m^6A modification-tuned sphingolipid metabolism regulates postnatal liver development in male mice
m^6A modification-tuned sphingolipid metabolism regulates postnatal liver development in male mice
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DOI：
10.1038/s42255-023-00808-9
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发表时间：
2023-05
影响因子：
20.8
通讯作者：
Shiguan Wang;Shanze Chen;Jianfeng Sun;Pan Han;Bowen Xu;Xinying Li;Youquan Zhong;Zaichao Xu;P. Zhang;Ping Mi;Cuijuan Zhang;Lixiang Li;Haiyan Zhang;Yuchen Xia;Shi-yu Li;Mathias Heikenwalder;Detian Yuan
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作者：
Shiguan Wang;Shanze Chen;Jianfeng Sun;Pan Han;Bowen Xu;Xinying Li;Youquan Zhong;Zaichao Xu;P. Zhang;Ping Mi;Cuijuan Zhang;Lixiang Li;Haiyan Zhang;Yuchen Xia;Shi-yu Li;Mathias Heikenwalder;Detian Yuan
不同的器官经历不同的转录，表观遗传和生理变化，保证其出生后的功能成熟。然而，epitranscriptomic机制在这些过程中的作用仍然难以捉摸。在这里，我们证明了RNA甲基转移酶Mettl 3和Mettl 14的表达在雄性小鼠出生后肝脏发育过程中逐渐下降。肝特异性Mettl 3缺乏导致肝细胞肥大、肝损伤和生长迟缓。转录组学和N6-甲基-腺苷（m6 A）分析鉴定中性鞘磷脂酶Smpd 3为Mettl 3的靶标。由于Mettl 3缺乏导致Smpd 3转录物的衰减减少导致鞘脂代谢重新布线，其特征在于毒性神经酰胺积累并导致线粒体损伤和内质网应激升高。Smpd 3的抑制、Smpd 3的敲低或Smpd 3的过表达均能改善Mettl 3缺陷性肝脏的异常。我们的研究结果表明，Mettl 3-N6-甲基-腺苷微调鞘脂代谢，突出了在出生后肝脏发育期间协调器官生长和功能成熟时机的epitranscriptomic机制的关键作用。
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 ofSmpd3transcripts 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.