Raptor通过组蛋白甲基转移酶Ezh2调控胚胎、新生期β细胞增殖和容量扩增

The onset of diabetes is mainly due to reduction of functional beta cell mass. The proliferation potential of embryonic and neonatal beta cells between E17.5 and P14, is crucial for the establishment of proper β cell mass and glycemic control in adulthood; however, the mechanism has not been clearly clarified. Our published results have confirmed that mTORC1 plays an important role in funtional maturation, growth, apoptosis and compensatory proliferation of β cells. Interestingly, our preliminary data showed that transgenic mice with Raptor-deficiency in endocrine progenitors (Ngn3RapKO) gave rise to early onset diabetes at 2 weeks of age, accompanied with impaired embryonic and neonatal beta cell proliferation and abnormal expression of Ezh2. The present study will use Ngn3RapKOGFP in vivo tracing mice, and purify GFP+ cells from different time points( E17.5, P0, P4, P14 ) to perform RNA sequencing and H3K27me3 CHIP-Sequencing and identify core factors that are regulated by mTORC1-Ezh2 histone methylation using bioinformatics analysis. We will also carry out Ezh2 mechanism experiments on MIN6 / INS1 cells. We believe our study on mTORC1/Ezh2 signaling in modulating embryonic and neonatal β cell proliferation would provide novel strategies to the treatment of diabetes.

糖尿病发病的核心环节是功能性胰岛β细胞容量的下调。胚胎新生期β细胞处于增殖高峰，对成体β细胞容量建立和血糖维持至关重要；但其机制研究非常匮乏。课题组已发表的研究证实，mTORC1在β细胞成熟，生长，凋亡和代偿性增殖中起到重要作用。课题组前期研究发现，内分泌前体细胞Raptor敲除小鼠（Ngn3RapKO）出现早发糖尿病，并伴有胚胎新生期β细胞增殖下调和组蛋白甲基转移酶Ezh2异常。本研究使用Ngn3RapKOGFP示踪小鼠，纯化E17.5-P14四个时间点GFP+细胞进行RNA-Seq和H3K27me3 CHIP-Seq测序，生物信息联合分析找到Ezh2组蛋白甲基化修饰的关键因子，并在MIN6/INS1细胞上深入探讨 mTORC1/Ezh2调控机制。相信“mTORC1/Ezh2参与胚胎新生β细胞增殖”的研究，将为糖尿病治疗和胰岛再生医学提供理论基础和研发思路。

糖尿病发病的核心环节是功能性胰岛β细胞容量的下调。胚胎新生期β细胞处于增殖 高峰，对成体β细胞容量建立和血糖维持至关重要;但其机制研究非常匮乏。课题组已发 表的研究证实，mTORC1在β细胞成熟，生长，凋亡和代偿性增殖中起到重要作用。课题组 前期研究发现，内分泌前体细胞Raptor敲除小鼠(Ngn3RapKO)出现早发糖尿病，并伴有 胚胎新生期β细胞增殖下调和组蛋白甲基转移酶Ezh2异常。本研究使用Ngn3RapKOGFP示踪小鼠，纯化E17.5-P14四个时间点GFP+细胞进行RNA-Seq和H3K27me3 CHIP-Seq测序，生物信息联合分析找到Ezh2组蛋白甲基化修饰的关键因子，并在MIN6/INS1细胞上深入探讨 mT ORC1/Ezh2调控机制。相信“mTORC1/Ezh2参与胚胎新生β细胞增殖”的研究，将为糖尿病治疗和胰岛再生医学提供理论基础和研发思路。