Proper differentiation of adult stem cells is crucial for maintaining tissue homeostasis, repairing tissue damage, and preventing oncogenesis. During adult stem cell differentiation, the transition from proliferation to terminal differentiation is akey step because it makes an irreversible commitment toward terminal cell fate and is marked by dramatic changes in gene expression. The proposed project uses the process of germ line stem cell differentiation in male Drosophila as a model system to investigate the key mechanisms that regulate the stepwise changes in chromatin and transcription that drive the transition from proliferating spermatogonia to terminal differentiation in spermatocytes. The project aims to understand how chromatin dynamics, cell- type specific master transcriptional activators tTAFs and tMAC, and a newly discovered transcriptional repressor tZnF act together to turn on the correct transcription program for terminal differentiation. Specifically, the proposed project will investigate whether and how the change in expression of terminal differentiation genes during this transition is accompanied by dynamic changes in compaction of chromatin regions and recruitment of stalled RNA polymerase II preceding transcription. The chromatin dynamic data will also facilitate the search for transcription factors that regulate the expression of genes tha encode the master regulators tTAFs, tMAC components and tZnF. Lastly, hypotheses will be tested to understand how tZnF selectively inhibits a sub group of tMAC-dependent target genes to enforce lineage-specific gene expression. These results will provide a more detailed picture of the transition from proliferation to terminal differentiation, and provide insights on how key regulatory components collaborate to achieve proper initiation of terminal differentiation in adult stem cell lineages.
The proposed project aims to understand the mechanisms that regulate the onset of terminal differentiation in male germ line stem cell lineage, which is a model system that has generated many insights on general principles of adult stem cell differentiation. Understanding how proper differentiation is regulated and achieved in adult stem cell lineages forms the foundation for regenerative medicine. Such understanding may also shed light on what goes wrong in diseases where proliferating progenitor cells fail to commit to proper terminal differentiation, such as certain types of male infertility or cancer.
