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

Abstract

The N⁶-methyladenosine (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 (Mettl3/14^nKO) developed hyperglycemia and hypoinsulinemia 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 transcription factor MafA expression at least partially via modulating its mRNA stability. Failure to maintain this modification impacted the ability to fulfill β-cell functional maturity. In both diabetic db/db mice and patients with type 2 diabetes (T2D), decreased Mettl3/14 expression in β-cells was observed, suggesting its possible role in T2D. 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.