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

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-Cre^ERT2 does not affect liver homeostasis. Our study identifies a dynamic role of Mettl3-mediated RNA m⁶A modification in liver development.