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
- Post-transcriptional regulation of mouse neurogenesis by Pumilio proteins. Zhang, M., Chen, D., Xia, J., Han, W., Hermes, G., Sestan, S., and Lin, H. (2017) Genes & Development 31,1-16.
Piwi maintains germline stem cells and oogenesis in Drosophila through negative regulation of Polycomb Group proteins.
Peng, J. C.*, Anton Valouev, A.*, Liu, N., and Lin, H. (2016). Nature Genetics 48, 283-291. (online: DOI 10.1038/ng.3486)
Tudor-SN interacts with Piwi antagonistically in regulating spermatogenesis but synergistically in silencing transposons in Drosophila.
Ku, H.-Y., Gangaraju, V. K., Qi, H., Liu, N., and Lin, H. (2016) PLoS Genetics, doi.org/10.1371/journal.pgen.1005813.
The Role of PIWIL4, an Argonaute family protein, in breast cancer.
Wang, Z., Liu, N., Shi, S., Liu, S. and Lin, H. (2016). J. Biol. Chem. 291, 10646–10658.
An important role of Pumilio 1 in regulating the development of the mammalian female germline.
Mak, W., Fang, C., Holden, T., Bockhur Dratver, M., and Lin, H. (2016) Biology of Reproduction (advanced online publication: biolreprod.115.137497).
Change point analysis of histone modifications reveals epigenetic blocks with distinct regulatory activity and biological functions
Chen, M., Lin, H., and Zhao, H. (2016) The Annals of Applied Statistics 10, 506–526.
Piwi is a key regulator of both somatic and germline stem cells in the Drosophila testis.
Gonzales, J. Qi, H., Liu, N. and Lin, H. (2015) Cell Reports 12: 150–161.
Embryonic stem cells license more dormant origins to protect the genome against replicative stress and to ensure robust embryogenesis.
Ge, X. Q., Cheng, E.-C., Yamaguchi, S., Shima, N., and Lin, H. (2015) Stem Cell Reports 5:185–194.
Retrotransposons and pseudogenes regulate mRNAs and lncRNAs via the piRNA pathway in the germline.
Watanabe, T., Cheng, E.-C., Zhong, M. Lin. H. (2015) Genome Research 25: 368-380.
Reassessment of Piwi Binding to the Genome and Piwi Impact on RNA Polymerase II Distribution.
Lin, H., Chen, M., Kundaje, A., Valouev, A.,,Yin, H., Liu, N., Neuenkirchen,N., Zhong, M., and Snyder, M. (2015) Developmental Cell 32, 772–774.
Noncoding RNAs in the regulation of DNA replication.
Ge, X. and Lin, H. (2014) Trends in Biochemical Sciences 39, 341-343.
The ever-expanding RNA world.
Lin, H. (2014) National Science Review 1, 182.
PIWI Proteins and Their interactors in piRNA biogenesis, germline development and gene expression.
Ku, H.Y. and Lin, H. (2014) National Science Review 1, 205-218.
PIWI Proteins and piRNAs in the Soma.
Ross, R., J., Weiner, M. M., and Lin, H. (2014) PIWI Proteins and piRNAs in the Soma. Nature 505, 353-359
Analysis of the PIWI-piRNA pathway in Hydra somatic stem cells.
Juliano, C. E., Reich, A., Liu, N., Uman, S., Wessel, G., W., Steele, R. E., and Lin, H. (2014) PNAS 111, 337-342..
PIWI proteins are essential for early Drosophila embryogenesis.
Mani, S. R, Megosh, H and Lin, H. (2013) Developmental Biology 385, 340-349.
Repressing the repressor: a role of a lincRNA in embryonic stem cell self-renewal.
Chang, E. and Lin, H. (2013) Developmental Cell 25:1-2.
Tdrkh is essential for spermatogenesis and participates in primary piRNA biogenesis in the germline.
Saxe, J. P., Chen, M., Zhao, H., and Lin, H. (2013) EMBO J. 32, 1869-1885.
A major epigenetic programming mechanism guided by piRNAs.
Huang, X. A., Yin, H., Sweeney, S., Raha, D., Snyder, M. and Lin, H. (2013) Developmental Cell 24 :502-516.
