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

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 showed that, similar to glycogen storage pattern, N6-methyladenosine (m6A) modification in mRNAs gradually increases during the growth of mice in liver. Strikingly, in the liver-specific Mettl3 knockout mice, loss of m6A modification disrupts liver glycogen storage. On the mechanism, we screened and identified that glycogen synthase 2 (Gys2) plays a critical role in m6A-mediated regulation of liver glycogen storage. Furthermore, IGF2BP2, as a “reader” of m6A, stabilizes the mRNA of Gys2. More importantly, reconstitution of GYS2 rescues liver glycogenesis in Mettl3-cKO mice. Collectively, a METTL3-IGF2BP2-GYS2 axis, in which METTL3 and IGF2BP2 regulate glycogenesis as “writer” and “reader” respectively, plays a critical role on maintenance of liver glycogenesis in mammals.