Dynamics of Genome Organization

Abstract

A human cell contains about 2m of DNA, packed into a nucleus with diameter ~10μm. The three-dimensional structure of this packing has been the subject of intense investigation essentially since the discovery of DNA itself, with an explosion of the field over the past 15 years, following the advent of chromosome conformation capture techniques. The fourth dimension---time---however, has remained elusive and the dynamics underlying the organization of the genome are much less known. In this thesis I present my contributions to our understanding of these dynamics, working towards a full four-dimensional characterization of genome organization. First, by pulling on a genomic locus in live cells, we revealed the rather liquid-like material properties of chromatin and dispelled the idea that chromatin in interphase forms a gel. Second, by tracking genomic elements known to act as boundary elements for loop formation, we quantified the dynamics of chromatin loops in live cells. My contribution to both projects lay in the development and application of novel data analysis, modeling, and inference methods, implementations of which have been made available to the community for future use. Finally, we devised a simple scaling argument to reconcile the orthogonal observations of chromosome structure, dynamics, and mechanics. In sum, these contributions further our understanding of the dynamical behavior of chromatin in living cells and provide valuable tools and directions for future research.