Dr. Chen is an HHMI Investigator and a Professor of the Department of Biology at the Johns Hopkins University. Dr. Chen joined the Department of Biology at Johns Hopkins in 2008. Her current research focuses on the epigenetic regulation in adult stem cell lineages. Her studies have led to the discovery that epigenetic information is asymmetrically inherited in stem cells. Furthermore, Dr. Chen’s recent studies illuminate that both DNA replication and mitotic cell division contribute to establishing and partitioning such an epigenetic asymmetry.
Dr. Chen received her Ph.D. in Molecular Cell & Developmental Biology from University of Texas at Austin (Drosophila eye development research). She was a postdoctoral fellow in the laboratory of Dr. Margaret Fuller at Stanford University School of Medicine, where she focused on how tissue-specific transcription factors regulate robust transcription of differentiation genes in germ cells.
During metazoan development, a single fertilized egg gives rise to various cell types, each with distinct appearances and functions. As the embryo develops, genetic information is reliably copied through DNA replication and subsequently transferred from one cell to its daughter cells through mitosis. Since the processes of DNA replication and mitosis always give rise to cells with identical genomes, it remains largely unknown how cells take on distinct cell fates in multicellular organisms. Cell fate is determined by selectively expressing a subset of the genome at the proper time, in the right place, and at the precise level. The unique gene expression program for each cell type is typically dictated by the epigenome; however, how the epigenetic information is transferred through mitosis in multicellular organisms remains unclear. Mis-regulation of cell fate specification underlies numerous diseases, such as various cancer and tissue degenerative diseases. Thus, understanding the mechanisms responsible for cell fate specification is not only important in enhancing our knowledge of basic biology, but also crucial for treating and preventing many diseases.
Previously, we made a novel discovery that preexisting old histones are selectively retained in the self-renewing stem cell, whereas newly synthesized histones are enriched in the differentiating daughter cell during asymmetric division of Drosophila male germline stem cells (Science, 2012, 338: 679). Mis-regulation of asymmetric histone inheritance leads to both stem cell loss and progenitor germ cell tumor phenotypes, suggesting that this process is critical to stem cell maintenance and progenitor cell differentiation (Cell, 2015, 163: 920). Since histone proteins are major carriers of epigenetic information in all eukaryotic organisms, our findings provide the first direct evidence that stem cell maintains its epigenetic information while the differentiating daughter cell undergoes epigenetic reprogramming. Notably, this asymmetry shows both cellular and molecular specificities. From a cellular perspective, asymmetric histone inheritance is specific to asymmetrically dividing stem cells, as symmetrically dividing progenitor germ cells show an overall symmetric histone inheritance pattern. From a molecular perspective, asymmetric histone inheritance is specific to canonical histones H3 and H4, but not H2A or H2B.
Since this significant finding in 2012, we have made several major discoveries that offer mechanistic insight to how asymmetric histones are established (Nature Struct. & Mol. Bio., 2019, 26: 732) and segregated (Cell Stem Cell, 2019, 25: 666) in Drosophila male germline stem cells. Recently, we discovered several unique features that differ between old and new histone-enriched sister chromatids, including nucleosome density, chromosomal condensation, and H3 Ser10 phosphorylation, leading to their differential association with Cdc6, an essential component of the pre-replication complex, and asynchronous initiation of DNA replication in the two resulting daughter cells [Developmental Cell, 2022, https://authors.elsevier.com/sd/article/S1534-5807(22)00247-7]. In addition, we systematically investigate histone inheritance patterns at a single-cell resolution in different systems. For example, we detected large genomic domains that distinctly display old versus new histones in both asymmetrically dividing Drosophila female germline stem cells (EMBO Reports, 2021, e51530) and Wnt3a-induced asymmetrically dividing mouse embryonic stem cells (Cell Reports, 2020, 32: 108003). We used two-color histone labeling with DNA Oligopaint FISH technology and found that the two daughter cells differentially inherit histones at key genes related to maintaining stem cell status or promoting differentiation, but not at genes that are constitutively active or silenced (EMBO Reports, 2021, e51530).
In summary, our previous discoveries have placed us at a unique position to solve the long-standing question in biology. We have already developed innovative strategies and plan to apply cutting-edge technologies to study how distinct epigenetic information is established and partitioned at any candidate DNA element in cell types of interest from multiple organisms. Our goal is to address a fundamental question: how do cells become different while faithfully maintaining the same genetic material? Addressing this question has far-reaching impact on our understanding of any complex living organism including human being.
