Xin Chen joined the Department of Biology at Johns Hopkins in 2008 after doing her postdoctoral work at Stanford University School of Medicine. Her research centers on epigenetic regulation of Drosophila germ cell differentiation from a stem cell lineage.
Epigenetic regulation of Drosophila germ cell differentiation from a stem cell lineage
A broad definition for “epigenetic phenomenon” refers to effects on gene expression or function that are heritable through many cell divisions without altering the primary DNA sequences. Epigenetic regulation can act through different mechanisms, including post-translational modifications of histones and localization of the chromatin modifiers to particular subnuclear regions. Failure in appropriate epigenetic regulation may lead to abnormalities in development and may also underlie early steps in cancer genesis.
During normal development, the mechanisms that regulate differentiation of cells from undifferentiated precursors play key roles in tissue/organ development and maintenance, such as gametogenesis. Precursor germ cells must commit to differentiate at the right place and with the right timing to generate and maintain the pools of functional gametes. The maintenance of the precursor germ cells in an undifferentiated and proliferative state and the subsequent reversal of these controls to allow terminal differentiation are both critical to continuous production of gametes throughout lifetime.
The Drosophila male germ line provides a powerful model system for studying the mechanisms that regulate differentiation in adult stem cell lineages. My laboratory utilizes it as a model system to study how genetic and epigenetic mechanisms interplay to ensure proper gene expression during spermatogenesis. We use molecular genetics and genomic strategies to systematically study the following questions: (1) Are there genes with stem cell-specific expression? (2) Is the specific expression of these genes maintained by a unique chromatin state? (3) How do the transcription and chromatin landscape change in continuously differentiating germ cells during normal development? (4) How do the epigenomic changes regulate proliferation versus differentiation processes in this lineage? (5) Can GSCs be regenerated if the differentiation process is reversed? Dramatic changes in the transcriptional program and chromatin landscape of male germ cells offer an excellent system to investigate these molecular mechanisms in vivo.
Epigenetic inheritance in germline stem cell lineage
We investigated epigenetic inheritance during GSC asymmetric cell division (Science 338: 679). It has been known for a long time that epigenetic changes are heritable. However, except for DNA methylation, little is known about the molecular mechanisms of epigenetic inheritance. We found that during the asymmetric division of Drosophila male germline stem cell (GSC), the preexisting histone 3 (H3) are selectively segregated to the GSC whereas newly synthesized histones during DNA replication are enriched in the differentiating daughter cell. The asymmetric H3 inheritance occurs in GSCs but not in symmetrically dividing progenitor cells. Furthermore, if GSCs are genetically manipulated to divide symmetrically, the asymmetric H3 inheritance mode is lost. In contrast to canonical histone H3, the histone variant H3.3 does not exhibit this asymmetric pattern during GSC divisions. Thus, our studies provide the direct evidence that stem cells retain preexisting canonical H3 during asymmetric cell divisions in vivo, which may contribute to maintain their epigenetic memory. We are continuing this exciting project by asking: (1) What are the molecular mechanism and cellular basis underlying asymmetric segregation pattern of H3? (2) What are the consequences of the mis-regulation of such an inheritance mode? (3) Is this asymmetric histone segregation mode used in other stem cells or asymmetrically dividing cells, and is it applicable in other organisms? Our studies will shed light on a long-standing question regarding whether and how stem cells retain their epigenetic memory.
Publications related to current work:
1. Wooten, M., Nizami, Z.*, Yang, X-X*, Snedeker, J.*, Ranjan, R.*, Kim, J-M., Urban, E., Tran, V., Buss, J., Gall, J., Xiao, J. and Chen, X. Asymmetric histone incorporation during DNA replication in Drosophila male germline stem cells, deposited into bioRxiv at: https://www.biorxiv.org/content/early/2018/01/04/242768. (* equal contribution).
2. Feng, L., Shi, Z.*, Xie, J.*, Ma, B.* and Chen, X. (2018) Enhancer of Polycomb maintains germline activity and genome integrity in Drosophila testis, Cell Death & Differentiation, in press. (* equal contribution).
