Abstract
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.
Highlights
N6-Methyladenosine (M6A) is a posttranscriptional modification found in eukaryotic messenger RNA, which is similar to DNA methylation and histone modification and is regulated by a variety of methyltransferases (Bushkin et al, 2019; Gu et al, 2019; Berulava et al, 2020)
We found 1122 Gene Ontology (GO) terms were significantly enriched in biological processes (Figure 4D), 210 GO terms were significantly enriched in cellular components (Figure 4E), and 476 GO terms were significantly enriched in molecular functions (Figure 4F), especially in the process of transcription, liver m6A Methylation in Liver Fibrosis development, response of endoplasmic reticulum to unfolded proteins, and protein binding
A study by Zhu Y. et al (2020) found that METTL3-mediated m6A methylation could be regulated by ASIC1a, which in turn affects the processing of miR-350, inducing the activation of hepatic stellate cell (HSC) and promoting the occurrence and development of Liver fibrosis (LF)
Summary
N6-Methyladenosine (M6A) is a posttranscriptional modification found in eukaryotic messenger RNA (mRNA), which is similar to DNA methylation and histone modification and is regulated by a variety of methyltransferases (Bushkin et al, 2019; Gu et al, 2019; Berulava et al, 2020). It has been confirmed that m6A modification affects the control of key cellular processes, including RNA stability (Wang et al, 2014), translation efficiency (Wang et al, 2015), secondary structure (Liu et al, 2015), subcellular localization (Meyer and Jaffrey, 2014), splicing and transport (Yang et al, 2018), and plays important roles in a variety of diseases (Zhang B. et al, 2020; Liu et al, 2020)
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