Epigenetic Regulation of Germ Cell Differentiation from a Stem Cell Lineage

调节未分化前体细胞分化的机制在 发育、成体组织维持和配子发生。前体生殖细胞必须致力于 在正确的位置和正确的时机进行区分，以生成/维护功能配子池。 维持未分化和增殖状态的前体生殖细胞和 随后逆转这些控制以允许末端分化对于连续 一生中配子的产生。我正在利用果蝇雄性生殖系细胞的分化 从成体干细胞谱系作为模型系统来研究表观遗传控制细胞类型的作用 特定的转录程序。我发现发育程序化的表情和动作 睾丸特异性TAP(TBP相关因子)同系物负责精子细胞的表达 通过中和多梳转录抑制子来分化基因。我现在提议调查 多梳基团(PcG)机制和表观遗传染色质修饰的作用和调控 前体生殖细胞增殖与终末分化。这些研究对以下方面具有重要意义 生殖生物学，因为越来越多的证据表明， 苍蝇和哺乳动物之间的精子发生。此外，不受控制的扩散以牺牲 分化导致癌症，而PcG蛋白与这两种前体细胞的命运有关 和肿瘤发生，例如，在哺乳动物的造血细胞中。因此，我的研究也将有助于 癌症进展和治疗的分子机制。我未来的工作将结合使用 分子、遗传和生化策略探索戏剧性疾病的分子机制 表观遗传开关，通过一组共价修饰的组蛋白的水平和/或定位的变化来可视化 和染色质修饰剂在精子发生过程中前体向分化的转变。 我的直接职业目标是在学术环境中获得一个终身教职的职位 我的博士后培训。我的最终研究计划是理解关于 在雄性生殖细胞发育过程中调节增殖和细胞分化的机制。我 我致力于生物医学的研究，并致力于未来科学家的教育。

The mechanisms that regulate differentiation of cells from undifferentiated precursors play key roles in development, adult tissue maintenance and gametogenesis. Precursor germ cells must commit to differentiate at the right place and with the right timing to generate/maintain the pools of functional gametes. The maintenance of the precursor germ cells in an undifferentiated and proliferative state and the subsequent reversal of these controls to allow terminal differentiation are both critical to continuous production of gametes throughout lifetime. I am using the differentiation of Drosophila male germline cells from an adult stem cell lineage as a model system to investigate the roles of epigenetic control of cell-type specific transcription programs. I discovered that developmentally programmed expression and action of testis specific TAP (TBP-associated factors) homologs are responsible for expression of spermatid differentiation genes by counteracting the Polycomb transcription represser. I now propose to investigate the roles and regulation of Polycomb group (PcG) machinery and epigenetic chromatin modifications in precursor germ cell proliferation vs. terminal differentiation. These studies have significant implications for reproductive biology, since the increasing evidence demonstrates conserved mechanisms that regulate spermatogenesis between flies and mammals. In addition, uncontrolled proliferation at the expense of differentiation leads to cancer, and PcG proteins have been implicated in both precursor cell fate and tumorigenesis, for example, in mammalian hematopoietic cells. Thus my studies will also shed light on the molecular mechanisms of cancer progression and treatment. My future work will use a combination of molecular, genetic and biochemical strategies to explore the molecular mechanisms underlying a dramatic epigenetic switch, visualized by changes in level and/or localization of a set of covalently modified histones and chromatin modifiers at the precursor-to-differentiation transition during spermatogenesis. My immediate career goal is to obtain a tenure-track faculty position in an academic environment after my postdoctoral training. My ultimate research plan is to understand fundamental biological questions about the mechanisms that regulate proliferation vs. cellular differentiation during male germ cell development. I am committed to the research in biomedical science, and to the education of future scientists.