The Physical genome : structure, elasticity, and transport in packaged DNA
- Elena F. Koslover.
- Mar. 2013.
- Physical description
- online resource (xvi, 247 pages) : illustrations (some color)
- Includes bibliographical references.
- The packaging and expression of the genome requires a cell to overcome elastic and entropic forces to form a highly compact structure that remains dynamically accessible to transcription machinery. The eukaryotic genome is packaged into a hierarchical structure collectively termed chromatin and the prokaryotic genome is also condensed and structured by the binding of architectural proteins along the DNA. We use a combination of analytic theory and computational techniques to study how the mechanical properties of DNA and associated proteins impact genome structure and dynamics across a wide range of length and time scales. We demonstrate that the elasticity of the DNA molecule can give rise to tension-mediated cooperative binding between DNA-bending proteins, allowing them to sense each other across a tunable length scale. At the lowest level of eukaryotic chromatin packing, DNA is wound around protein cores to form nucleosomes, which then condense into regular helical fibers under physiologic conditions. Using energy landscape optimization methods, we investigate the role of DNA mechanics in determining the structure of these compact chromatin fibers. We then proceed to examine how he statistical properties of DNA at long length scales are modulated by its interactions with proteins that modify its geometry. To this end, we develop a generalized approach for coarse-grained modeling of polymer systems by mapping to continuous and discrete elastic models. Moving into the realm of dynamics, we uncover an important role for force fluctuations in biomolecular kinetics, demonstrating how microsecond fluctuations can qualitatively alter nucleosomal transcription by RNA polymerase, an essential process for eukaryotic gene expression. Finally, we use a combination of analytic reaction-diffusion models and simulations to study the target site search process of DNA-binding proteins under a variety of conditions relevant to in vitro and in vivo systems, elucidating a key role for confinement and a surprising robustness to DNA configuration. These multi-scale studies further our fundamental understanding of how the complex hierarchy of genome packing and processing arises from the basic physical properties of DNA and interacting proteins.
- Publication date
- Submitted to the Department of Biophysics and the Committee on Graduate Studies of Stanford University.
- Thesis (Ph.D.)--Stanford University, 2013.