N6-methyladenosine modification governs liver glycogenesis by stabilizing the glycogen synthase 2 mRNA

Xiang Zhang, Huilong Yin, Xiaofang Zhang, Xunliang Jiang, Yongkang Liu, Haolin Zhang, Yingran Peng, Da Li, Yanping Yu, Jinbao Zhang, Shuli Cheng, Angang Yang and Rui Zhang ()
Additional contact information
Xiang Zhang: Fourth Military Medical University
Huilong Yin: Fourth Military Medical University
Xiaofang Zhang: Fourth Military Medical University
Xunliang Jiang: Fourth Military Medical University
Yongkang Liu: Fourth Military Medical University
Haolin Zhang: Fourth Military Medical University
Yingran Peng: Fourth Military Medical University
Da Li: Fourth Military Medical University
Yanping Yu: Fourth Military Medical University
Jinbao Zhang: Fourth Military Medical University
Shuli Cheng: Fourth Military Medical University
Angang Yang: Xinxiang Medical University
Rui Zhang: Fourth Military Medical University

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: Abstract Hepatic glycogen is the main source of blood glucose and controls the intervals between meals in mammals. Hepatic glycogen storage in mammalian pups is insufficient compared to their adult counterparts; however, the detailed molecular mechanism is poorly understood. Here, we show that, similar to glycogen storage pattern, N6-methyladenosine (m6A) modification in mRNAs gradually increases during the growth of mice in liver. Strikingly, in the hepatocyte-specific Mettl3 knockout mice, loss of m6A modification disrupts liver glycogen storage. On the mechanism, mRNA of Gys2, the liver-specific glycogen synthase, is a substrate of METTL3 and plays a critical role in m6A-mediated glycogenesis. Furthermore, IGF2BP2, a “reader” protein of m6A, stabilizes the mRNA of Gys2. More importantly, reconstitution of GYS2 almost rescues liver glycogenesis in Mettl3-cKO mice. Collectively, a METTL3-IGF2BP2-GYS2 axis, in which METTL3 and IGF2BP2 regulate glycogenesis as “writer” and “reader” proteins respectively, is essential on maintenance of liver glycogenesis in mammals.

Date: 2022
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DOI: 10.1038/s41467-022-34808-2

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