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

Gao，Siyun1,2; Sun，Haifeng3; Chen，Kejing1,2; Gu，Xueying3; Chen，Hongyu3; Jiang，Liudan1,2; Chen，Lei1,2; Zhang，Shengqi1,2; Liu，Yi1,2,4,5; Shi，Dan1,2,4; Liang，Dandan1,2,4; Xu，Liang1,2,4; Yang，Jian1,2,4,5; Ruan，Yanjiao6; Chen，Hao6; Shen，Bin3; Ma，Honghui1,2,4,5,7; Chen，Yi Han1,2,4,5

2021

10.1111/jcmm.16955

JOURNAL OF CELLULAR AND MOLECULAR MEDICINE   影响因子和分区

1582-1838

N-methyladenosine (mA) is the most prevalent modification in mRNA and engages in multiple biological processes. Previous studies indicated that mA methyltransferase METTL3 (‘writer’) and demethylase FTO (‘eraser’) play critical roles in heart-related disease. However, in the heart, the function of mA ‘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 mA-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 mA 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 mA reader in cardiac biofunction and provide a novel potential target for the treatment of DCM.

dilated cardiomyopathy epitranscriptomics heart failure RNA modification YTHDC1

SCI

英语

其他

WOS:000712752700001

MOLECULAR BIOLOGY & GENETICS

2-s2.0-85118401635

Scopus

1.Department of Cardiology,Shanghai East Hospital,Tongji University School of Medicine,Shanghai,China
2.Key Laboratory of Arrhythmias of the Ministry of Education of China,Shanghai East Hospital,Tongji University School of Medicine,Shanghai,China
3.State Key Laboratory of Reproductive Medicine,Center for Global Health,Gusu School,Women’s Hospital of Nanjing Medical University,Nanjing Maternity and Child Health Hospital,Nanjing Medical University,Nanjing,China
4.Institute of Medical Genetics,Tongji University,Shanghai,China
5.Department of Pathology and Pathophysiology,Tongji University School of Medicine,Shanghai,China
6.School of Medicine,Southern University of Science and Technology,Shenzhen,China
7.Research Units of Origin and Regulation of Heart Rhythm,Chinese Academy of Medical Sciences,Shanghai,China

Gao，Siyun,Sun，Haifeng,Chen，Kejing,et al. Depletion of m6A reader protein YTHDC1 induces dilated cardiomyopathy by abnormal splicing of Titin[J]. JOURNAL OF CELLULAR AND MOLECULAR MEDICINE,2021.

Gao，Siyun.,Sun，Haifeng.,Chen，Kejing.,Gu，Xueying.,Chen，Hongyu.,...&Chen，Yi Han.(2021).Depletion of m6A reader protein YTHDC1 induces dilated cardiomyopathy by abnormal splicing of Titin.JOURNAL OF CELLULAR AND MOLECULAR MEDICINE.

Gao，Siyun,et al."Depletion of m6A reader protein YTHDC1 induces dilated cardiomyopathy by abnormal splicing of Titin".JOURNAL OF CELLULAR AND MOLECULAR MEDICINE (2021).