Mettl3-mediated mRNA m(6)A modification controls postnatal liver development by modulating the transcription factor Hnf4a

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.