Assistant Professor of Genetics

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Contact Information

564 Clinical Research Building
415 Curie Boulevard
Philadelphia, PA 19104-6145
Office: 215-898-1229
Lab: 215-746-5734

Research Interest

Our laboratory studies the spatial organization of the genome, with implications for gene regulation, genome integrity, and diseases such as cancer, aging, and neurodegenerative disorders. We use Drosophila and mammalian systems in combination with cellular, molecular, genetic, and computational tools to elucidate how the structure and position of chromosomes within the nucleus is established and inherited across cell divisions.

Contribution to Science

Regulatory control of meiotic recombination. The segregation of homologous chromosomes during meiosis in most organisms is dependent upon genetic recombination, or crossing over. Although studies have identified numerous factors that are necessary for crossover formation, far less is known about how the distribution and number of crossovers are controlled. As a graduate student, I discovered a novel meiotic checkpoint in Drosophila females, known as the pachytene checkpoint, which delays meiotic progression when there is a defect in crossover formation. Our evidence suggests this delay results in additional attempts at crossing over to maintain homeostatic levels of recombination. I further identified two genes which are required for this checkpoint pathway, Drosophila pch2 and sir2, and isolated the substrate monitored by this checkpoint as the meiotic chromosome axis and not DNA damage or recombination intermediates. These results have provided new insights into this highly conserved surveillance mechanism as well as its relationship to meiotic progression, crossover control, and chromosome structure.

  • Joyce E.F., McKim K.S. (2009) Drosophila PCH2 is required for a pachytene checkpoint that monitors double-strand-break-independent events leading to meiotic crossover formation.Genetics. 181(1). PMID: 18957704.
  • Joyce E.F., Tanneti S.N., McKim K.S. (2009). Drosophila hold’em is required for a subset of meiotic crossovers and interacts with the DNA repair endonuclease complex subunits MEI-9 and ERCC1.Genetics. 181(1). PMID: 18957705.
  • Joyce E.F., McKim K.S. (2010) Chromosome axis defects induce a checkpoint-mediated delay and interchromosomal effect on crossing over during Drosophila meiosis.PLoS Genetics. 6(8). PMID: 20711363.
  • Joyce E.F., Pedersen M., Tiong S., White-Brown S.K., Paul A., Campbell S.D., McKim K.S. (2011) Drosophila ATM and ATR have distinct activities in the regulation of meiotic DNA damage and repair.Journal of Cell Biology. PMID: 22024169.

High-throughput FISH-based screening for novel architectural factors. The least understood aspects of spatial genome organization are the mechanisms that determine where a gene or genomic region is localized in the cell nucleus. As a postdoctoral fellow, I spearheaded the development of Hi-FISH, a fully automated FISH-based imaging pipeline to quantitatively determine the position of multiple loci in the nucleus. Using this tool, I was able to conduct the first FISH-based genome-wide RNAi screen for factors important for nuclear organization in Drosophila. The screen targeted two heterochromatic sequences, located on different chromosomes, and revealed a complex network of genes that either promote or antagonize interchromosomal associations between these regions, shifting our viewpoint of chromosome interactions towards a more dynamic process. In particular, we isolated the condensin II complex as a major organizing factor that antagonizes chromosome pairing and heterochromatin clustering during interphase, consistent with a general role in antagonizing interchromosomal interactions. Intriguingly, our identification of condensin II as an anti-pairing factor is in line with the intrachromosmal functions of compaction and chromatin looping being a mechanism by which long-range interactions are inhibited. The implications of this model are especially profound with respect to DNA repair, replication, and gene expression.

  • Joyce E.F., Williams B.R., Xie T., Wu CT. (2012). Identification of genes that promote or antagonize somatic homolog pairing using a high-throughput FISH-based screen.PLoS Genetics. 8(5). PMID: 22589731.
  • Senaratne T.N., Joyce E.F., Nguyen S.C., Wu CT. (2016). Investigating the Interplay between Sister Chromatid Cohesion and Homolog Pairing in Drosophila Nuclei.PLoS Genetics. 12(8). PMID: 27541002.
  • Joyce E.F., Erceg J., Wu CT. Pairing and anti-pairing: a balancing act in the diploid genome. (2016)Current Opinions in Genetics & Development. April 9. PMID: 27065367.
  • Joyce E.F.. Toward high-throughput and multiplexed imaging of genome organization. (2017)Assay and Drug Development Technologies. Jan 15. PMID: 28092459.

