Comprehensive Analysis of the Transcriptome-Wide m6A Methylation Modification Difference in Liver Fibrosis Mice by High-Throughput m6A Sequencing.
Comprehensive Analysis of the Transcriptome-Wide m6A Methylation Modification Difference in Liver Fibrosis Mice by High-Throughput m6A Sequencing.
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DOI：
10.3389/fcell.2021.767051
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发表时间：
2021
影响因子：
5.5
通讯作者：
Wu F
中科院分区：
文献类型：
--
作者：
Fan C;Ma Y;Chen S;Zhou Q;Jiang H;Zhang J;Wu F
N6-甲基腺苷(M6A)是真核生物中一种独特而常见的mRNA修饰方法，参与多种疾病的发生发展。肝纤维化(LF)是慢性肝损伤的常见反应，可导致肝硬变甚至肝癌。然而，m6A甲基化在LF的发生发展中的作用仍不清楚。在这项研究中，我们使用LF小鼠对m6A-seq和RNA-seq对肝脏基因组范围的m6A修饰和mRNA表达进行了系统的评估。有3,315个基因的m6A水平存在显著差异，其中2,498个基因高甲基化，817个基因低甲基化。GO和KEGG分析表明，差异表达的m6A基因与内质网应激反应、PPAR信号通路和转化生长因子-β信号通路等过程密切相关。此外，m6A-seq和RNA-seq联合分析显示，共有90个基因的m6A水平和mRNA表达都发生了显著变化。因此，通过RT-qPCR和Western印迹证实了m6A修饰的关键元件，包括甲基转移酶WTAP、去甲基酶ALKBH5和结合蛋白YTHDF1。在另一项细胞实验中，我们还观察到WTAP表达的减少通过促进肝星状细胞(HSC)的激活而导致LF的发生。因此，本研究揭示了LF小鼠独特的M6A甲基化模式，提示M6A甲基化在一定程度上与LF的发生和病程有关。
N6-Methyladenosine (m6A), a unique and common mRNA modification method in eukaryotes, is involved in the occurrence and development of many diseases. Liver fibrosis (LF) is a common response to chronic liver injury and may lead to cirrhosis and even liver cancer. However, the involvement of m6A methylation in the development of LF is still unknown. In this study, we performed a systematic evaluation of hepatic genome-wide m6A modification and mRNA expression by m6A-seq and RNA-seq using LF mice. There were 3,315 genes with significant differential m6A levels, of which 2,498 were hypermethylated and 817 hypomethylated. GO and KEGG analyses illustrated that differentially expressed m6A genes were closely correlated with processes such as the endoplasmic reticulum stress response, PPAR signaling pathway and TGF-β signaling pathway. Moreover, a total of 90 genes had both a significant change in the m6A level and mRNA expression shown by joint analysis of m6A-seq and RNA-seq. Hence, the critical elements of m6A modification, including methyltransferase WTAP, demethylases ALKBH5 and binding proteins YTHDF1 were confirmed by RT-qPCR and Western blot. In an additional cell experiment, we also observed that the decreased expression of WTAP induced the development of LF as a result of promoting hepatic stellate cell (HSC) activation. Therefore, this study revealed unique differential m6A methylation patterns in LF mice and suggested that m6A methylation was associated with the occurrence and course of LF to some extent.
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DOI：
10.1126/science.aad8711
发表时间：
2016-06-17
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Gilbert WV;Bell TA;Schaening C
通讯作者：
Schaening C
影响因子：
4.6
作者：
Choi S;Woo JK;Jang YS;Kang JH;Hwang JI;Seong JK;Yoon YS;Oh SH
通讯作者：
Oh SH
Mettl14通过Notch1的N-6-甲基腺苷抑制膀胱TIC自我更新和膀胱肿瘤发生
影响因子：
37.3
作者：
Gu, Chaohui;Wang, Zhiyu;Tian, Fengyan
通讯作者：
Tian, Fengyan
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
WTAP 通过 m(6)A 依赖性抑制 HMBOX1 表达促进骨肉瘤肿瘤发生
影响因子：
9
作者：
Chen, Shijie;Li, Yuezhan;Li, Jinsong
通讯作者：
Li, Jinsong