m6A mRNA Methylation Controls Functional Maturation in Neonatal Murine β-Cells
m6A mRNA Methylation Controls Functional Maturation in Neonatal Murine β-Cells
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m(6)A mRNA 甲基化控制新生鼠 β 细胞的功能成熟
DOI：
10.2337/db19-0906
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发表时间：
2020-08-01
期刊：
影响因子：
7.7
通讯作者：
Ning, Guang
中科院分区：
文献类型：
--
作者：
Wang, Yanqiu;Sun, Jiajun;Ning, Guang
TheN(6)-methyladenosine (m(6)A) 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 beta-cells before weaning. Transcriptome and m(6)A methylome analyses provided m(6)A-dependent mechanisms in regulating cell identity, insulin secretion, and proliferation in neonatal beta-cells. Importantly, we found that Mettl3/14 were dispensable for beta-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 beta-cell functional maturity. In both diabeticdb/dbmice and patients with type 2 diabetes (T2D), decreased Mettl3/14 expression in beta-cells was observed, suggesting its possible role in T2D. Our study unraveled the essential role of Mettl3/14 in neonatal beta-cell development and functional maturation, both of which determined functional beta-cell mass and glycemic control in adulthood.
