Different organs undergo distinct transcriptional, epigenetic and physiological alterations that guarantee their functional maturation after birth. However, the roles of epitranscriptomic machineries in these processes have remained elusive. Here we demonstrate that expression of RNA methyltransferase enzymes Mettl3 and Mettl14 gradually declines during postnatal liver development in male mice. Liver-specific Mettl3 deficiency causes hepatocyte hypertrophy, liver injury and growth retardation. Transcriptomic and N6-methyl-adenosine (m⁶A) profiling identify the neutral sphingomyelinase, Smpd3, as a target of Mettl3. Decreased decay of Smpd3 transcripts due to Mettl3 deficiency results in sphingolipid metabolism rewiring, characterized by toxic ceramide accumulation and leading to mitochondrial damage and elevated endoplasmic reticulum stress. Pharmacological Smpd3 inhibition, Smpd3 knockdown or Sgms1 overexpression that counteracts Smpd3 can ameliorate the abnormality of Mettl3-deficent liver. Our findings demonstrate that Mettl3–N⁶-methyl-adenosine fine-tunes sphingolipid metabolism, highlighting the pivotal role of an epitranscriptomic machinery in coordination of organ growth and the timing of functional maturation during postnatal liver development.

不同的器官经历不同的转录、表观遗传和生理变化，保证其功能在出生后成熟。然而，表观转录组机制在这些过程中的作用仍然难以捉摸。在这里，我们证明，在雄性小鼠出生后肝脏发育过程中，RNA 甲基转移酶 Mettl3 和 Mettl14 的表达逐渐下降。肝脏特异性 Mettl3 缺乏会导致肝细胞肥大、肝损伤和生长迟缓。转录组和 N6-甲基-腺苷 (m ⁶ A) 分析确定中性鞘磷脂酶Smpd3是 Mettl3 的靶标。由于 Mettl3 缺陷，Smpd3转录本的衰减减少会导致鞘脂代谢重新布线，其特征是有毒神经酰胺积累，并导致线粒体损伤和内质网应激升高。药理学抑制Smpd3、敲低Smpd3或抵消Smpd3的Sgms1过表达可以改善Mettl3缺陷型肝脏的异常。我们的研究结果表明，Mettl3–N ⁶ -甲基腺苷可微调鞘脂代谢，突显表观转录组机制在协调器官生长和出生后肝脏发育过程中功能成熟时间方面的关键作用。