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.

肝脏规格和功能成熟在整个开发过程中受到严格控制。N6-甲基腺苷 (m ⁶ A) 是真核生物 mRNA 中最丰富的 RNA 修饰，参与各种生理和病理过程。然而，m ⁶ A 在肝脏发育中的作用仍然难以捉摸。在这里，我们剖析了 Mettl3 介导的 m ⁶ A 修饰在出生后肝脏发育和体内平衡中的作用。围产期用Alb-Cre ( Mettl3 cKO) 敲除 Mettl3 会诱导肝细胞凋亡和脂肪变性，导致严重的肝损伤，并最终在 7 周内导致产后死亡。米⁶A-RIP 测序和 RNA 测序表明，一系列重要的富含肝脏的转录因子的 mRNA 被 m ⁶ A 修饰，包括Hnf4a，肝实质形成的主要调节因子。删除 Mettl3 可减少 Hnf4a 的 m ⁶ A 修饰，以Igf2bp1依赖性方式降低其转录稳定性，并下调Hnf4a表达，而用 AAV8 过表达 Hnf4a 可减轻肝损伤并延长Mettl3 cKO 小鼠的寿命。然而，使用Alb-Cre ^ERT2在成人中敲除 Mettl3不会影响肝脏稳态。我们的研究确定了 Mettl3 介导的 RNA m ^{6的动态作用}肝脏发育的改变。