Abstract

Chromatin organization is essential for differential gene expression in humans, enabling a diverse array of cell types to develop from the same genetic code. The architecture of chromatin is dictated by patterns of epigenetic marks–chemical modifications to DNA and histones–which must be reestablished during each cell replication cycle. Dysregulation of chromatin organization has drastic medical consequences and can contribute to aging, obesity, and cancer progression. During this study, we develop a Monte Carlo simulator called “Chromo” to investigate factors affecting chromatin organization. The simulator proposes and evaluates random configurational changes to chromatin, which include geometric transformations and effector protein binding/unbinding to the biopolymer. By iteratively sampling configurations, Chromo generates snapshots of energetically favorable chromatin architectures. Unlike previous models fit to experimental data, Chromo is rooted in fundamental polymer theory, allowing us to predict biophysical mechanisms governing chromatin organization. By leveraging a computationally efficient field theoretic approach, we can simulate full human chromosomes with nucleosome-scale resolution. To confirm the validity of our simulator, we reproduce theoretical chain statistics for flexible and semiflexible homopolymers and recapitulate heterochromatin compartments expected in chromatin contact maps. Using Chromo, we will evaluate how the quality of structural prediction changes with the simulation of additional epigenetic marks. We will also identify which combinations of marks best explain the architecture of the chromosome.