Dataset Information

Depletion of m⁶ A reader protein YTHDC1 induces dilated cardiomyopathy by abnormal splicing of Titin.

ABSTRACT: N⁶ -methyladenosine (m⁶ A) is the most prevalent modification in mRNA and engages in multiple biological processes. Previous studies indicated that m⁶ A methyltransferase METTL3 ('writer') and demethylase FTO ('eraser') play critical roles in heart-related disease. However, in the heart, the function of m⁶ A 'reader', such as YTH (YT521-B homology) domain-containing proteins remains unclear. Here, we report that the defect in YTHDC1 but not other YTH family members contributes to dilated cardiomyopathy (DCM) in mice. Cardiac-specific conditional Ythdc1 knockout led to obvious left ventricular chamber enlargement and severe systolic dysfunction. YTHDC1 deficiency also resulted in the decrease of cardiomyocyte contractility and disordered sarcomere arrangement. By means of integrating multiple high-throughput sequence technologies, including m⁶ A-MeRIP, RIP-seq and mRNA-seq, we identified 42 transcripts as potential downstream targets of YTHDC1. Amongst them, we found that Titin mRNA was decorated with m⁶ A modification and depletion of YTHDC1 resulted in aberrant splicing of Titin. Our study suggests that Ythdc1 plays crucial role in regulating the normal contractile function and the development of DCM. These findings clarify the essential role of m⁶ A reader in cardiac biofunction and provide a novel potential target for the treatment of DCM.

SUBMITTER: Gao S

PROVIDER: S-EPMC8642692 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Depletion of m6 A reader protein YTHDC1 induces dilated cardiomyopathy by abnormal splicing of Titin.

Gao Siyun S Sun Haifeng H Chen Kejing K Gu Xueying X Chen Hongyu H Jiang Liudan L Chen Lei L Zhang Shengqi S Liu Yi Y Shi Dan D Liang Dandan D Xu Liang L Yang Jian J Ruan Yanjiao Y Chen Hao H Shen Bin B Ma Honghui H Chen Yi-Han YH

Journal of cellular and molecular medicine 20211030 23

N6 -methyladenosine (m6 A) is the most prevalent modification in mRNA and engages in multiple biological processes. Previous studies indicated that m6 A methyltransferase METTL3 ('writer') and demethylase FTO ('eraser') play critical roles in heart-related disease. However, in the heart, the function of m6 A 'reader', such as YTH (YT521-B homology) domain-containing proteins remains unclear. Here, we report that the defect in YTHDC1 but not other YTH f ...[more]

PMID: 34716659

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Project description:BackgroundDilated cardiomyopathy and hypertrophic cardiomyopathy arise from mutations in many genes. TTN, the gene encoding the sarcomere protein titin, has been insufficiently analyzed for cardiomyopathy mutations because of its enormous size.MethodsWe analyzed TTN in 312 subjects with dilated cardiomyopathy, 231 subjects with hypertrophic cardiomyopathy, and 249 controls by using next-generation or dideoxy sequencing. We evaluated deleterious variants for cosegregation in families and assessed clinical characteristics.ResultsWe identified 72 unique mutations (25 nonsense, 23 frameshift, 23 splicing, and 1 large tandem insertion) that altered full-length titin. Among subjects studied by means of next-generation sequencing, the frequency of TTN mutations was significantly higher among subjects with dilated cardiomyopathy (54 of 203 [27%]) than among subjects with hypertrophic cardiomyopathy (3 of 231 [1%], P=3×10(-16)) or controls (7 of 249 [3%], P=9×10(-14)). TTN mutations cosegregated with dilated cardiomyopathy in families (combined lod score, 11.1) with high (>95%) observed penetrance after the age of 40 years. Mutations associated with dilated cardiomyopathy were overrepresented in the titin A-band but were absent from the Z-disk and M-band regions of titin (P≤0.01 for all comparisons). Overall, the rates of cardiac outcomes were similar in subjects with and those without TTN mutations, but adverse events occurred earlier in male mutation carriers than in female carriers (P=4×10(-5)).ConclusionsTTN truncating mutations are a common cause of dilated cardiomyopathy, occurring in approximately 25% of familial cases of idiopathic dilated cardiomyopathy and in 18% of sporadic cases. Incorporation of sequencing approaches that detect TTN truncations into genetic testing for dilated cardiomyopathy should substantially increase test sensitivity, thereby allowing earlier diagnosis and therapeutic intervention for many patients with dilated cardiomyopathy. Defining the functional effects of TTN truncating mutations should improve our understanding of the pathophysiology of dilated cardiomyopathy. (Funded by the Howard Hughes Medical Institute and others.).

Dataset Information

Depletion of m⁶ A reader protein YTHDC1 induces dilated cardiomyopathy by abnormal splicing of Titin.

Publications

Depletion of m<sup>6</sup> A reader protein YTHDC1 induces dilated cardiomyopathy by abnormal splicing of Titin.

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