Mettl3-mediated mRNA m6A modification controls postnatal liver development by modulating the transcription factor Hnf4a
Brief intro:
- Author: Yan Xu, Zhuowei Zhou, Xinmei Kang, Lijie Pan, Chang Liu, Xiaoqi Liang, Jiajie Chu, Shuai Dong, Yanli Li, Qiuli Liu, Yuetong Sun, Shanshan Yu, and Qi Zhang
- Journal: Nat Commun
- Doi: https://www.doi.org/10.1038/s41467-022-32169-4
- Publication Date: 2022 Aug 5
Products/Services used in the paper
Quotation shows PackGene:Serotype 8 AAV (AAV8) was used in this study. Hnf4a coding sequencing was cloned into an AAV8 vector under the control of TBG promoter to achieve liver-specific overexpression of Hnf4a protein. The virus was packaged by Packgene Biotech Co., Ltd (Guangzhou, China) with a final titer larger than 2.0 × 10^13 viral genomes/mL.
Research Field:Liver
AAV Serotype:AAV8
Targeted organ:liver
Abstract
Hepatic specification and functional maturation are tightly controlled throughout development. N6-methyladenosine (m6A) is the most abundant RNA modification of eukaryotic mRNAs and is involved in various physiological and pathological processes. However, the function of m6A in liver development remains elusive. Here we dissect the role of Mettl3-mediated m6A modification in postnatal liver development and homeostasis. Knocking out Mettl3 perinatally with Alb-Cre (Mettl3 cKO) induces apoptosis and steatosis of hepatocytes, results in severe liver injury, and finally leads to postnatal lethality within 7 weeks. m6A-RIP sequencing and RNA-sequencing reveal that mRNAs of a series of crucial liver-enriched transcription factors are modified by m6A, including Hnf4a, a master regulator for hepatic parenchymal formation. Deleting Mettl3 reduces m6A modification on Hnf4a, decreases its transcript stability in an Igf2bp1-dependent manner, and down-regulates Hnf4a expression, while overexpressing Hnf4a with AAV8 alleviates the liver injury and prolongs the lifespan of Mettl3 cKO mice. However, knocking out Mettl3 in adults using Alb-CreERT2 does not affect liver homeostasis. Our study identifies a dynamic role of Mettl3-mediated RNA m6A modification in liver development.
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