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  3. m6A modification-tuned sphingolipid metabolism regulates postnatal liver development in male mice

m6A modification-tuned sphingolipid metabolism regulates postnatal liver development in male mice

  • Nat Metab. 2023 May 15. doi: 10.1038/s42255-023-00808-9.
Shiguan Wang # 1,  Shanze Chen # 2,  Jianfeng Sun # 1,  Pan Han # 1,  Bowen Xu 1,  Xinying Li 1,  Youquan Zhong 3,  Zaichao Xu 3,  Peng Zhang 1,  Ping Mi 1,  Cuijuan Zhang 4,  Lixiang Li 5 6,  Haiyan Zhang 7,  Yuchen Xia 8,  Shiyang Li 9 10,  Mathias Heikenwalder 11 12,  Detian Yuan 13 14
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
  • 2 Department of Pulmonary and Critical Care Medicine, Shenzhen Institute of Respiratory Diseases, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, China.
  • 3 State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, Hubei Jiangxia Laboratory, Institute of Medical Virology, TaiKang Center for Life and Medical Sciences, TaiKang Medical School, Wuhan University, Wuhan, China.
  • 4 Institute of Pathology and Pathophysiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
  • 5 Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan, China.
  • 6 Shandong Provincial Clinical Research Center for Digestive Disease, Jinan, China.
  • 7 Pediatric Research Institute, Children's Hospital Affiliated to Shandong University, Jinan, China.
  • 8 State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, Hubei Jiangxia Laboratory, Institute of Medical Virology, TaiKang Center for Life and Medical Sciences, TaiKang Medical School, Wuhan University, Wuhan, China. [email protected].
  • 9 Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan, China. [email protected].
  • 10 Advanced Medical Research Institute, Shandong University, Jinan, China. [email protected].
  • 11 Division of Chronic Inflammation and Cancer, German Cancer Research Center, Heidelberg, Germany. [email protected].
  • 12 The M3 Research Institute, Eberhard Karls University Tübingen, Tübingen, Germany. [email protected].
  • 13 Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China. [email protected].
  • 14 Shandong Provincial Clinical Research Center for Digestive Disease, Jinan, China. [email protected].
  • # Contributed equally.
PMID: 37188818 DOI: 10.1038/s42255-023-00808-9
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 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.

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