m6A mRNA Methylation Controls Functional Maturation in Neonatal Murine β Cells.

m6A RNA modification is essential during embryonic development of various organs; however, its role in embryonic and early postnatal islet development remains unknown. Mice in which RNA methyltransferase-like 3/14 (Mettl3/14) were deleted in Ngn3+ endocrine progenitors (Mettl3/14nKO) developed hyperglycemia and hypo-insulinemia at 2 weeks after birth. We found that Mettl3/14 specifically regulated both functional maturation and mass expansion of neonatal β cells before weaning. Transcriptome and m6A methylome analyses provided m6A-dependent mechanisms in regulating cell identity, insulin secretion and proliferation in neonatal β cells. Importantly, we found that Mettl3/14 were dispensable for β cell differentiation, but directly regulated essential transcriptional factor MafA expression at least partially via modulating its mRNA stability and failure to maintain this modification impacted the ability to fulfill β cell functional maturity. In both diabetic db/db mice and type 2 diabetes patients, decreased Mettl3/14 expression in β cells were observed, suggesting its possible role in type 2 diabetes. Our study unraveled the essential role of Mettl3/14 in neonatal β cell development and functional maturation, both of which determined functional β cell mass and glycemic control in adulthood.