Post-doctoral positions are available to investigate fundamental principles of chromosome dynamics from physical biology and molecular biology perspectives.
Candidates with new ideas; a background in engineering, physics, biophysics and/or genetics are particularly welcome.
Questions of interest include:
(i) Physical and molecular biology of chromosome movement. Can we formulate a new conceptual framework, beyond apparent diffusion coefficients, for how DNA/chromatin/chromosome segments move in vivo? And in this context, can we understand how a double-strand break searches chromosomal space to identify an homologous partner sequence? And can we understand how homologous whole chromosomes identify one another and come together in space (i.e. "pair"), as seen during monoallelic expression in mammalian cells and as a basic feature of meiosis. These questions can now be addressed in yeast and mammalian cells using our new (unpublished) method for 3D spot tracking at high time density over long times.
(ii) Global chromosome stress cycles: a new fundamental principle of chromosome dynamics. Our recent work reveals global chromosome compaction/expansion stress cycles as a basic feature of eukaryotic and prokaryotic chromosomes. What are the general mechanisms and implications of this newly-revealed process? What is its fundamental functional significance? What are its specific roles in mammalian cells (where it mediates progressive changes in chromosome organization) and in E.coli (where it underlies sister nucleoid segregation and likely comprises a basic cell cycle engine and a segregation mechanism for primordial life). Also: what are the mechanism(s) and role(s) of short-time scale longitudinal density waves discovered in E.coli and also seen in mammalian cells? These and other questions can be addressed by (unpublished) high throughput 4D (3D over time) analysis of global and local chromosomal features. [Fisher et al. , 2013, Four-dimensional imaging of E. coli organization and dynamics in living cells. Cell 153, 882-895; Liang et al., 2015. Chromosomes progress to metaphase in multiple discrete steps via global compaction/expansion cycles. Cell 161, 1124-1137.]
(iii) Spatial patterning of stochiastic chromosomal events. Many basic chromosomal events occur at different positions in different nuclei but, nonetheless, along any given chromosome, tend to be evenly spaced. Examples include DNA replication origin firings, sister chromatid linkages and, during meiosis, positioning of crossover recombination complexes (the phenomenon of "crossover interference"). In principle, spatial patterning of this nature could occur by mechanical stress-and-stress relief or reaction-diffusion biochemistry. For meiotic crossover interference, we have proposed a mechanically-based mechanism, tests of which remain to be developed. Our recent work also identifies a molecular pathway involving chromosome structural axes, SUMO-targeted ubiquitin ligase activity and Topoisomerase II, setting the stage for full mechanistic exploration of this process. [Zhang et al., 2014, Topoisomerase II mediates meiotic crossover interference. Nature 511, 551-556.]
Note: post-doctoral fellows in our laboratory are free to continue their projects in their subsequent careers as independent investigators.
If you are interested in a position, please email us at: kleckner [at] fas.harvard.edu