Modeling the Origin of Long-Range Correlation of DNA Methylation in Chromosomal DNA

DNA methylation is critical for modulating gene expression and chromosomal organization within the cell. Characterization of this epigenetic modification in vivo has revealed correlation of DNA methylation that spans more than three magnitudes of genomic distance. This research focuses on unraveling the mechanisms behind this long-range DNA methylation correlation. In our study, we introduce a dynamic model that captures the transport behavior of methyltransferases. Chromosomal DNA is modeled as a polymer strand whose multi-scale behavior recapitulates in vivo chromosomal organization. The methyltransferase is modelled as a particle that alternates between a polymer-bound state, where it diffuses along the polymer depositing methyl groups, and an unbound state, where it engages in a 3D diffusion throughout the environment and explores the multi-scale polymer conformation. Our model allows us to determine the impact of methylation rate, diffusivity, and processivity on methylation dynamics. Intriguingly, our model recapitulates the extensive range of DNA methylation correlation data, as well as other qualitative features, challenging the notion of complex biological mechanisms governing this phenomenon. Instead, it suggests that nuclear confinement, which results in condensed DNA structures, may be a key driver in the expansive reach of DNA methyltransferase. This research highlights the intricate connection between methylation and chromatin structure, emphasizing the role of polymer physics in deciphering epigenetic regulation.