Publications related to current work:
- Chandrasekhara, C.*, Ranjan, R.*, Urban, J. A.*, Davis, B.E.M., Ku, W-L., Snedeker, J., Zhao, K., Chen, X. (2023) A single N-terminal amino acid determines the distinct roles of histones H3 and H3.3 in the Drosophila male germline stem cell lineage, PLoS Biology, 21(5):e3002098, DOI: 10.1371/journal.pbio.3002098. (*: equal contribution)
- Zion, E., Ringwalt, D.*, Rinaldi, K.*, Kahney, E.W., Li, Y. and Chen, X. (2023) Old and newly synthesized histones are asymmetrically distributed in Drosophila intestinal stem cell divisions, EMBO Reports, in press. DOI:10.15252/embr.202256404. (*equal contribution)
- Gleason, R.J.*, Guo, Y., Semancik, C.S., Ow, C., Lakshminarayanan, G. and Chen, X.* (2023) Developmentally programmed histone H3 expression regulates cellular plasticity at the parental-to-early embryo transition, Science Advances, 7;9(14): eadh0411 (*: co-corresponding)
- Ranjan, R.#,*, Snedeker, J.#, Wooten, M.#, Chu, C., Bracero, S., Mouton, T. and Chen, X.* (2022) Differential condensation of sister chromatids coordinates with Cdc6 to ensure distinct cell cycle progression in Drosophila male germline stem cell lineage, Developmental Cell, 57(9):1102-1118 (#: equal contribution; *: co-corresponding)
- Kahney, E.W., Zion, E. H., Sohn, L., Viets-Layng, K., Johnston, R. and Chen, X. (2021) Characterization of histone inheritance patterns in the Drosophila female germline, EMBO Reports, 22(7): e51530, PMCID: PMC8406404.
- Ranjan, R.* and Chen, X.* (2021) Super-resolution live cell imaging of subcellular structures. Journal of Visualized Experiments (JoVE), doi: 10.3791/61563, video at: https://www.jove.com/v/61563, PMCID: PMC8197282. (* co-corresponding authors)
- Ma, B. Trieu, T., Habib, S. and Chen, X. (2020) Establishing mouse embryonic stem cells as a system to study histone inheritance pattern at single-cell resolution, STAR Protocols, 1,100178, https://doi.org/10.1016/j.xpro.2020.100178. PMCID: PMC7757403
- Ma, B., Trieu, T., Cheng, J., Zhou, S., Tang, Q., Xie, J., Liu, J., Zhao, K., Habib, S. and Chen, X. (2020) Differential histone distribution patterns in induced asymmetrically dividing mouse embryonic stem cells, Cell Reports, https://doi.org/10.1016/j.celrep.2020.108003
- Shi, Z.*, Lim, C.*, Tran, V., Cui, K., Zhao, K. and Chen, X. (2020) Single-cyst transcriptome analysis of Drosophila male germline stem cell lineage, Development,147(8), doi: 10.1242/dev.184259. (* equal contribution).
- Wooten, M., Li, Y.*, Snedeker, J.*, Nizami, Z., Gall, J., and Chen, X. (2020) Superresolution imaging of chromatin fibers to visualize epigenetic information on replicative DNA, Nature Protocols, 15:1188-1208. (* equal contribution).
- Ranjan, R., Snedeker, J., and Chen, X. (2019) Asymmetric centromeres differentially coordinate with mitotic machinery to ensure biased sister chromatid segregation in germline stem cells, Cell Stem Cell, 25:666-681 e665. Featured in Faculty of 1000 Biology.
- Wooten, M., Snedeker, J.*, Nizami, Z.*, Yang, X-X*, Ranjan, R., Urban, E., Kim, J-M., Gall, J., Xiao, J. and Chen, X. (2019) Asymmetric histone inheritance via strand specific incorporation and biased replication fork movement, Nature Structural & Molecular Biology, 26: 732–743. (* equal contribution) Featured in Faculty of 1000 Biology.
- 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, 25(8):1486-1502. (* equal contribution)
- 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, 429:2030-2041 (* equal contribution).
- 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.
- 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. Featured in Faculty of 1000 Biology.
Previewed by Pirrotta, V. (2015) Histone Marks Direct Chromosome Segregation. Cell 163(4): 792-793. Highlighted by Strzyz, P. (2015) Stem cells: Histone mark of stemness. Nat Rev Mol Cell Biol. 16(12):703.
- 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.
- 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).
- 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.
- 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”.
- Eun, S., Stoiber, P.M., Wright, H. J., McMurdie, K.E., Choi, C.H., Gan, Q., Lim, C., Chen, X. (2013) MicroRNAs downregulate Bag of marbles to ensure proper terminal differentiation in Drosophila male germline lineage. Development, 140, 23-30.
- 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.
- 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, (* co-corresponding authors).
- 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).
- 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.
- Zion, E.* and Chen, X.* (2023) Studying histone inheritance in different systems using imaging-based methods and perspectives, Biochemical Society Transactions, BST20220983, DOI: 10.1042/BST20220983.
