(712b) Physics-Based Modeling of Chromosomal Organization Impacted By Multiple Epigenetic Factors
AIChE Annual Meeting
2022
2022 Annual Meeting
Engineering Sciences and Fundamentals
Thermodynamics of Biomolecular Folding and Assembly
Friday, November 18, 2022 - 12:45pm to 1:00pm
In this study, we apply a custom-built, physics-based copolymer simulator to model DNA folding from patterns of epigenetic modifications and characteristic effector protein interactions. We leverage the wormlike chain model to capture the semiflexible properties of DNA. Epigenetic modifications along our polymer are fixed based on experimental chromatin immunoprecipitation sequencing (ChIP-seq) data from literature. We sample binding patterns of effector proteins based on their affinities for different chemical modifications and their concentrations in the nuclear environment. Using a field-theoretic approach, we calculate the energy associated with effector protein interactions based on their local densities. Individual components are modeled with experimentally measured interaction parameters, and we modulate these parameters to represent cooperative, noncooperative, and anticooperative interactions between different effector proteins. Through a Monte Carlo algorithm, we sample thermodynamically favorable DNA configurations under variable degrees of effector protein cooperativity. We validate our model using theoretical polymer chain statistics and experimental contact maps.
Our physics-based approach enables us to elucidate causal relationships between environmental factors and DNA organization. We aim to predict chromatin structures for variable effector protein interaction strengths to identify conditions that cause the chromosome to adopt aberrant configurations associated with age-related disease. We also simulate how effector protein interactions affect susceptibility to epigenetic drift. Overall, the study applies polymer theory and simulation to advance mechanistic understanding into biophysical factors contributing to epigenetic diseases.