The m 6 A methyltransferase Mettl3 deficiency attenuates hepatic stellate cell activation and liver fibrosis

Activation of hepatic stellate cells (HSCs) is a central driver of liver fibrosis. Previous investigations have identified various altered epigenetic landscapes during the cellular progression of HSC activation. N6-methyladenosine (m A) is the most abundant internal RNA modification in eukaryotic ce...

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Published inMolecular therapy Vol. 30; no. 12; p. 3714
Main Authors Li, Yanli, Kang, Xinmei, Zhou, Zhuowei, Pan, Lijie, Chen, Huaxin, Liang, Xiaoqi, Chu, Jiajie, Dong, Shuai, Liu, Chang, Yu, Shanshan, Tu, Dan, Zhang, Yiwang, Ge, Mian, Chen, Wenjie, Xu, Yan, Zhang, Qi
Format Journal Article
LanguageEnglish
Published United States 07.12.2022
Subjects
Animals
Hepatic Stellate Cells
Liver Cirrhosis - genetics
Methyltransferases - deficiency
Methyltransferases - genetics
Mice
Multiomics
Protein Serine-Threonine Kinases - genetics
Tumor Suppressor Proteins
Hippo/YAP
liver fibrosis
LATS2
N6-methyladenosine (mA)
hepatic stellate cells (HSCs)
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Summary:Activation of hepatic stellate cells (HSCs) is a central driver of liver fibrosis. Previous investigations have identified various altered epigenetic landscapes during the cellular progression of HSC activation. N6-methyladenosine (m A) is the most abundant internal RNA modification in eukaryotic cells and is dynamically regulated under various physiological and pathophysiological conditions. However, the functional role of Mettl3-mediated m A in liver fibrosis remains elusive. Here, we found that the HSC-specific knockout of m A methyltransferase Mettl3 suppressed HSC activation and significantly alleviated liver fibrosis. Multi-omics analysis of HSCs showed that Mettl3 depletion reduced m A deposition on mRNA transcripts of Lats2 (a central player of the Hippo/YAP signaling pathway) and slowed down their degradation. Elevated Lats2 increased phosphorylation of the downstream transcription factor YAP, suppressed YAP nuclear translocation, and decreased pro-fibrotic gene expression. Overexpressing YAP mutant resistant to phosphorylation by Lats2 partially rescued the activation and pro-fibrotic gene expression of Mettl3-deficient HSCs. Our study revealed that disruption of Mettl3 in HSCs mitigated liver fibrosis by controlling the Hippo/YAP signaling pathway, providing potential therapeutic strategies to alleviate liver fibrosis by targeting epitranscriptomic machinery.
ISSN:1525-0024