- Gleason, R.J. and Chen, X. (2022) Epigenetic dynamics during germline stem cell maintenance, differentiation, and early embryogenesis in Drosophila and C. elegans. Current Opinion in Genes and Development 78:102017.
- Urban, J.A.*, Ranjan, R.* and Chen, X. (2022) Asymmetric Inheritance of Histones/Chromatin, Annual Review of Genetics, Volume 56, in press, https://doi.org/10.1146/annurev-genet-072920-125226. (* equal contribution)
- Ranjan, R.* and Chen, X.* (2022) Mitotic drive in asymmetric epigenetic inheritance, Biochemical Society Transactions 50(2):675-688. (* equal contribution as co-corresponding authors)
- Vidaurre, V. and Chen, X. (2021) Epigenetic regulation in Drosophila female and male germline, Developmental Biology, 473:105-118. PMCID: PMC7992187.
- Zion, E.* and Chen, X.* (2021) Asymmetric Epigenetic Inheritance, The Biochemist, 43 (1): 14–19. (* co-corresponding authors), PMCID: PMC8330550.
- Zion, E.*, Chandrasekhara, C.* and Chen, X. (2020) Asymmetric inheritance of epigenetic states in asymmetrically dividing stem cells, Current Opinion in Cell Biology, 67: 27-36, PMCID: PMC7736099.
- Urban, J.*, Ranjan, R.* and Chen, X. (2022) Asymmetric Inheritance of Histones/Chromatin, Annual Review of Genetics, Volume 56, in press, https://doi.org/10.1146/annurev-genet-072920-125226. (* equal contribution)
- Ranjan, R. * and Chen, X.* (2021) Mitotic drive in asymmetric epigenetic inheritance, Biochemical Society Transactions, Portland Press, in press. (* equal contribution as co-corresponding authors (* equal contribution)
- Urban, J. and Chen, X. (2020) Stem cells and their niches in Drosophila, eLS. John Wiley & Sons, Ltd: Chichester. doi: 10.1002/9780470015902.a0021854.pub2.
- Wooten, M.*, Ranjan, R.* and Chen, X. (2020) Asymmetric histone distribution in stem cells. Trends in Genetics 36(1): 30-43. (* equal contribution)
- Kahney, E.*, Snedeker, J.* and Chen, X. (2019) Regulation of Drosophila germline stem cells. Current Opinion in Cell Biology 60:27-35. (* equal contribution)
- Kahney, E.*, Ranjan, R.*, Gleason, R.J. * and Chen, X. (2018) Symmetry from Asymmetry or Asymmetry from Symmetry? Cold Spring Harbor Symposium Chromosome Segregation and Structure, 82:305-318. (* equal contribution)
- Gleason, R.J.*, Anand, A.*, Kai T.# and Chen, X.# (2018) Protecting and diversifying the germline, invited review to Genetics FlyBook, 208 (2): 435-471. (* equal contribution; # co-corresponding authors).
- Snedeker, J.*,#, Wooten, M.*,# and Chen, X.# (2017) The inherent asymmetry of DNA replication, Annual Review of Cell and Developmental Biology, 33:291-318, (* equal contribution; # co-corresponding authors).
- Xie, J.*, Wooten, M.*, Tran, V. and Chen, X. (2017) Breaking symmetry-asymmetry histone inheritance in stem cells, Trends in Cell Biology, 27:527-540 (* equal contribution).
- Feng, L.J. and Chen, X. (2015) Epigenetic Regulation of Germ Cells - Remember or Forget? Current Opinion in Genes and Development, 31:20-27.
- Tarayrah, L.# and Chen, X.# (2013) Epigenetic regulation in adult stem cells and cancers. Cell and Bioscience, 3:41 (# co-corresponding authors).
- Tran,V.*, Feng, L.J.* and Chen, X. (2013) Asymmetric distribution of histones during Drosophila male germline stem cell asymmetric divisions. Chromosome Research 21(3):255-269 (* co-first authors).
- Chepelev, I. and Chen, X. (2013) Alternative splicing switching in stem cell lineages. Frontiers in Biology 8(1):50-59.
- Lim, C.*, Tarayrah, L.* and Chen, X. (2012) Transcriptional regulation during Drosophila spermatogenesis. Spermatogenesis 2:3, 1-9 (* co-first authors).
- 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).
- Chen, X. (2008) Stem cells- what can we learn from flies? Invited review for Fly. FLY 2-1: 19- 28.
Selected earlier publications:
- 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.
Reviewed by Ringrose, L. in BioEssays (2006) 28:330-334; and featured in Faculty of 1000 Biology.
- 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.
- 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.
- Chen, X. and Fischer, J. A. (2000) In vivo structure/function analysis of the Drosophila fat facets deubiquitinating enzyme gene. Genetics 156: 1829-1836
- 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.)