Physical modeling of the spreading and maintenance of epigenetic modifications - Sandholtz, Sarah Haymore; Spakowitz, Andrew James; Markland, Thomas E; Martinez, Todd J. (Todd Joseph), 1968-; Stanford University, Department of Chemistry ([Stanford, California] : [Stanford University], 2020)
Epigenetics refers to variations in gene expression that are caused not by changes in the sequence of DNA base pairs but by chemical modifications to chromosomal DNA and post-translational modifications to DNA-packaging proteins. Abnormal patterns of epigenetic marks disrupt typical gene expression and are associated with many prevalent diseases, including cancer, diabetes, obesity, and developmental disorders. Understanding the biophysical processes underlying epigenetic regulation is therefore a critical first step towards eventual advances in diagnosing and treating such epigenetic diseases. Towards this aim, this thesis addresses how epigenetic modifications spread along chromosomal DNA and, once a profile of modifications is established, how that profile is maintained. We employ theoretical modeling and simulation to explore the physical mechanisms that govern the spreading and maintenance of epigenetic modifications along chromosomal DNA. We focus on a particular modification, methylation of lysine 9 of histone H3 (H3K9), which affects chromatin structure and gene expression and is one of the most common and consequential epigenetic marks. First, we develop a kinetic model for methyl mark spreading that captures the dynamics of thermally-mediated, transient loop formation. We then extend our model by incorporating heterogeneous polymer elasticity and nucleosome positioning and investigating the impact of the mechanics of the chromatin fiber on looping behavior. Our model reproduces several features of experimental methyl spreading measurements and indicates that spreading is sensitive to heterogeneity in chromatin organization and the resulting variability in the chromatin's mechanical properties. Finally, we develop a comprehensive model of the reestablishment and preservation of the epigenetic sequence following DNA replication. Our model is based on the interplay between the proteins that control chromosomal compaction and those that confer post-translational modifications to histone proteins within chromosomal DNA. Our framework reliably maintains methylation over several generations, thereby confirming the robustness of the epigenetic sequence
Submitted to the Department of Chemistry
Thesis Ph.D. Stanford University 2020
Rights: (c) Copyright 2020 by Sarah Haymore Sandholtz
Rights: This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
Keywords: theses; text