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

Xinyun Chen, Ying Liu, Chen Xu, Lina Ba, Zhuo Liu, Xiuya Li, Jie Huang, Ed Simpson, Hongyu Gao, Dayan Cao, Wei Sheng, Hanping Qi, Hongrui Ji, Maria Sanderson, Chen-Leng Cai, Xiaohui Li, Lei Yang, Jie Na, Kenichi Yamamura, Yunlong Liu, Guoying Huang (), Weinian Shou () and Ning Sun ()
Additional contact information
Xinyun Chen: Fudan University
Ying Liu: Indiana University School of Medicine
Chen Xu: Fudan University
Lina Ba: Indiana University School of Medicine
Zhuo Liu: Indiana University School of Medicine
Xiuya Li: Fudan University
Jie Huang: Fudan University
Ed Simpson: Indiana University School of Medicine
Hongyu Gao: Indiana University School of Medicine
Dayan Cao: Army Medical University
Wei Sheng: Children’s Hospital of Fudan University
Hanping Qi: Indiana University School of Medicine
Hongrui Ji: Indiana University School of Medicine
Maria Sanderson: Indiana University School of Medicine
Chen-Leng Cai: Indiana University School of Medicine
Xiaohui Li: Army Medical University
Lei Yang: Indiana University School of Medicine
Jie Na: Tsinghua University
Kenichi Yamamura: Kumanoto University
Yunlong Liu: Indiana University School of Medicine
Guoying Huang: Children’s Hospital of Fudan University
Weinian Shou: Indiana University School of Medicine
Ning Sun: Fudan University

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-020-20327-5

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