Study epigenetic inheritance during development, homeostasis and regeneration

Project Summary/Abstract: Epigenetics refers to effects on gene expression or function that are inheritable through mitosis or meiosis without altering the primary DNA sequences. Epigenetic mechanisms play important roles in regulating cell identity and activity. Failure in appropriate epigenetic regulation leads to abnormal behaviors of cells, which underlies many diseases such as diabetes, muscular dystrophy, neurodegenerative disease, infertility, and many forms of cancer. Many types of stem cells undergo asymmetric cell divisions to give rise to two daughter cells with distinct cell fates: a self-renewed stem cell and to another daughter cell that differentiates. We found that during the asymmetric division of Drosophila male germline stem cell (GSC), the preexisting histones are selectively segregated to the GSC whereas newly synthesized histones are enriched in the differentiating daughter cell. Our studies provide the first direct evidence that stem cells retain preexisting histones during asymmetric cell divisions in vivo, which may contribute to maintain their unique epigenetic memory. In this proposal, we plan to: (1) explore what mechanisms control asymmetric versus symmetric histone incorporation in Drosophila male germline; (2) study asymmetric histone inheritance and its biological functions in Drosophila neuroblast and intestinal stem cell systems; (3) develop a new method to identify genetic locus with epigenetic signature. We anticipate that our studies will lead to (1) a series of findings to resolve fundamental questions in biology and yield new insights in explaining cell fate determination in multicellular organisms, (2) the development of new tools that will benefit the broader scientific community, and (3) insight on therapeutic strategies against various diseases, such as degenerative disease and many forms of cancer, due to mis-regulated cell fate determination.