QKI is a critical pre-mRNA alternative splicing regulator of cardiac myofibrillogenesis and contractile function

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...

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Veröffentlicht in:Nature communications 2021-01, Vol.12 (1), p.89-89, Article 89
Hauptverfasser: Chen, Xinyun, Liu, Ying, Xu, Chen, Ba, Lina, Liu, Zhuo, Li, Xiuya, Huang, Jie, Simpson, Ed, Gao, Hongyu, Cao, Dayan, Sheng, Wei, Qi, Hanping, Ji, Hongrui, Sanderson, Maria, Cai, Chen-Leng, Li, Xiaohui, Yang, Lei, Na, Jie, Yamamura, Kenichi, Liu, Yunlong, Huang, Guoying, Shou, Weinian, Sun, Ning
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Sprache:eng
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Zusammenfassung: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- QKI del ) using CRISPR/Cas9 gene editing technology, we analyze the physiological role of QKI in cardiomyocyte differentiation, maturation, and contractile function. hESCs- QKI del 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.
ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-020-20327-5