Mettl3-mediated mRNA m6A modification controls postnatal liver development by modulating the transcription factor Hnf4a

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 ()
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Yan Xu: Sun Yat-sen University
Zhuowei Zhou: Sun Yat-sen University
Xinmei Kang: Sun Yat-sen University
Lijie Pan: Sun Yat-sen University
Chang Liu: Sun Yat-sen University
Xiaoqi Liang: Sun Yat-sen University
Jiajie Chu: Sun Yat-sen University
Shuai Dong: Sun Yat-sen University
Yanli Li: Sun Yat-sen University
Qiuli Liu: Sun Yat-sen University
Yuetong Sun: Sun Yat-sen University
Shanshan Yu: Sun Yat-sen University
Qi Zhang: Sun Yat-sen University

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-32169-4

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