Visualizing the genome with Oligopaint FISH probes. Typically, studies of chromosome positioning have been stymied by the lack of affordable, high-resolution FISH probes, which are usually targeted to only a few loci at a time. Moreover, not only are conventional technologies not a practical source of probe for use in high-throughput methodologies, they fall short of revealing the location of whole chromosomes or specific sub-chromosomal regions in interphase nuclei. As a postdoctoral fellow, I co-developed Oligopaint FISH probes, which, in contrast to conventional probes, are computationally designed, synthesized on microarrays, and generated via PCR amplification. This strategy provides precise control over the sequences they target and allows for single and multicolor imaging at a fraction of the cost of conventional probes. In collaboration with Dr. Xiaowei Zhuang, we have also shown the suitability of Oligopaints for single-molecule super-resolution imaging of chromosomes and introduced a robust and reliable system to visually distinguish the maternal and paternal homologous chromosomes. These advances should substantially expand the capability to query parent-of-origin-specific chromosome positioning and gene expression on a cell-by-cell basis. In my independent position, my group scaled the Oligopaint design to label large genomic regions, including whole chromosomes, which we have shown can also be multiplexed to visualize different chromatin states and gene activity (Nguyen and Joyce in prep.). We anticipate this technology will lead to an enhanced ability to visualize interphase and metaphase chromosomes, providing a novel battery of assays to better characterize how chromatin is packaged and spatially partitioned in the nucleus and how these events impact genome integrity.

  • Beliveau B.J., Joyce E.F.*, Apostolopoulos N., Yilmaz F., Fonseka C.Y., McCole R.B., Chang Y., Li J.B., Senaratne T.N., Williams B.R., Rouillard J.M., Wu CT. (2012). Versatile design and synthesis platform for visualizing genomes with Oligopaint FISH probes.PNAS. 109(52). PMID: 23236188. (*equal authorship)
  • Beliveau B.J., Boettiger A.N., Avendaño M.S., Jungmann R., McCole R.B., Joyce E.F., Kim-Kiselak C., Bantignies F., Fonseka C.Y., Erceg J., Hannan M.A., Hoang H.G., Colognori D., Lee J.T., Shih W.M., Yin P., Zhuang X., Wu CT. (2015). Single-molecule super-resolution imaging of chromosomes and in situ haplotype visualization using Oligopaint FISH probes.Nature Communications. 6(7147). PMID: 25962338.

Inheritance of chromosome positioning. Chromosome positioning plays important roles in genome stability and gene function. However, it remains unclear how this information gets transmitted from mother to daughter cell and whether genome organization, in general, is a component of heritable information through meiosis. To address these questions, I examined nuclear organization across different developmental time points in the Drosophila germline, from early embryogenesis to adulthood. The goal of this work was to establish if germ cells exhibit the same pattern and degree of homologous chromosome pairing as is observed in every somatic tissue in Drosophila that has been examined. Instead, we found dramatic evidence to the contrary. Using our custom Oligopaint FISH technology, I was able to target multiple regions across the genome and found that homologous chromosomes are unpaired and occupy separate territories in primordial germ cell nuclei from the moment the germline can be distinguished from the soma in the embryo and remain unpaired even in the germline stem cells of the adult gonad. Likewise, the spatial clustering of heterochromatic domains was only observed following the differentiation of adult stem cells. These discoveries indicate that the spatial organization of the genome differs between the germline and the soma from the earliest moments of development. It is currently unclear how different tissues could acquire such different organizational fates in the early embryo; however, we favor a model in which germline nuclei actively suppress or delay the mechanisms that drive interchromosomal interactions in the soma. This model is consistent with our screen results, described above, that argue for a controlled process reflecting genes that promote as well as those that antagonize these types of interactions.

  • Joyce E.F., Apostolopoulos N., Beliveau B.J., Wu CT. (2013). Germline progenitors escape the widespread phenomenon of homolog pairing during Drosophila development.PLoS Genetics. 9(12). PMID: 24385920.
  • Joyce E.F.., Erceg J., Wu CT. (2016). Pairing and anti-pairing: a balancing act in the diploid genome.Current Opinion in Genetics & Development.  PMID: 27065367.