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

• Published in: Nature communications 2022-08, Vol.13 (1), p.4555-4555, Article 4555
• Main Authors: Xu, Yan, Zhou, Zhuowei, Kang, Xinmei, Pan, Lijie, Liu, Chang, Liang, Xiaoqi, Chu, Jiajie, Dong, Shuai, Li, Yanli, Liu, Qiuli, Sun, Yuetong, Yu, Shanshan, Zhang, Qi
• Format: Article
• Language: English
• Subjects: 13/1; 13/106; 13/51; 14; 14/19; 14/34; 14/63; 38; 38/90; 38/91; 45; 631/208/135; 631/337/572/2102; 64; 64/60; 692/4020/4021/288/2032; Apoptosis; Gene sequencing; Hepatocyte nuclear factor 4; Hepatocytes; Homeostasis; Humanities and Social Sciences; Lethality; Life span; Liver; multidisciplinary; N6-methyladenosine; Physiology; RNA modification; Science; Science (multidisciplinary); Steatosis; Transcription factors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-32169-4

Hepatic specification and functional maturation are tightly controlled throughout development. N6-methyladenosine (m 6 A) is the most abundant RNA modification of eukaryotic mRNAs and is involved in various physiological and pathological processes. However, the function of m 6 A in liver development remains elusive. Here we dissect the role of Mettl3-mediated m 6 A 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. m 6 A-RIP sequencing and RNA-sequencing reveal that mRNAs of a series of crucial liver-enriched transcription factors are modified by m 6 A, including Hnf4a , a master regulator for hepatic parenchymal formation. Deleting Mettl3 reduces m 6 A 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-Cre ERT2 does not affect liver homeostasis. Our study identifies a dynamic role of Mettl3-mediated RNA m 6 A modification in liver development. m 6 A is the most abundant RNA modification of eukaryotic mRNAs and is involved in various physiological and pathological processes. Here the authors show a role for Mettl3-mediated RNA m 6 A modification in postnatal liver development by regulating the Hnf4a-centered transcriptional network