Epigenetic Regulation of Germ Cell Differentiation from a Stem Cell Lineage

标题：干细胞谱系中生殖细胞分化的表观遗传调控 项目总结： 许多人类疾病是由自我更新/增殖和 成体干细胞的分化。因此，确定分子和细胞机制是至关重要的。 调节干细胞功能，以了解癌症和组织退化等疾病。另外， 要在治疗应用中利用干细胞，关键是要了解维持干细胞的机制。 细胞，调节祖细胞的适当增殖，并计划干细胞谱系中的细胞分化。 以干细胞为基础的再生医学也有望治疗癌症、神经变性、 肌肉营养不良、糖尿病和不孕不育。 表观遗传机制的广义定义是指改变基因的DNA相关因子 在不改变原始DNA序列的情况下进行表达。表观遗传机制在定义 干细胞识别和调节干细胞活动。在已知的表观遗传调控因子中，Polycomb组 (PCG)转录抑制蛋白在不同的干细胞谱系中具有关键功能 从果蝇到哺乳动物的物种。除了它们在沉默基因中所具有功能之外 除了表达，许多实验室的研究表明PcG在DNA复制和细胞等领域还发挥着其他作用 循环递增。 我的实验室使用果蝇雄性生殖系干细胞(GSC)谱系作为模型系统来研究 表观遗传机制如何调控干细胞的维持、增殖、分化和去分化。 我们之前的研究揭示了在GSC谱系中调节多个事件的表观遗传学机制 包括GSC的维持和生殖细胞的分化。我们最近的工作揭示了被低估的功能 DNA复制和可能的新角色的表观遗传调节，如Polycomb(Pc)。我们建议 使用分子遗传学、细胞生物学、生物物理学和生物物理学中成熟和新开发的方法 基因组学为关键的表观遗传学参与者如何调控干细胞提供深入和系统的了解 在活体内。成功完成拟议的研究将对干细胞生物学、生殖细胞产生广泛影响 生物学、DNA复制、染色质生物学、癌症生物学、生殖生物学和再生医学。

Title: Epigenetic Regulation of Germ Cell Differentiation from a Stem Cell Lineage Project Summary: Many human diseases are caused by imbalances between self-renewal/proliferation versus differentiation of adult stem cells. Therefore, it is critical to characterize the molecular and cellular mechanisms that regulate stem cell function to understand the diseases such as cancers and tissue degeneration. Additionally, to utilize stem cells in therapeutic applications, it is critical to understand the mechanisms that maintain stem cells, regulate proper proliferation of progenitor cells and program cellular differentiation in stem cell lineages. Stem cell-based regenerative medicine also holds promise for diseases such as cancers, neurodegeneration, muscle dystrophy, diabetes, and infertility. A broad definition of epigenetic mechanisms refers to DNA-associated factors that change gene expression without altering the primary DNA sequences. Epigenetic mechanisms play crucial roles in defining stem cell identity and regulating stem cell activity. Among known epigenetic regulators, the Polycomb group (PcG) transcriptional repressive proteins have critical functions in multiple stem cell lineages across different species from Drosophila to mammals. In addition to their well-characterized functions in silencing gene expression, studies from many labs have shown other roles of PcG in areas such as DNA replication and cell cycle progression. My lab uses the Drosophila male germline stem cell (GSC) lineage as a model system to investigate how epigenetic mechanisms regulate stem cell maintenance, proliferation, differentiation, and dedifferentiation. Our previous studies have shed light on epigenetic mechanisms in regulating multiple events in GSC lineage including GSC maintenance and germ cell differentiation. Our recent work reveals under-appreciated functions of DNA replication and potentially new roles of epigenetic regulators such as Polycomb (Pc). We propose to use well-established and newly developed methods in molecular genetics, cell biology, biophysics and genomics to provide an in-depth and systematic understanding of how key epigenetic players regulate stem cells in vivo. Successful completion of the proposed studies will have a broad impact on stem cell biology, germ cell biology, DNA replication, chromatin biology, cancer biology, reproductive biology, and regenerative medicine.