3. Eun, S.*, Feng, L.*, Cedeno-Rosario, L., Gan, Q., Wei, G., Cui, K., Zhao, K., and Chen, X. (2017) Polycomb group gene E(z) is required for spermatogonial dedifferentiation in Drosophila adult testis, Journal of Molecular Biology, PMCID: PMC5516936 (* equal contribution).
4. Feng, L., Shi, Z. and Chen, X. (2017) Enhancer of Polycomb coordinates multiple signaling pathways to promote both cyst and germline stem cell differentiation in Drosophila adult testis, PLoS Genetics, 13:e1006571. PMCID: PMC5308785.
5. Xie, J., Wooten, M., Tran, V., Chen, B-C., Pozmanter, C., Simbolon, C., Betzig, E. and Chen, X. (2015) Histone H3 Threonine phosphorylation regulates asymmetric histone inheritance in the Drosophila male germline. Cell 163(4): 920-933. PMCID: PMC4636931.
Previewed by Pirrotta, V. (2015) Histone Marks Direct Chromosome Segregation. Cell 163(4): 792-793.
6. Lim, C., Gandhi, S., Biniossek,M., Feng, L., Schilling, O., Urban, S. and Chen, X. (2015) An aminopepetidase acts in the Drosophila testicular niche for germline stem cell maintenance and spermatogonial dedifferentiation. Cell Reports, 13(2):315-325. PMCID: PMC4607668.
7. Tarayrah, L.*,#, Li, Y. *, Eun, S., Shi, Z., Gan, Q. and Chen, X.# (2015) Histone demethylase Lid maintains germline stem cells through regulating JAK-STAT signaling pathway activity, Biology Open, 4(11):1518-1527 (* equal contribution; # co-corresponding authors). PMCID: PMC4728359.
8. Eun, S., Shi, Z., Cui, K., Zhao, K. and Chen, X. (2014) A non-cell-autonomous role of E(z) histone methyltransferase to prevent germ cells from turning on somatic cell marker. Science, 343:1513-1516. Featured in Faculty of 1000 Biology. PMCID: PMC4040133.
9. Tarayrah, L., Herz, H-M., Shilatifard, A. and Chen, X. (2013) Histone demethylase dUTX directly antagonizes JAK-STAT signaling to maintain the Drosophila testis niche architecture. Development, 140, 1014-1023. Featured article "In this issue". PMCID: PMC3583039.
10. Eun, S., Stoiber, P.M., Wright, H. J., McMurdie, K.E., Choi, C.H., Gan, Q., Lim, C., Chen, X. (2012) MicroRNAs downregulate Bag of marbles to ensure proper terminal differentiation in Drosophila male germline lineage. Development, 140, 23-30. PMCID: PMC3513990.
11. Tran, V.*, Lim, C.*, Xie, J. and Chen, X. (2012) Asymmetric division of Drosophila male germline stem cell shows asymmetric histone distribution. Science 338, 679-682 (* co-first authors). Featured in Faculty of 1000 Biology. PMCID: PMC3532436.
12. Cuddapah, S.*, Roh, T-Y., Cui, K., Fuller, M.T., Zhao, K. and Chen, X.* (2012) A novel human polycomb binding site acts as a functional polycomb response element in Drosophila, PLoS One 7(5):e36365, PMCID: PMC3343078. (* co-corresponding authors).
13. Chen, X.*, Lu, C., Morillo, J., Eun, S. and Fuller, M.T.* (2011) Sequential changes at differentiation gene promoters as they become active in a stem cell lineage. Development 138: 2441-2450. (*co-corresponding authors.) Featured article â€œIn this issueâ€. PMCID: PMC3100706.
14. Gan, Q.*, Chepelev, I.*, Wei, G., Tarayrah, L., Cui, K., Zhao, K. and Chen, X. (2010) Dynamic regulation of alternative splicing and chromatin structure in Drosophila gonads revealed by RNA-seq. Cell Research 20(7): 763-783 (*co-first authors). PMCID: PMC2919574.
15. Gan, Q., Schones, D.E., Eun, S., Wei, G., Cui, K., Zhao, K. and Chen, X. (2010) Monovalent and unpoised status of most genes in undifferentiated cell-enriched Drosophila testis. Genome Biology 11(4): R42. PMCID: PMC2884545.
