CAREER: Molecular and physical mechanisms of chromosome condensation

University Of North Carolina At Chapel Hill, Chapel Hill NC

Investigators

Abstract

DNA encodes the blueprint for all of life's forms and functions and must be coiled, bundled and compacted into different packages, depending on the nature of the cell where it resides. Understanding how DNA changes shape in space and time is the next great hurdle in discovering how genes are regulated and passed down through generations. The work encompassed in this research program is aimed at innovating technologies to reveal the three-dimensional dynamics of DNA over time in living, dividing cells. Results from this project will serve and enrich society due to the critical nature of cell division to predicting, diagnosing and treating diseases, improving food crop yield and hardiness, and conserving ecological biodiversity. These broader goals will be realized by training students at multiple levels (undergraduate, graduate, Ph.D.) to work as a team and creatively employ cutting edge light microscopy and data analysis. Finally, through public meetings and displays (both permanent and travelling), the outreach program will teach the general public the history and impact of light microscopy on the study of DNA and cell division. Chromosomes (single DNA strands) compact several orders of magnitude upon entry into mitosis via a yet unknown mechanism. One hundred years of research has culminated in a model wherein this compaction is achieved by the organization of chromatin (nucleosomal DNA) into regularly spaced loops. Evidence from as long as 50 years ago, however, concluded that mitotic chromosomes do not adopt a "static" regular conformation. The proposed work utilizes the C. elegans early embryo as a model cell type to discover the basic biophysical properties governing mitotic chromosome condensation. The research project will employ a newly invented light sheet modality, wherein chromosomes in living developing embryos are imaged with high temporal and spatial resolution (by using high numerical aperture (1.4 or greater) objective lenses). Fulfillment of this project will define how subresolution chromatin dynamics change during condensation, the molecules responsible for these changes, and how these dynamics are modulated through development. Correlation of dynamic, single-cell data generated here with static, population-based genomic bio-informatics data will be synthesized to provide fundamental understanding of how chromosomes maintain their shape, and quickly transform, to meet the demands of their cellular functions.