Unit on Chromosome Dynamics
Rosin lab @ NICHD
Precisely regulating inter-chromosomal interactions in all cell types is absolutely essential. In meiotic germline cells, homologs (maternal and paternal copies of the same chromosome) must come together and pair from end-to-end for accurate genetic recombination and chromosome segregation (Figure 1). Errors in chromosome segregation during meiosis can lead to reduced fertility, miscarriages, or chromosomal disorders in progeny, such as Down Syndrome or Turner Syndrome (1). While pairing must be robust in meiotic cells, interactions between homologs in somatic cells are tightly regulated and occur only under specialized circumstances. For example, somatic pairing in mammals facilitates DNA repair and the inter-chromosomal communication required for X-chromosome inactivation during early embryogenesis (2,3).
Figure 1. The sub-stages of meiotic homolog pairing. First, homologs must find each other in 3D nuclear space and be able to distinguish self from non-self (homolog recognition). Homologs then align from end to end before becoming physically linked – first by the synaptonemal complex (shown in gray) and then by crossovers/chiasmata (pairing stabilization).
Despite the essential nature of pairing, we still know very little about this process. How homologs find each other in 3D nuclear space and distinguish “self” from “non-self” remains one of the biggest mysteries in chromosome biology.
Understanding this central aspect of genome organization will not only provide insights into how disruption of pairing and related processes can result in infertility and cancer, but will provide many potential new avenues for therapeutic targets for genome instability-related human diseases and disorders. Imagine a world where we know how homologs find each other for meiotic recombination. We could harness this information to engineer strategies to inhibit pairing in tumors, thereby reducing DNA repair efficiency for more robust DNA damage-based cancer treatments like radiation therapy (4,5). Similarly, methods to promote pairing could have profound impacts on treatments for infertility, as premature loss of pairing is one of the leading causes of human aneuploidies and reduced fertility (6,7).
My research group will focus on dissecting the mechanisms regulating homolog pairing and inter-chromosomal communications using Oligopaint fluorescence in-situ hybridization (FISH; 8,9) and live imaging approaches combined with high-throughput genomics-based assays. To tackle these questions, we will utilize insect and vertebrate model systems.
For more information on my current and previous research, these tools, or model systems, please follow the links in the menu at the top of the page.
References1. Bascom-Slack, C. A., Ross, L. O. & Dawson, D. S. Chiasmata, crossovers, and meiotic chromosome segregation. Adv. Genet. (1997).2. Apte, M. S. & Meller, V. H. Homologue Pairing in Flies and Mammals: Gene Regulation When Two Are Involved. Genetics Research International (2011).3. Joyce, E. F., Erceg, J. & Wu, C.-T. Pairing and anti-pairing: a balancing act in the diploid genome. Curr. Opin. Genet. Dev. (2016).4. Li, L., Guan, Y., Chen, X., Yang, J. & Cheng, Y. DNA Repair Pathways in Cancer Therapy and Resistance. Frontiers in Pharmacology. (2021).5. Helleday, T., Petermann, E., Lundin, C., Hodgson, B. & Sharma, R. A. DNA repair pathways as targets for cancer therapy. Nat Rev Cancer (2008).6. Zielinska, A. P., Holubcova, Z., Blayney, M., Elder, K. & Schuh, M. Sister kinetochore splitting and precocious disintegration of bivalents could explain the maternal age effect. eLife. (2015).7. Hassold, T. & Hunt, P. Maternal age and chromosomally abnormal pregnancies: what we know and what we wish we knew. Curr Opin Pediatr. (2009).8. Nguyen, S. C. & Joyce, E. F. Programmable Chromosome Painting with Oligopaints. Imaging Gene Expression: Methods and Protocols. (2019). 9. Beliveau, B. J. et al. Versatile design and synthesis platform for visualizing genomes with Oligopaint FISH probes. Proc. Natl. Acad. Sci. (2012).