Physical modeling of DNA in heterochromatin condensation and looping kinetics
Abstract/Contents
- Abstract
- Deoxyribonucleic acid, or DNA, is the central molecule for heredity in all cellular organisms, from bacteria to humans. Understanding how the cell regulates access to the genes encoded in the DNA requires knowledge of the physical properties of the DNA and its associated proteins, including how they move, deform, and interact. One process of particular interest is DNA looping, where two segments of the DNA strand are brought together. DNA looping plays a critical role in gene regulation, whether through supercoiling to help organize the genome, facilitating the spread of chemical marks that control access, or blocking progress of RNA polymerase. We use our model for protein-mediated DNA looping to understand the balance between DNA deformation including the bending and twisting of the DNA chain, and the protein interaction energy and flexibility. We use our model to explain several features of in vitro looping time measurements for the canonical Lac repressor protein. We also develop a new method for Brownian dynamics simulations that will enable improved computational efficiency by changing the shortest length-scales captured by the simulation during the course of it, a process we call dynamic rediscretization. We use this new method in polymer looping simulations, but it has wide applicability. Another key process for proper gene regulation is the segregation of silenced genomic regions into densely packed heterochromatin, leaving the active genes in euchromatin regions more accessible. We introduce a model that connects the presence of epigenetically-inherited histone marks, methylation at histone 3 lysine-9, to the physical compaction of chromatin fibers via the binding of heterochromatin protein 1 (HP1). We demonstrate that strong cooperative interactions among the HP1 proteins are necessary to see the phase segregation of heterochromatin and euchromatin regions. Finally, we extended our physical theory of chromatin compaction from a quadratic-order self-consistent field theory approach to the renormalization group, a method that allows a much better handling of the fluctuations closer to the system's critical point, and gave us more insight on the role of disorder in this biological context.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Publication date | 2014 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Mulligan, Peter J | |
|---|---|---|
| Associated with | Stanford University, Department of Chemical Engineering. | |
| Primary advisor | Spakowitz, Andrew James | |
| Thesis advisor | Spakowitz, Andrew James | |
| Thesis advisor | Dunn, Alexander Robert | |
| Thesis advisor | Straight, Aaron, 1966- | |
| Advisor | Dunn, Alexander Robert | |
| Advisor | Straight, Aaron, 1966- |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Peter J. Mulligan. |
|---|---|
| Note | Submitted to the Department of Chemical Engineering. |
| Thesis | Thesis (Ph.D.)--Stanford University, 2014. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2014 by Peter John Mulligan
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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