Depletion of m(6) A reader protein YTHDC1 induces dilated cardiomyopathy by abnormal splicing of Titin.
Depletion of m(6) A reader protein YTHDC1 induces dilated cardiomyopathy by abnormal splicing of Titin.
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DOI：
10.1111/jcmm.16955
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发表时间：
2021-12
影响因子：
5.3
通讯作者：
Chen YH
中科院分区：
文献类型：
--
作者：
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;Chen YH
N 6-甲基腺苷（M6A）是mRNA中最普遍的修饰，并参与了多个生物学过程。但是，在心脏中，M6A“读取器”的功能，例如YTH（YT521 -B同源性）含量的蛋白质尚不清楚。 DCM）在心脏特异性的条件YTHDC1敲除中，左心室膨胀和严重的收缩功能障碍。 M6A -MERIP，RIP -SEQ和mRNA -SEQ，我们确定了42个转录本为YTHDC1的潜在靶标YTHDC1在调节正常收缩功能和DCM的发展中起着至关重要的作用。
N 6‐methyladenosine (m6A) is the most prevalent modification in mRNA and engages in multiple biological processes. Previous studies indicated that m6A methyltransferase METTL3 (‘writer’) and demethylase FTO (‘eraser’) play critical roles in heart‐related disease. However, in the heart, the function of m6A ‘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 m6A‐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 m6A 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 m6A reader in cardiac biofunction and provide a novel potential target for the treatment of DCM.
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影响因子：
20.1
作者：
McNally EM;Mestroni L
通讯作者：
Mestroni L
DOI：
10.1152/ajpheart.00339.2017
发表时间：
2018-04-01
期刊：
American journal of physiology. Heart and circulatory physiology
影响因子：
--
作者：
Lindsey ML;Kassiri Z;Virag JAI;de Castro Brás LE;Scherrer-Crosbie M
通讯作者：
Scherrer-Crosbie M
影响因子：
20.1
作者：
Cheedipudi, Sirisha M.;Matkovich, Scot J.;Marian, Ali J.
通讯作者：
Marian, Ali J.
影响因子：
16
作者：
Heinz S;Benner C;Spann N;Bertolino E;Lin YC;Laslo P;Cheng JX;Murre C;Singh H;Glass CK
通讯作者：
Glass CK
影响因子：
56.9
作者：
Liu, Jun;Do, Xiaoyang;Hei, Chuan
通讯作者：
Hei, Chuan