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Abstract
The RNA-binding protein QKI belongs to the hnRNP K-homology domain protein family, a well-known regulator of pre-mRNA alternative splicing and is associated with several neurodevelopmental disorders. Qki is found highly expressed in developing and adult hearts. By employing the human embryonic stem cell (hESC) to cardiomyocyte differentiation system and generating QKI-deficient hESCs (hESCs-QKIdel) using CRISPR/Cas9 gene editing technology, we analyze the physiological role of QKI in cardiomyocyte differentiation, maturation, and contractile function. hESCs-QKIdel largely maintain normal pluripotency and normal differentiation potential for the generation of early cardiogenic progenitors, but they fail to transition into functional cardiomyocytes. In this work, by using a series of transcriptomic, cell and biochemical analyses, and the Qki-deficient mouse model, we demonstrate that QKI is indispensable to cardiac sarcomerogenesis and cardiac function through its regulation of alternative splicing in genes involved in Z-disc formation and contractile physiology, suggesting that QKI is associated with the pathogenesis of certain forms of cardiomyopathies.
RNA binding protein Quaking (QKI) is known for its broad function in pre-mRNA splicing and modification and its association with several neurodevelopmental disorders. Here the authors reveal that QKI-mediated regulation of RNA splicing is indispensable to cardiac development and contractile physiology.
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1 Fudan University, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Shanghai, China (GRID:grid.8547.e) (ISNI:0000 0001 0125 2443); Children’s Hospital of Fudan University, Shanghai Key Laboratory of Birth Defects, Shanghai, China (GRID:grid.411333.7) (ISNI:0000 0004 0407 2968); Indiana University School of Medicine, Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indianapolis, USA (GRID:grid.257413.6) (ISNI:0000 0001 2287 3919)
2 Indiana University School of Medicine, Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indianapolis, USA (GRID:grid.257413.6) (ISNI:0000 0001 2287 3919)
3 Fudan University, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Shanghai, China (GRID:grid.8547.e) (ISNI:0000 0001 0125 2443); Indiana University School of Medicine, Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indianapolis, USA (GRID:grid.257413.6) (ISNI:0000 0001 2287 3919)
4 Fudan University, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Shanghai, China (GRID:grid.8547.e) (ISNI:0000 0001 0125 2443)
5 Indiana University School of Medicine, Department of Bioinformatics, Indianapolis, USA (GRID:grid.257413.6) (ISNI:0000 0001 2287 3919)
6 Army Medical University, Institute of Materia Medica and Center of Translational Medicine, College of Pharmacy, Chongqing, China (GRID:grid.257413.6)
7 Children’s Hospital of Fudan University, Shanghai Key Laboratory of Birth Defects, Shanghai, China (GRID:grid.411333.7) (ISNI:0000 0004 0407 2968); Indiana University School of Medicine, Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indianapolis, USA (GRID:grid.257413.6) (ISNI:0000 0001 2287 3919)
8 Tsinghua University, Center for Stem Cell Biology and Regenerative Medicine, School of Medicine, Beijing, China (GRID:grid.12527.33) (ISNI:0000 0001 0662 3178)
9 Kumanoto University, Institute of Resource Development and Analysis, Kumanoto, Japan (GRID:grid.12527.33)
10 Children’s Hospital of Fudan University, Shanghai Key Laboratory of Birth Defects, Shanghai, China (GRID:grid.411333.7) (ISNI:0000 0004 0407 2968)
11 Fudan University, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Shanghai, China (GRID:grid.8547.e) (ISNI:0000 0001 0125 2443); Children’s Hospital of Fudan University, Shanghai Key Laboratory of Birth Defects, Shanghai, China (GRID:grid.411333.7) (ISNI:0000 0004 0407 2968)