Haifan Lin PhD
Professor of Cell Biology and of Genetics; Director, Yale Stem Cell Center
Research Interests
RNA-mediated epigenetic programming and post-transcriptional regulation of stem cells
Research Summary
We study molecular mechanisms underlying the self-renewing division of stem cells. Currently, we focus on small RNA-mediated epigenetic programming and translational regulation that are required for the self-renewal of germline and embryonic stem cells. Meanwhile, we are exploring the clinical implications of our findings. Stem cells are characterized by their abilities to self-renew and to produce numerous differentiated daughter cells. These two special properties enable stem cells to play a central role in generating and maintaining most tissues in higher organisms. Over-proliferation of stem cells can cause cancer, whereas under-proliferation of stem cells leads to tissue dystrophy, anemia, immuno-deficiency, or infertility. Drosophila and the mouse represent two powerful systems for studying stem cells since they allow easy access to combined genetic, cell biological, and molecular analyses. We use Drosophila as a pilot model to explore molecular mechanisms underlying stem cell division, and the mouse as an advanced model to expand what we learn from Drosophila to mammalian and human systems. Previously, we identified germline stem cells in the Drosophila ovary and revealed their self-renewing asymmetric division. We and others showed that the asymmetric division of these stem cells is controlled by both niche signaling and intracellular mechanisms. Using systematic genetic screens, we have identified key genes involved in both niche signaling and intracellular regulation of stem cell division. Among them, piwi/argonaute genes represent the only known family of genes required for stem cell self-renewal in both animal and plant kingdoms. Currently, our research is focused on epigenetic programming and translational regulation of germline stem cell self-renewal mediated by the Piwi/Argonaute proteins and a novel class of non-coding small RNAs called piwi-Interacting RNAs (piRNAs) that we and others recently discovered. Meanwhile, we have begun to explore the role of these mechanisms in human embryonic stem cell division and oncogenesis.
Selected Publications
- Huang, X. A. *, Yin*, H., Sweeney, S., Raha, D., Snyder, M. and Lin, H. (2013) A major epigenetic programming mechanism guided by piRNAs. Developmental Cell (in press, *co-first authors)
- Darricarrère, N., Liu, N., Watanabe, T., and Lin, H. (2013) The function of Piwi, a nuclear Piwi/Argonaute protein, is independent of its slicer activity, PNAS 110:1297-1302.
- Chen, D., Zheng, W. Lin, A., Uyhazi, K., Zhao, H., and Lin, H.. (2012) Pumilio 1 Suppresses Multiple Activators of p53 to Safeguard Spermatogenesis. Current Biology 22, 420-425.
- Qi, H., Watanabe, T., Ku, H.-Y., Liu, N., Zhong, M., and Lin, H. (2011) The Yb body, a major site for piRNA biogenesis and a gateway for Piwi expression and transport to the nucleus in somatic cells. J. Biol. Chem. 286, 3789-97.
- Watanabe, T., Chuma, S., Yamamoto, Y., Kuramochi-Miyagawa, S., Totoki, Y., Toyoda, A., Hoki, Y., Fujiyama, A., Shibata, T., Sado, T., Noce, T., Nakano, T., Nakatsuji, N., Lin, H. and Sasaki, H. (2011) MitoPLD Is a mitochondrial protein essential for nuage formation and piRNA biogenesis in the mouse germline. Developmental Cell 20, 364-375.
- Liu, L., Qi, H., Wang, J., and Lin, H. (2011) PAPI, a Novel TUDOR-domain protein, complexes with AGO3, ME31B and TRAL in the nuage to silence transposition Development 138, 1863-1873.
- Beyret, E. and Lin, H. (2011) Pinpointing the expression of piRNAs and function of the PIWI protein subfamily during spermatogenesis in the mouse. Dev. Biol. 355, 215-226.
- Hang Yin, H., Sweeney, S., Raha, D., Snyder, M., and Lin, H. (2011) A high-resolution whole-genome map of key chromatin modifications in the adult Drosophila melanogaster. PLoS Genetics 7(12): e1002380. doi:10.1371/journal.pgen.1002380.
- Gangaraju, V. K., Yin, H., Weiner, M. M., Wang, J., Huang, A. X., and Lin, H. (2010) Drosophila Piwi Functions in Hsp90-Mediated Suppression of Phenotypic Variation. Nature Genetics 43, 153-158.
