Title: Study epigenetic inheritance during development and across generations using multiple model organisms 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 histone 3 (H3) are selectively segregated to the GSC whereas newly synthesized H3 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. These unprecedented discoveries have placed us at a unique position to solve a long-standing question regarding whether and how cells maintain their epigenetic memories through many cell divisions and across generations, which have become our major research focuses. Our current work has three main directions: (1) to understand the molecular mechanisms and cellular basis of asymmetric histone inheritance using Drosophila male GSC as a model system; (2) to investigate the generality of asymmetric epigenetic inheritance in other cell types of Drosophila and in other organisms/systems, such as C.elegans and mouse embryonic stem cells; (3) to study intergenerational and transgenerational epigenetic inheritance in C.elegans and Drosophila. We propose to use molecular genetics, cell biology, genomic, and biophysical approaches in our research, which will have far-reaching impact on a broad range of fields, including stem cell biology, chromatin biology, developmental biology, and reproductive biology.