The function of Piwi, a nuclear Piwi/Argonaute protein, is independent of its slicer activity
Darricarrère, N., Liu, N., Watanabe, T., and Lin, H. (2013) PNAS 110:1297-1302.
Piwi genes are dispensable for normal hematopoiesis in mice.
Nolde, M.J., Cheng E.-C., Guo, S., Lin, H. (2013) PLoS ONE 8: e71950. doi:10.1371/ journal. pone.0071950.
Beyond Transposons: the Epigenetic and Somatic Functions of the Piwi-piRNA Mechanism.
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.
- Small RNA Discovery and Expression Analysis by High-throughput Sequencing. Yin, H., Lin, H. (2013) In Genomic analysis using high-throughput sequencing (eds. Snyder, M. et al.) Cold Spring Harbor Laboratory Press. pp1-12.
Full List of PubMed Publications
- Weng W, Liu N, Toiyama Y, Kusunoki M, Nagasaka T, Fujiwara T, Wei Q, Qin H, Lin H, Ma Y, Goel A: Novel evidence for a PIWI-interacting RNA (piRNA) as an oncogenic mediator of disease progression, and a potential prognostic biomarker in colorectal cancer. Mol Cancer. 2018 Jan 30; 2018 Jan 30. PMID: 29382334
- Zhang M, Chen D, Xia J, Han W, Cui X, Neuenkirchen N, Hermes G, Sestan N, Lin H: Post-transcriptional regulation of mouse neurogenesis by Pumilio proteins. Genes Dev. 2017 Aug 9; 2017 Aug 9. PMID: 28794184
- Jacobs DI, Qin Q, Lerro MC, Fu A, Dubrow R, Claus EB, DeWan AT, Wang G, Lin H, Zhu Y: PIWI-Interacting RNAs in Gliomagenesis: Evidence from Post-GWAS and Functional Analyses. Cancer Epidemiol Biomarkers Prev. 2016 Jul; 2016 May 13. PMID: 27197292
- Mak W, Fang C, Holden T, Dratver MB, Lin H: An Important Role of Pumilio 1 in Regulating the Development of the Mammalian Female Germline. Biol Reprod. 2016 Jun; 2016 May 11. PMID: 27170441
- Wang Z, Liu N, Shi S, Liu S, Lin H: The Role of PIWIL4, an Argonaute Family Protein, in Breast Cancer. J Biol Chem. 2016 May 13; 2016 Mar 8. PMID: 26957540
- Chen M, Lin H, Zhao H: CHANGE POINT ANALYSIS OF HISTONE MODIFICATIONS REVEALS EPIGENETIC BLOCKS LINKING TO PHYSICAL DOMAINS. Ann Appl Stat. 2016 Mar; 2016 Mar 25. PMID: 27231496
- Peng JC, Valouev A, Liu N, Lin H: Piwi maintains germline stem cells and oogenesis in Drosophila through negative regulation of Polycomb group proteins. Nat Genet. 2016 Mar; 2016 Jan 18. PMID: 26780607
- Ku HY, Gangaraju VK, Qi H, Liu N, Lin H: Tudor-SN Interacts with Piwi Antagonistically in Regulating Spermatogenesis but Synergistically in Silencing Transposons in Drosophila. PLoS Genet. 2016 Jan; 2016 Jan 25. PMID: 26808625
- Ge XQ, Han J, Cheng EC, Yamaguchi S, Shima N, Thomas JL, Lin H: Embryonic Stem Cells License a High Level of Dormant Origins to Protect the Genome against Replication Stress. Stem Cell Reports. 2015 Aug 11; 2015 Jul 16. PMID: 26190528
- Gonzalez J, Qi H, Liu N, Lin H: Piwi Is a Key Regulator of Both Somatic and Germline Stem Cells in the Drosophila Testis. Cell Rep. 2015 Jul 7; 2015 Jun 25. PMID: 26119740
- Lin H, Chen M, Kundaje A, Valouev A, Yin H, Liu N, Neuenkirchen N, Zhong M, Snyder M: Reassessment of Piwi binding to the genome and Piwi impact on RNA polymerase II distribution. Dev Cell. 2015 Mar 23. PMID: 25805139
- Watanabe T, Cheng EC, Zhong M, Lin H: Retrotransposons and pseudogenes regulate mRNAs and lncRNAs via the piRNA pathway in the germline. Genome Res. 2015 Mar; 2014 Dec 5. PMID: 25480952
