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

Nat Commun. 2021 Jan 04;12(1):89

Xinyun Chen ¹ , Ying Liu ¹ , Chen Xu ¹ , Lina Ba ¹ , Zhuo Liu ¹ ,

Xinyun Chen ¹ , Ying Liu ¹ , Chen Xu ¹ , Lina Ba ¹ , Zhuo Liu ¹ , Xiuya Li ² , Jie Huang ² , Ed Simpson ³ , Hongyu Gao ³ , Dayan Cao ⁴ , Wei Sheng ¹ , Hanping Qi ¹ , Hongrui Ji ¹ , Maria Sanderson ¹ , Chen-Leng Cai ¹ , Xiaohui Li ⁴ , Lei Yang ¹ , Jie Na ⁵ , Kenichi Yamamura ⁶ , Yunlong Liu ³ , Guoying Huang ⁷ , Weinian Shou ⁸ , Ning Sun ⁹

+ et al

Author information

¹ Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA.
² Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
³ Department of Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA.
⁴ Institute of Materia Medica and Center of Translational Medicine, College of Pharmacy, Army Medical University, Chongqing, China.
⁵ Center for Stem Cell Biology and Regenerative Medicine, School of Medicine, Tsinghua University, Beijing, China.
⁶ Institute of Resource Development and Analysis, Kumanoto University, Kumanoto, Japan.
⁷ Shanghai Key Laboratory of Birth Defects, Children's Hospital of Fudan University, Shanghai, China. gyhuang@shmu.edu.cn.
⁸ Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA. wshou@iu.edu.
⁹ Shanghai Key Laboratory of Birth Defects, Children's Hospital of Fudan University, Shanghai, China. sunning@fudan.edu.cn.

摘要

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.

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