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REC-8 cohesins have a defined orientation within the meiotic chromosome axes. This schematic shows the cohesin ring complex structure, as determined by single-particle EM imaging and crystallographic analysis. We inserted epitope tags at various positions on cohesin subunits and analyzed their spatial distributions using super-resolution microscopy (PALM and STORM).
Chromosome Architecture and Dynamics
Chromosome Architecture and Dynamics
During meiosis chromosomes undergo remarkable and dynamic reorganization. A hallmark of meiotic entry is the reorganization of each replicated chromosome into a linear array of loops anchored to a central axis, which regulates many aspects of meiosis. We have characterized the molecular organization and function of chromosome axes through diverse biochemical and structural approaches, including crystallography (in collaboration with the laboratory of Kevin Corbett, UCSD/LICR) and superresolution microscopy (with Michal Wojcik and Ke Xu, UC Berkeley). Meiotic chromosomes also interact with molecular motors in the cytoplasm via a "LINC" complex, which enables them to move rapidly along the nuclear surface. By directly imaging these movements in living animals, we learned how they accelerate chromosomes' ability to find their partners and regulate their interactions with other chromosomes. In many organisms this movement is mediated by telomeres, the special repetitive DNA sequences at the ends of chromosomes, but in C. elegans this role has been acquired by "pairing centers," broad regions near one end of each chromosome that span hundreds of kilobases. We defined the molecular requirements for pairing center function and continue to investigate their roles in meiotic dynamics and regulation.
Phase separation, protein dynamics, and meiotic crossover control
Phase separation, protein dynamics, and meiotic crossover control
Meiotic recombination underlies eukaryotic evolution, chromosome inheritance, and genetic variation. How meiotic cells regulate recombination between homologous chromosomes remains enigmatic and controversial. In C. elegans, as in many other species, one and only one crossover occurs between each pair of homologs. The synaptonemal complex (SC), a unique protein polymer that assembles between paired chromosomes, plays a central role in crossover control. Through live imaging in C. elegans, we discovered that the SC behaves as a liquid crystalline compartment. We also characterized a family of RING proteins that associates with this structure and plays essential roles in stabilizing and patterning crossover intermediates. We are exploring how this unusual material self-assembles through biomolecular condensation and how its dynamic properties contribution to meiotic regulation.
a. Schema for the formation of recombination nodules along SCs. b. Illustration of our model for patterning of recombination nodules through a coarsening process (Ostwald ripening). c-e. simulations based on our coarsening model. See our preprint!
Schematic of the auxin-inducible degradation (AID) system and a derived auxin-inducible proximity system. The latter was engineered by incorporating 2 amino acid substitutions in TIR1 that abrogate its interaction with cullin proteins. Work from Mark Estelle's group revealed that D170E and M473L substitutions enhance the affinity of TIR1 for auxin, whereas the E12K and E15K mutations disrupt its ability to form an SCF complex.
Check out our publications to learn more.
Tool Development
Tool Development
New insights in biology are often driven by novel technologies. Advances in fluorescence microscopy, DNA sequencing, genome editing, and mass spectrometry, among others, have enabled our lab to answer longstanding questions. While our research group focuses on hypothesis-driven projects, we also work to expand our experimental toolbox through collaboration and innovation. For example, we developed methods for long-term in vivo imaging of adult C. elegans, which has enabled us to probe the dynamics of chromosome movement and synaptonemal complex assembly. We also adapted the auxin-inducible degradation (AID) system for use in C. elegans. This method enables rapid, robust protein depletion in response to an inexpensive, nontoxic small molecule, and also makes it possible to create more complex strains than we could using conventional loss-of-function alleles. We welcome potential researchers who are interested in developing and applying cutting-edge tools to the study of chromosome organization.
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