- Watanabe T, Lin H: Posttranscriptional regulation of gene expression by Piwi proteins and piRNAs. Mol Cell. 2014 Oct 2. PMID: 25280102
- Cheng EC, Kang D, Wang Z, Lin H: PIWI proteins are dispensable for mouse somatic development and reprogramming of fibroblasts into pluripotent stem cells. PLoS One. 2014; 2014 Sep 19. PMID: 25238487
- Juliano CE, Lin H, Steele RE: Generation of transgenic Hydra by embryo microinjection. J Vis Exp. 2014 Sep 11; 2014 Sep 11. PMID: 25285460
- Ge XQ, Lin H: Noncoding RNAs in the regulation of DNA replication. Trends Biochem Sci. 2014 Aug; 2014 Jul 12. PMID: 25027733
- Lin H: Special Topic: Frontiers in RNA Research: The ever-expanding RNA world. Natl Sci Rev. 2014 Jun 1. PMID: 25520852
- Ku HY, Lin H: PIWI proteins and their interactors in piRNA biogenesis, germline development and gene expression. Natl Sci Rev. 2014 Jun. PMID: 25512877
- Ma X, Wang S, Do T, Song X, Inaba M, Nishimoto Y, Liu LP, Gao Y, Mao Y, Li H, McDowell W, Park J, Malanowski K, Peak A, Perera A, Li H, Gaudenz K, Haug J, Yamashita Y, Lin H, Ni JQ, Xie T: Piwi is required in multiple cell types to control germline stem cell lineage development in the Drosophila ovary. PLoS One. 2014; 2014 Mar 21. PMID: 24658126
- Ross RJ, Weiner MM, Lin H: PIWI proteins and PIWI-interacting RNAs in the soma. Nature. 2014 Jan 16. PMID: 24429634
- Mani SR, Megosh H, Lin H: PIWI proteins are essential for early Drosophila embryogenesis. Dev Biol. 2014 Jan 15; 2013 Oct 31. PMID: 24184635
- Juliano CE, Reich A, Liu N, Götzfried J, Zhong M, Uman S, Reenan RA, Wessel GM, Steele RE, Lin H: PIWI proteins and PIWI-interacting RNAs function in Hydra somatic stem cells. Proc Natl Acad Sci U S A. 2014 Jan 7; 2013 Dec 23. PMID: 24367095
- Nolde MJ, Cheng EC, Guo S, Lin H: Piwi genes are dispensable for normal hematopoiesis in mice. PLoS One. 2013; 2013 Aug 23. PMID: 24058407
- Saxe JP, Chen M, Zhao H, Lin H: Tdrkh is essential for spermatogenesis and participates in primary piRNA biogenesis in the germline. EMBO J. 2013 Jul 3; 2013 May 28. PMID: 23714778
- Cheng EC, Lin H: Repressing the repressor: a lincRNA as a MicroRNA sponge in embryonic stem cell self-renewal. Dev Cell. 2013 Apr 15. PMID: 23597480
- Peng JC, Lin H: Beyond transposons: the epigenetic and somatic functions of the Piwi-piRNA mechanism. Curr Opin Cell Biol. 2013 Apr; 2013 Mar 4. PMID: 23465540
- Huang XA, Yin H, Sweeney S, Raha D, Snyder M, Lin H: A major epigenetic programming mechanism guided by piRNAs. Dev Cell. 2013 Mar 11; 2013 Feb 21. PMID: 23434410
- Darricarrère N, Liu N, Watanabe T, Lin H: Function of Piwi, a nuclear Piwi/Argonaute protein, is independent of its slicer activity. Proc Natl Acad Sci U S A. 2013 Jan 22; 2013 Jan 7. PMID: 23297219
- Lin H: Capturing the cloud: UAP56 in nuage assembly and function. Cell. 2012 Nov 9. PMID: 23141532
- Beyret E, Liu N, Lin H: piRNA biogenesis during adult spermatogenesis in mice is independent of the ping-pong mechanism. Cell Res. 2012 Oct; 2012 Aug 21. PMID: 22907665
- Wang J, Gu H, Lin H, Chi T: Essential roles of the chromatin remodeling factor BRG1 in spermatogenesis in mice. Biol Reprod. 2012 Jun; 2012 Jun 22. PMID: 22495890
