蛋白精氨酸N端甲基化转移酶5（PRMT5）在胚胎干细胞、多种成体干细胞以及肿瘤干细胞中扮演促进角色，然而PRMT5在乳腺正常干细胞和肿瘤干细胞的功能缺乏研究。我们前期研究发现转录因子KLF5参与维持小鼠乳腺正常干细胞和人乳腺癌干细胞，PRMT5可以增加KLF5蛋白的稳定性并且促进其下游基因表达。我们假设PRMT5通过甲基化修饰KLF5,促进KLF5蛋白稳定，从而促进乳腺细胞干性和增殖生存。我们在本项目中将首先明确PRMT5是否通过甲基化KLF5增加KLF5蛋白表达，然后解析PRMT5是否通过稳定KLF5促进乳腺细胞干性和增殖生存，最后构建乳腺组织特异性Prmt5敲除小鼠阐明Prmt5是否在动物体内促进Klf5表达以及乳腺干细胞和乳腺发育。完成本项目将帮助我们理解Prmt5在乳腺干细胞中的功能和作用机制，解析它在乳腺发育中的角色，阐明KLF5甲基化修饰调控机制，为乳腺癌防治奠定基础。

Protein arginine N-methyltransferase 5 (PRMT5) promotes self-renewal of embryonic stem cells, adult tissue stem cells and cancer stem cells. However, the roles of PRMT5 in mammary gland normal stem cells and breast cancer stem cells have not been explored. Our previous studies suggest that KLF5 transcription factor promotes self-renewal of mammary gland normal stem cells and breast cancer stem cells. PRMT5 increases the expression of KLF5 and its downstream target genes in breast epithelial cells. We hypothesize that PRMT5 is an arginine methyltransferase for KLF5 and can stabilize KLF5 to promote self-renewal, proliferation and survival of mammary gland normal stem cells and breast cancer stem cells. We will first determine if PRMT5 stabilizes KLF5 through protein methylation. Following that, we will test if PRMT5 promotes breast epithelial cell stemness, proliferation and survival through KLF5. Finally, we will generate a breast specific Prmt5 knockout mouse model to study the roles of Prmt5 in mouse mammary gland development and stem cells. Completion of this project will not only reveal the function and action mechanism of PRMT5 in breast stem cells and development but also build foundation for breast cancer prevention and treatment.