Depletion of m6A reader protein YTHDC1 induces dilated cardiomyopathy by abnormal splicing of Titin

Gao S, Sun H, Chen K, Gu X, Chen H, Jiang L, Chen L, Zhang S, Liu Y, Shi D, Liang D, Xu L, Yang J, Ruan Y, Chen H, Shen B, Ma H, and Chen YH.

Journal of Cellular and Molecular Medicine, 2021.

Scientists demonstrate the role of YTHDC1 in the development of cardiomyopathy and reveal a potential new therapeutic target

Research has shown that titin mutations are responsible for about 20-25% of dilated cardiomyopathy (DCM) cases with a genetic cause but the regulatory molecular mechanisms of titin splicing are not well understood. However, research using Ythdc1 conditional knockout (cKO) animal models suggests that depletion of the m6A reader protein YTHDC1 leads to aberrant splicing of Titin, which ultimately results in DCM—a discovery that expands the knowledge of post- transcriptional regulation and may lead to new therapeutic targets for heart disease.

Because impaired contractility is the hallmark of DCM, researchers used Axion’s Maestro Pro multi-well MEA platform and microscopy to assess function in cultured cardiomyocytes from cKO mice and controls. The results confirmed the critical role of YTHDC1 in regulating contractility by demonstrating prolonged relaxation duration, reduced contraction amplitude, and conduction velocity. Taken along with other findings from the study, the results demonstrate the role of YTHDC1 in the development of DCM and a potential new therapeutic target.