- Ma Y, Lin H, Qiu C: High-efficiency transfection and siRNA-mediated gene knockdown in human pluripotent stem cells. Curr Protoc Stem Cell Biol. 2012 May. PMID: 22605647
- Chen D, Zheng W, Lin A, Uyhazi K, Zhao H, Lin H: Pumilio 1 suppresses multiple activators of p53 to safeguard spermatogenesis. Curr Biol. 2012 Mar 6; 2012 Feb 16. PMID: 22342750
- Huang XA, Lin H: The microRNA regulation of stem cells. Wiley Interdiscip Rev Dev Biol. 2012 Jan-Feb; 2011 Nov 17. PMID: 23801669
- Huang XA, Lin H: The miRNA Regulation of Stem Cells. Wiley Interdiscip Rev Membr Transp Signal. 2012 Jan 1; 2011 Nov 17. PMID: 23024929
- Yin H, Sweeney S, Raha D, Snyder M, Lin H: A high-resolution whole-genome map of key chromatin modifications in the adult Drosophila melanogaster. PLoS Genet. 2011 Dec; 2011 Dec 15. PMID: 22194694
- Saxe JP, Lin H: Small noncoding RNAs in the germline. Cold Spring Harb Perspect Biol. 2011 Sep 1; 2011 Sep 1. PMID: 21669983
- Liu L, Qi H, Wang J, Lin H: PAPI, a novel TUDOR-domain protein, complexes with AGO3, ME31B and TRAL in the nuage to silence transposition. Development. 2011 May; 2011 Mar 29. PMID: 21447556
- 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, Sasaki H: MITOPLD is a mitochondrial protein essential for nuage formation and piRNA biogenesis in the mouse germline. Dev Cell. 2011 Mar 15. PMID: 21397847
- Peng S, Chen LL, Lei XX, Yang L, Lin H, Carmichael GG, Huang Y: Genome-wide studies reveal that Lin28 enhances the translation of genes important for growth and survival of human embryonic stem cells. Stem Cells. 2011 Mar. PMID: 21425412
- Qi H, Watanabe T, Ku HY, Liu N, Zhong M, Lin H: 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. 2011 Feb 4; 2010 Nov 24. PMID: 21106531
- Gangaraju VK, Yin H, Weiner MM, Wang J, Huang XA, Lin H: Drosophila Piwi functions in Hsp90-mediated suppression of phenotypic variation. Nat Genet. 2011 Feb; 2010 Dec 26. PMID: 21186352
- Juliano C, Wang J, Lin H: Uniting germline and stem cells: the function of Piwi proteins and the piRNA pathway in diverse organisms. Annu Rev Genet. 2011; 2011 Sep 19. PMID: 21942366
- Ma Y, Jin J, Dong C, Cheng EC, Lin H, Huang Y, Qiu C: High-efficiency siRNA-based gene knockdown in human embryonic stem cells. RNA. 2010 Dec; 2010 Oct 26. PMID: 20978109
- Smulders-Srinivasan TK, Szakmary A, Lin H: A Drosophila chromatin factor interacts with the Piwi-interacting RNA mechanism in niche cells to regulate germline stem cell self-renewal. Genetics. 2010 Oct; 2010 Jul 20. PMID: 20647505
- Wang J, Saxe JP, Tanaka T, Chuma S, Lin H: Mili interacts with tudor domain-containing protein 1 in regulating spermatogenesis. Curr Biol. 2009 Apr 28; 2009 Apr 2. PMID: 19345100
- Gangaraju VK, Lin H: MicroRNAs: key regulators of stem cells. Nat Rev Mol Cell Biol. 2009 Feb. PMID: 19165214
- Thomson T, Lin H: The biogenesis and function of PIWI proteins and piRNAs: progress and prospect. Annu Rev Cell Dev Biol. 2009. PMID: 19575643
- Blakaj A, Lin H: Piecing together the mosaic of early mammalian development through microRNAs. J Biol Chem. 2008 Apr 11; 2008 Feb 13. PMID: 18272516
- Lin H: Cell biology of stem cells: an enigma of asymmetry and self-renewal. J Cell Biol. 2008 Jan 28. PMID: 18227277
- Lin H: piRNAs in the germ line. Science. 2007 Apr 20. PMID: 17446387