Study the generality of asymmetric histone inheritance

Johns Hopkins University, Baltimore MD

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Abstract

? DESCRIPTION (provided by applicant): Study the generality of asymmetric histone inheritance Project Summary: Epigenetic phenomena are heritable changes in gene expression or function through cell divisions without altering primary DNA sequences. Importantly, it is the epigenetic information that directs cells with identical genomes to become distinct cell types in multicellular organisms, including humans. Stem cells are unique in their abilities to both self-renew and give rise to a variety of differentiated cell types. Mis-determination of stem cell fate and malfunction of stem cell derivatives are common causes of many human diseases. However, a long-standing question has been how stem cells retain their epigenetic memory throughout many cell divisions, and, does the loss of proper stem cell epigenetic information lead to diseases? Many types of stem cells undergo asymmetric cell divisions to give rise to daughter cells with distinct cell fates: one that retains stem cell identity and another that differentiates. Recently, we found that during the asymmetric division of Drosophila male germline stem cell (GSC), the preexisting histone 3 (H3) is selectively segregated to the GSC whereas newly synthesized H3 is enriched in the differentiating daughter cell. Since post-translational modification of histones is a key component of epigenetic information, our studies provide the first direct evidence suggesting that stem cells may selectively retain preexisting histones that define its stem cell identity. We are now at a unique position to explore the generality of this intriguing phenomenon to investigate whether it applies to other histones, other adult stem cells, and in other species. These studies will allow us to understand whether this is a general mechanism for cells to have distinct fates during development and homeostasis, which will provide an unprecedented foundation to explore the biological significance and human health relevance of epigenetic regulation.