1. Kahney, E.*, Ranjan, R.*, Gleason, R.J. * and Chen, X. (2018) Symmetry from Asymmetry or Asymmetry from Symmetry? Cold Spring Harbor Symposium 82: Chromosome Segregation and Structure, in press. (* equal contribution)
2. Gleason, R.J.*, Anand, A.*, Kai T.Â§ and Chen, X.Â§ (2018) Protecting and diversifying the germline, invited review to Genetics FlyBook, in press. (* equal contribution; Â§ co-corresponding authors).
3. Snedeker, J.*,#, Wooten, M.*,# and Chen, X.# (2017) The inherent asymmetry of DNA replication, Annual Review of Cell and Developmental Biology, 33:291-318, PMID: 28800257, PMCID: in progress (* equal contribution; # co-corresponding authors).
4. Xie, J.*, Wooten, M.*, Tran, V. and Chen, X. (2017) Breaking symmetry-asymmetry histone inheritance in stem cells, invited review to Trends in Cell Biology, Online publication 6-MAR-2017 DOI information: 10.1016/j.tcb.2017.02.001 (* equal contribution).
5. Feng, L.J. and Chen, X. (2015) Epigenetic Regulation of Germ Cells - Remember or Forget? Invited review to Current Opinion in Genes and Development, 31:20-27.
6. Tarayrah, L.* and Chen, X.* (2013) Epigenetic regulation in adult stem cells and cancers. Invited review to Cell and Bioscience, 3:41 (* co-corresponding authors).
7. Tran,V.*, Feng, L.J.* and Chen, X. (2013) Asymmetric distribution of histones during Drosophila male germline stem cell asymmetric divisions. Invited review to Chromosome Research 21(3):255-269 (* co-first authors).
8. Chepelev, I. and Chen, X. (2013) Alternative splicing switching in stem cell lineages. Invited review to Frontiers in Biology 8(1):50-59. PMCID: PMC3566875.
9. Lim, C.*, Tarayrah, L.* and Chen, X. (2012) Transcriptional regulation during Drosophila spermatogenesis. Invited review to Spermatogenesis 2:3, 1-9 (* co-first authors).
10. Eun, S.*, Gan, Q.*, and Chen, X. (2010) Epigenetic regulation of germ cell differentiation. Current Opinion in Cell Biology 22: 737-743 (*co-first authors).
11. Chen, X. (2008) Stem cells- what can we learn from flies? Invited review for Fly. FLY 2-1: 19- 28.
Selected earlier publications:
1. Chen, X., Hiller, M., Sancak, Y. and Fuller, M. T. (2005) Tissue specific TAFs counteract Polycomb to turn on terminal differentiation. Science 310: 869- 872.
This paper was reviewed by Ringrose, L. in BioEssays (2006) 28:330-334; and featured in Faculty of 1000 Biology.
2. Hiller, M., Chen, X., Pringle, M.J., Suchorolski, M., Sancak, Y., Viswanathan, S., Bolival, B., Marino, S. and Fuller, M.T. (2004) Testis-specific TAF homologs collaborate to control a tissue-specific transcription program. Development 131: 5297-5308.
3. Chen, X., Zhang, B. and Fischer, J. A. (2002) A specific protein substrate for deubiquitinating enzyme: Liquid facets is the substrate of Fat facets. Genes and Development 16: 289-294. One of the cover stories.
4. Chen, X. and Fischer, J. A. (2000) In vivo structure/function analysis of the Drosophila fat facets deubiquitinating enzyme gene. Genetics 156: 1829-1836
5. Chen, X.*, Li, Q.* and Fischer, J. A. (2000) Genetic analysis of the Drosophila DNAprim gene: The function of the 60-kD primase subunit of DNA polymerase opposes the fat facets signaling pathway in the developing eye. Genetics 156: 787-1795. (* indicating authors of equal contribution.)
- Chinmayi Chandrasekhara
- Ryan Gleason
- Rajesh Ranjan
- Jennifer Urban
- Matthew Wooten
- Elizabeth Kahney
- Carolina Chu
- Roy Cheng
- Jasmin Johnson
- Gita Lakshminarayanan
- Jonathan Snedeker
- Lydia Sohn