m6A mRNA Methylation Controls Functional Maturation in Neonatal Murine β Cells
<a>m<sup>6</sup>A RNA modification is essential during embryonic development of various organs; however, its role in embryonic and early postnatal islet development remains unknown.</a><a></a><a> </a>Mice in which RNA methyltransferase-like 3/14 (Mettl3/14) were deleted in Ngn3<sup>+</sup> endocrine progenitors (<i>Mettl3/14<sup>nKO</sup></i>) developed hyperglycemia and hypo-insulinemia at 2 weeks after birth. <a></a><a>We found that Mettl3/14 specifically regulated both functional maturation and mass expansion of neonatal</a><a></a><a> β cell</a>s before weaning. Transcriptome and m<sup>6</sup>A methylome analyses provided m<sup>6</sup>A-dependent mechanisms in regulating<a> cell</a> identity, insulin secretion and proliferation in neonatal<a></a><a> </a><a></a><a>β</a> cells.<a></a><a> Importantly, we found that Mettl3/14 were dispensable for β cell differentiation, but directly regulated essential transcriptional factor MafA expression</a><a> at least partially via modulating its mRNA stability and failure to maintain this modification impacted the ability to fulfill β cell functional maturity. </a>In both diabetic <i>db/db</i> mice and type 2 diabetes patients, decreased Mettl3/14 expression in <a></a><a>β</a> cells were observed, suggesting its possible role in type 2 diabetes. Our stud<sub></sub>y 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.<b></b>