Our goal is to learn how the self-renewing ability of stem cells is achieved?a question central to the understanding of tissue development, maintenance, and repair, with profound implications in regenerative medicine and cancer treatment. Our strategy is to use Drosophila as a model to address this question, and to extend what we learn from Drosophila to mammalian and clinical settings. We previously identified germline stem cells (GSCs) in Drosophila and revealed the self-renewing pattern of their divisions. We then discovered key genes that define inter- and intracellular mechanisms of stem cell division, and demonstrated the essential role of intercellular signaling in GSC maintenance. This has led to the development of the current stem cell niche theory. Moreover, our studies of the piwi (a.k.a., argonaute) family genes, the only known family of genes with stem cell function highly conserved in both animal and plant kingdoms, start to link epigenetic regulation to stem cell function. Our focus will be on how epigenetic mechanisms dictate stem cell fate. We will investigate what regulates changes of chromatin organization and activity to generate the unique gene expression profile of the genome that defines stem cell fate. Specifically, we are in a unique position to study epigenetic program-ing mediated by PIWI family proteins and small RNAs?an exciting new frontier of stem cell research. Our working hypothesis is that PIWI controls stem cell fate by regulating the transcriptional activity of the chromatin via heterochromatin protein 1 (HP1) and small RNA-mediated processes. This regulation can occur in stem cells or niche cells. To test and to further develop this hypothesis, we propose to: 1. Test the fundamental hypothesis that epigenetic programming determines stem cell fate. 2. Define and characterize the functional domains of PIWI. 3. Identify PlWI-interacting proteins and characterize their potential epigenetic function in the stem/niche cell genomes. 4. Identify the small RNA targets of PIWI and characterize their function in the epigenetic regulation of stem and niche cell genomes.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Special Emphasis Panel (ZRG1-EMNR-H (03))
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Ravindranath, Neelakanta
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Yale University
Anatomy/Cell Biology
Schools of Medicine
New Haven
United States
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Ge, Xin Quan; Han, Jinah; Cheng, Ee-Chun et al. (2015) Embryonic Stem Cells License a High Level of Dormant Origins to Protect the Genome against Replication Stress. Stem Cell Reports 5:185-94
Mani, Sneha Ramesh; Megosh, Heather; Lin, Haifan (2014) PIWI proteins are essential for early Drosophila embryogenesis. Dev Biol 385:340-9
Huang, Xiao Albert; Lin, Haifan (2012) The miRNA Regulation of Stem Cells. Wiley Interdiscip Rev Membr Transp Signal 1:83-95
Huang, Xiao Albert; Lin, Haifan (2012) The microRNA regulation of stem cells. Wiley Interdiscip Rev Dev Biol 1:83-95
Liu, Li; Qi, Hongying; Wang, Jianquan et al. (2011) PAPI, a novel TUDOR-domain protein, complexes with AGO3, ME31B and TRAL in the nuage to silence transposition. Development 138:1863-73
Gangaraju, Vamsi K; Yin, Hang; Weiner, Molly M et al. (2011) Drosophila Piwi functions in Hsp90-mediated suppression of phenotypic variation. Nat Genet 43:153-8
Juliano, Celina; Wang, Jianquan; Lin, Haifan (2011) Uniting germline and stem cells: the function of Piwi proteins and the piRNA pathway in diverse organisms. Annu Rev Genet 45:447-69
Qi, Hongying; Watanabe, Toshiaki; Ku, Hsueh-Yen et al. (2011) The Yb body, a major site for Piwi-associated RNA biogenesis and a gateway for Piwi expression and transport to the nucleus in somatic cells. J Biol Chem 286:3789-97
Yin, Hang; Sweeney, Sarah; Raha, Debasish et al. (2011) A high-resolution whole-genome map of key chromatin modifications in the adult Drosophila melanogaster. PLoS Genet 7:e1002380
Smulders-Srinivasan, Tora K; Szakmary, Akos; Lin, Haifan (2010) A Drosophila chromatin factor interacts with the Piwi-interacting RNA mechanism in niche cells to regulate germline stem cell self-renewal. Genetics 186:573-83

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