2020-04-28_revised-Supplemental_Info.pdf (3.17 MB)

m6A mRNA Methylation Controls Functional Maturation in Neonatal Murine β Cells

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posted on 13.05.2020 by Ada Admin, Yanqiu Wang, Jiajun Sun, Zhen Lin, Weizhen Zhang, Shu Wang, Weiqing Wang, Qidi Wang, Guang Ning
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.

Funding

This work was supported by the National Natural Sciences Foundation of China Grants (81670700, 81870527).

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