Dynamic RNA modifications that control gene expression in diabetes

项目摘要 遗传和环境因素在糖尿病的病因学中起重要作用。这些因素如何相互作用， 疾病的发展还不清楚。N6-甲基腺苷（m6 A）是一种动态的mRNA修饰，可以直接 剪接命运和稳定，促进mRNA的翻译，并整合营养信息。果蝇 在胰岛素产生细胞（IPC）中具有降低水平的m6 A的黑腹果蝇是糖尿病;这种表型是 营养丰富的饮食会使病情恶化在胰岛素系统中编码蛋白质的mRNA是 在果蝇的大脑中甲基化。这些结果表明，m6 A在胰岛素系统中起着关键作用。然而， m6 A促进糖尿病发展的机制尚不清楚。的力量 果蝇遗传学，内分泌细胞的解剖学，系统的相对简单性，以及最近的发展 直接RNA测序将被用来揭示m6 A控制基因的机制， 在IPC中表达。中心假设是IPC中减少的m6 A损害了必要的动力学。 胰岛素系统的翻译控制。目标1和2（K99）将重点关注细胞内在机制， 对m6 A调节的丧失敏感。这些将揭示依赖于m6 A的细胞生物学特性， 适当的胰岛素输出。目的2和4（R 00）将探测需要m6 A的细胞外源因子， 外部输入。这些将阐明m6 A如何影响胰岛素受体翻译以及m6 A的水平如何影响胰岛素受体翻译。 对营养状况作出反应。总之，这项拟议的工作将确定m6 A mRNA甲基化在肿瘤细胞中的作用。 IPC的功能，并揭示代谢输入如何调节m6 A对mRNA的控制。这将推动我们的 了解RNA控制，可能有助于发现预防糖尿病的治疗靶点 和心理治疗

Project Summary Genetic and environmental factors play important roles in the etiology of diabetes. How these factors interact to promote disease remains unclear. N6-methyladenosine (m6A) is a dynamic mRNA modification that can direct splicing fate and stabilization, promote translation of mRNAs, and integrate nutritional information. Drosophila melanogaster, flies, with lowered levels of m6A in insulin-producing cells (IPCs) are diabetic; this phenotype is exacerbated by exposure to a nutrient-rich diet. mRNAs that encode proteins in the insulin system are methylated in the brain of flies. These results suggest that m6A plays a critical role in the insulin system. Yet, the mechanisms through which m6A contributes to the development of diabetes are unknown. The power of Drosophila genetics, the anatomy of the IPCs, the relative simplicity of the system, and the recent development of direct RNA-sequencing will be leveraged to uncover mechanisms through which m6A controls gene expression in IPCs. The central hypothesis is that reduced m6A in IPCs impairs necessary dynamic translational control over the insulin system. Aims 1 and 2 (K99) will focus on cell-intrinsic mechanisms that are sensitive to the loss of m6A regulation. These will uncover cell biological properties that depend on m6A for proper insulin output. Aims 2 and 4 (R00) will probe cell-extrinsic factors, which require m6A, that integrate external inputs. These will elucidate how m6A impacts insulin receptor translation and how the levels of m6A respond to nutritional state. Together, this proposed work will define a role for m6A methylation of mRNA in the function of IPCs and reveal how metabolic inputs modulate m6A control over mRNAs. This will advance our understanding of RNA control and may facilitate the discovery of therapeutic targets for diabetes prevention and therapy.