The RNA-binding Protein QKI Governs a Muscle-specific Alternative Splicing Program That Shapes the Contractile Function of Cardiomyocytes

Overview

Journal Cardiovasc Res

Specialty Cardiology & Vascular Diseases

Date 2023 Jan 10

PMID 36627242

Authors

Pablo Montanes-Agudo

Simona Aufiero

Eva N Schepers

Ingeborg van der Made

Lucia Cocera-Ortega

Auriane C Ernault

Stephane Richard

Diederik W D Kuster

Vincent M Christoffels

Yigal M Pinto

Esther E Creemers

Affiliations

Soon will be listed here.

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 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.

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