Mettl3/14通过m6A甲基化调控新生期胰岛β细胞的成熟分化

最新研究显示，N6-甲基腺嘌呤（m6A）修饰与癌症、胚胎发育、脂类代谢等均有着密切的联系；然而，m6A修饰是否参与胰岛发育和新生β细胞成熟分化未见报道。本课题组在糖尿病小鼠以及糖尿病患者的胰岛β细胞中发现RNA甲基转移酶Mettl3和Mettl14表达明显下调。我们首次构建了在Ngn3+胰岛内分泌前体细胞中特异性敲除Mettl3和/或Mettl14的转基因小鼠模型，前期结果显示m6A缺失会导致敲除小鼠在2周即出现血糖升高和低胰岛素血症并特异性影响新生胰岛β细胞功能成熟和容量扩增。本研究将通过对不同成熟时间点的敲除小鼠β细胞进行转录组学和m6A甲基化组学联合分析，并通过比对3周敲除小鼠装胰岛素泵纠正高血糖后β细胞成熟分化改变，结合分子生物学实验，以探寻m6A直接调控胰岛成熟分化的关键靶点及具体机制。深入解析RNA甲基化修饰对新生β细胞成熟分化的调控将为糖尿病的防治提供理论基础和科学依据。

Recent studies have found that m6A methylation is closely related to cancer, embryonic development, lipid metabolism etc; however, its role in islet development and neonatal beta cell functional maturation remains unknown. Our preliminary data showed that decreased Mettl3/14 expression in β cells in both diabetic db/db mice and Type 2 diabetes patients. We generated knockout mice in which RNA methyltransferase-like 3/14 (Mettl3/14) were deleted in Ngn3+ endocrine progenitors (Mettl3/14nKO) and these mice developed hyperglycemia and hypo-insulinemia at 2 weeks after birth. We found that Mettl3/14 was dispensable for endocrine cell lineage formation, but specifically regulated both functional maturation and mass expansion of neonatal β cells before weaning. By joint analysis of transcriptome and MeRip-seq on KO βcell, implantation insulin-releasing pump to normalize blood glucose in KO mice, as well as performing in vitro experiments, the present study aims to find out key factors and specific mechanisms via which m6A regulates neonatal β cell function maturation and to clarify the key role of m6A in diabetes progression. We believe that understanding of how RNA methylation regulates functional maturation and mass expansion in neonatal beta cell will provide new insight for the prevention and treatment of diabetes.