TY - JOUR
T1 - The RNA-binding protein QKI governs a muscle-specific alternative splicing program that shapes the contractile function of cardiomyocytes
AU - Montañés-Agudo, Pablo
AU - Aufiero, Simona
AU - Schepers, Eva N.
AU - van der Made, Ingeborg
AU - Cócera-Ortega, Lucia
AU - Ernault, Auriane C.
AU - Richard, Stéphane
AU - Kuster, Diederik W. D.
AU - Christoffels, Vincent M.
AU - Pinto, Yigal M.
AU - Creemers, Esther E.
N1 - Funding Information: This work was supported by grants from the Rembrandt Institute for Cardiovascular Sciences (2017) to E.E.C. and from the Netherlands Cardiovascular Research Initiative CVON (CVON-ARENA-PRIME) to Y.M.P. Publisher Copyright: © The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.
PY - 2023/5/1
Y1 - 2023/5/1
N2 - 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.
AB - 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.
KW - Alternative splicing
KW - Cardiomyocytes
KW - Quaking
KW - RNA-binding proteins
UR - http://www.scopus.com/inward/record.url?scp=85152893830&partnerID=8YFLogxK
U2 - https://doi.org/10.1093/cvr/cvad007
DO - https://doi.org/10.1093/cvr/cvad007
M3 - Article
C2 - 36627242
SN - 0008-6363
VL - 119
SP - 1161
EP - 1174
JO - Cardiovascular research
JF - Cardiovascular research
IS - 5
ER -