m6A modification-tuned sphingolipid metabolism regulates postnatal liver development

Abstract 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 remain elusive. Here, we show that RNA methyltransferase enzymes Mettl3 and Mettl14 highly express in murine hepatocytes at embryonic and neonatal stages, and gradually decline during the postnatal development. 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 excessive sphingomyelin hydrolysis, leading to mitochondrial damage and elevated ER stress. Pharmacological inhibition of Smpd3 ameliorates the abnormality of Mettl3-deficent liver. Our findings demonstrate that Mettl3/m6A fine-tunes sphingolipid metabolism, highlighting the pivotal role of an epitranscriptomic machinery in coordinating metabolic homeostasis and functional maturation during postnatal liver development.