Epigenetic Regulation of Germ Cell Differentiation from a Stem Cell Lineage

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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.