QKI deficiency in human embryonic stem cells and mouse models severely impaired cardiac sarcomerogenesis and contractile function by disrupting alternative splicing of genes involved in Z-disc formation.
Does QKI deficiency impair cardiomyocyte differentiation and contractile function in hESCs and mouse models?
QKI is a critical regulator of alternative splicing essential for cardiac sarcomerogenesis and contractile function, suggesting a potential role in the pathogenesis of certain cardiomyopathies.
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- 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.
Chen et al. (Mon,) conducted a other in Cardiac development and cardiomyopathies. QKI deficiency (CRISPR/Cas9 knockout and Qki-deficient mouse model) vs. Wild-type / Control hESCs and mice was evaluated on Cardiomyocyte differentiation, myofibrillogenesis, and contractile function. QKI deficiency in human embryonic stem cells and mouse models severely impaired cardiac sarcomerogenesis and contractile function by disrupting alternative splicing of genes involved in Z-disc formation.
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