CtBP-HDAC3/P300介导蜕皮激素-E93引发细胞凋亡的表观调控机制

组蛋白修饰调节细胞分裂、分化和凋亡，在机体生长发育和疾病发生中至关重要。在昆虫变态和组织重塑过程中，蜕皮激素20E诱导转录因子E93的表达而引发细胞凋亡；哺乳动物中CtBP招募组蛋白去乙酰化酶抑制肿瘤细胞的凋亡；但两者之间有无关联尚不清楚。申请人等前期发现：在预蛹-蛹转变时，唾液腺和脂肪体组织发生重塑，20E诱发E93表达和细胞凋亡；大规模RNAi筛选显示，CtBP和组蛋白去乙酰化酶HDAC3功能丧失导致该过程提前；而组蛋白乙酰转移酶P300作用相反。据此，将利用果蝇遗传学和生化分子等方法，以组织重塑中发生细胞凋亡的唾液腺和脂肪体解析乙酰化/去乙酰化修饰调节E93时期特异表达而引发细胞凋亡的分子机制；同时以组织重塑中不发生细胞凋亡的翅芽探究细胞抗凋亡的分子机制。本项目不仅可以拓展激素信号时空特异性地诱导组织重塑和细胞凋亡的表观调控机制，还可为高等动物疾病发生的相关研究提供借鉴和参考。

Histone modification participates in the regulation of cell division, differentiation, apoptosis, and etc., which are crucial for developmental progression and disease occurrence in organisms. During insect metamorphosis and tissue remolding, 20E (20-hydroxyecdsone) induces the expression of transcription factor E93 to trigger cell apoptosis. Meanwhile, CtBP (C-terminal binding protein) recruits histone deacetylase to suppress apoptosis of tumor cells in mammals. However, it is unknown whether there is any a correlation between these two events. Through large-scale RNAi screening during tissue remolding of the salivary gland and fat body in Drosophila, the applicant found that loss-of-function of both CtBP and HDAC3 (histone deacetylase 3) led to premature apoptosis, while loss-of-function of P300 (a histone acetyltransferase) blocked apoptosis. Therefore, in this project, we aim to solve two objectives using Drosophila genetics and molecular methods. First, to analyze how histone acetylation/deacetylation participates in the stage-specific regulation of 20E-E93 action, which subsequently triggers apoptosis in the salivary gland and fat body. Second, to explore the molecular mechanism how histone modification is involved in anti-apoptosis in the wing disc that does not undergo apoptosis during metamorphosis and tissue remodeling. This project will not only expand the epigenetic regulatory mechanism of spatiotemporal-specific hormone-induced apoptosis during tissue remodeling, but also provide references and guidance for related disease studies in higher animals.