Cell Biology; Genetics; Gynecology; RNA Processing, Post-Transcriptional; Stem Cells; Embryonic Stem Cells; Argonaute Proteins
Small RNAs in Development
Stem Cell Center, Yale: Stem Cell Genetics | Stem Cell Self-Renewal and Cell Symmetry | Transcriptional Regulation of Stem and Progenitor Cells
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.
Specialized Terms: Stem cell RNA-mediated epigenetic programming, post-transcriptional regulation
- Peng, J. C.*, Anton Valouev, A.*, Liu, N., and Lin, H. (2016) Piwi maintains germline stem cells and oogenesis in Drosophila through negative regulation of Polycomb Group proteins. Nature Genetics 48, 283-291. (online: DOI 10.1038/ng.3486)
- Ku, H.-Y., Gangaraju, V. K., Qi, H., Liu, N., and Lin, H. (2016) Tudor-SN interacts with Piwi antagonistically in regulating spermatogenesis but synergistically in silencing transposons in Drosophila. PLoS Genetics, doi.org/10.1371/journal.pgen.1005813.
- Wang, Z., Liu, N., Shi, S., Liu, S. and Lin, H. (2016) The Role of PIWIL4, an Argonaute family protein, in breast cancer. J. Biol. Chem. 291, 10646–10658.
- Mak, W., Fang, C., Holden, T., Bockhur Dratver, M., and Lin, H. (2106) An important role of Pumilio 1 in regulating the development of the mammalian female germline. Biology of Reproduction (advanced online publication: biolreprod.115.137497).
- Chen, M., Lin, H., and Zhao, H. (2016) Change point analysis of histone modifications reveals epigenetic blocks with distinct regulatory activity and biological functions. The Annals of Applied Statistics 10, 506–526.
- Gonzales, J. Qi, H., Liu, N. and Lin, H. (2015) Piwi is a key regulator of both somatic and germline stem cells in the Drosophila testis. Cell Reports 12: 150–161.
- Ge, X. Q., Cheng, E.-C., Yamaguchi, S., Shima, N., and Lin, H. (2015) Embryonic stem cells license more dormant origins to protect the genome against replicative stress and to ensure robust embryogenesis. Stem Cell Reports 5:185–194.
- Watanabe, T., Cheng, E.-C., Zhong, M. Lin. H. (2015) Retrotransposons and pseudogenes regulate mRNAs and lncRNAs via the piRNA pathway in the germline. Genome Research 25: 368-380.
- Lin, H., Chen, M., Kundaje, A., Valouev, A.,,Yin, H., Liu, N., Neuenkirchen,N., Zhong, M., and Snyder, M. (2015) Reassessment of Piwi Binding to the Genome and Piwi Impact on RNA Polymerase II Distribution. Developmental Cell 32, 772–774.
- Ge, X. and Lin, H. (2014) Noncoding RNAs in the regulation of DNA replication. Trends in Biochemical Sciences 39, 341-343.
- Lin, H. (2014) The ever-expanding RNA world. National Science Review 1, 182.
- Ku, H.Y. and Lin, H. (2014) PIWI Proteins and Their interactors in piRNA biogenesis, germline development and gene expression. National Science Review 1, 205-218.
- Ross, R., J., Weiner, M. M., and Lin, H. (2014) PIWI Proteins and piRNAs in the Soma. Nature 505, 353-359
- Juliano, C. E., Reich, A., Liu, N., Uman, S., Wessel, G., W., Steele, R. E., and Lin, H. (2014) Analysis of the PIWI-piRNA pathway in Hydra somatic stem cells. PNAS 111, 337-342..
- Mani, S. R, Megosh, H and Lin, H. (2013) PIWI proteins are essential for early Drosophila embryogenesis. Developmental Biology 385, 340-349.
- Chang, E. and Lin, H. (2013) Repressing the repressor: a role of a lincRNA in embryonic stem cell self-renewal. Developmental Cell 25:1-2.
- Saxe, J. P., Chen, M., Zhao, H., and Lin, H. (2013) Tdrkh is essential for spermatogenesis and participates in primary piRNA biogenesis in the germline. EMBO J. 32, 1869-1885.
- 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 24 :502-516.
- 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.
- Nolde, M.J., Cheng E.-C., Guo, S., Lin, H. (2013) Piwi genes are dispensable for normal hematopoiesis in mice. PLoS ONE 8: e71950. doi:10.1371/ journal. pone.0071950.
- Peng, J. and Lin, H. (2013) Beyond Transposons: the Epigenetic and Somatic Functions of the Piwi-piRNA Mechanism. Current Opinion in Cell Biology 25, 190–194.
- Yin, H., Lin, H. (2013) Small RNA Discovery and Expression Analysis by High throughput Sequencing. In Genomic analysis using high-throughput sequencing (eds. Snyder, M. et al.) Cold Spring Harbor Laboratory Press. pp1-12.