Epigenetic Regulation of Germ Cell Differentiation from a Stem Cell Lineage

Stanford University, Stanford CA

Investigators

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Abstract

[unreadable] DESCRIPTION (provided by applicant): 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 or 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. The candidate is 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. She 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 repressor. She now proposes to investigate the roles and regulation of Polycomb group (PcG) machinery and epigenetic chromatin modifications in precursor germ cell proliferation versus 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 the studies will also shed light on the molecular mechanisms of cancer progression and treatment. The candidate's 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. [unreadable] [unreadable] The candidate's immediate career goal is to obtain a tenure-track faculty position in an academic environment after her postdoctoral training. Her ultimate research plan is to understand fundamental biological questions about the mechanisms that regulate proliferation versus cellular differentiation during male germ cell development. The candidate is committed to the research in biomedical science, and to the education of future scientists. [unreadable] [unreadable] [unreadable]