocytes by the Cre-Lox system. Mice with cardiomyocyte-specific and results 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.

Original languageEnglish
Pages (from-to)1161-1174
Number of pages14
JournalCardiovascular research
Volume119
Issue number5
DOIs
Publication statusPublished - 1 May 2023

Keywords

  • Alternative splicing
  • Cardiomyocytes
  • Quaking
  • RNA-binding proteins

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