- Wang, J., Saxe, J. P., Tanaka, T., Chuma, S., and Lin, H. (2009) Mili interacts with Tudor Domain Containing Protein 1 (Tdrd1) in regulating spermatogenesis. Curr. Biol. 19:640 - 644 (Cover story).
Selected Publications
- Huang, X. A. *, Yin*, H., Sweeney, S., Raha, D., Snyder, M. and Lin, H. (2013) A major epigenetic programming mechanism guided by piRNAs. Developmental Cell (in press, *co-first authors)
- Darricarrère, N., Liu, N., Watanabe, T., and Lin, H. (2013) The function of Piwi, a nuclear Piwi/Argonaute protein, is independent of its slicer activity, PNAS 110:1297-1302.
- Chen, D., Zheng, W. Lin, A., Uyhazi, K., Zhao, H., and Lin, H.. (2012) Pumilio 1 Suppresses Multiple Activators of p53 to Safeguard Spermatogenesis. Current Biology 22, 420-425.
- Qi, H., Watanabe, T., Ku, H.-Y., Liu, N., Zhong, M., and Lin, H. (2011) The Yb body, a major site for piRNA biogenesis and a gateway for Piwi expression and transport to the nucleus in somatic cells. J. Biol. Chem. 286, 3789-97.
- Watanabe, T., Chuma, S., Yamamoto, Y., Kuramochi-Miyagawa, S., Totoki, Y., Toyoda, A., Hoki, Y., Fujiyama, A., Shibata, T., Sado, T., Noce, T., Nakano, T., Nakatsuji, N., Lin, H. and Sasaki, H. (2011) MitoPLD Is a mitochondrial protein essential for nuage formation and piRNA biogenesis in the mouse germline. Developmental Cell 20, 364-375.
- Liu, L., Qi, H., Wang, J., and Lin, H. (2011) PAPI, a Novel TUDOR-domain protein, complexes with AGO3, ME31B and TRAL in the nuage to silence transposition Development 138, 1863-1873.
- Beyret, E. and Lin, H. (2011) Pinpointing the expression of piRNAs and function of the PIWI protein subfamily during spermatogenesis in the mouse. Dev. Biol. 355, 215-226.
- Hang Yin, H., Sweeney, S., Raha, D., Snyder, M., and Lin, H. (2011) A high-resolution whole-genome map of key chromatin modifications in the adult Drosophila melanogaster. PLoS Genetics 7(12): e1002380. doi:10.1371/journal.pgen.1002380.
- Gangaraju, V. K., Yin, H., Weiner, M. M., Wang, J., Huang, A. X., and Lin, H. (2010) Drosophila Piwi Functions in Hsp90-Mediated Suppression of Phenotypic Variation. Nature Genetics 43, 153-158.
- Wang, J., Saxe, J. P., Tanaka, T., Chuma, S., and Lin, H. (2009) Mili interacts with Tudor Domain Containing Protein 1 (Tdrd1) in regulating spermatogenesis. Curr. Biol. 19:640 - 644 (Cover story).
- Brower-Toland, B*., Findley, S.*, Jiang, L., Liu, L., Dus, M., Zhou, P., Elgin, S., and Lin, H. (2007) Drosophila PIWI Associates with Chromatin and Interacts Directly with HP1a. Genes & Development 21: 2300-2311 (Cover story; * co-first authors)
- Yin, H. and Lin, H. (2007) An epigenetic activation role of PIWI and a PIWI-associated piRNA in Drosophila melanogaster. Nature 450, 304-308.
- Lin, H. (2007). piRNA in the germline. Science 316:397.
- Grivna, S. T. *, Beyret, E. *, Wang, Z. and Lin, H. (2006) A novel class of small RNAs in mouse spermatogenic cells. Genes & Development (Advanced online publication: June 9, 2006, 10.1101/gad.1434406. *co-first authors)
- Grivna, S. T., Pyhtila, B. and Lin, H. (2006) MIWI associates with translational machinery and PIWI-interacting RNAs (piRNAs) in regulating spermatogenesis. Proc. Natl. Acad. Sci. 103, 13415-13420. Early online: 10.1073/pnas.0605506103.
