Polymer model predicts history dependent epigenetic and lamin-associated domain sizes.

Abstract

The association of epigenetic markers with phase-separated genomic compartments is well known. Although correlated changes in 3D organization and epigenetics in response to stimuli have been observed, current physical models cannot explain this behavior. To tackle this problem, we develop a dynamic, reaction-based polymer model which takes input from ChIP-seq data to identify the initial active, repressed, and CTCF-associated beads on a string to represent the chromatin. The interaction potentials between different epigenetic states are tuned against known spatial distance-genomic distance relationships and show established hierarchical structures in the obtained HiC contact map. The proposed dynamics of the polymer form finite-size domains and prevent spatial domain coarsening. We further show that the dynamics succeed in maintaining epigenetic domain stability and spatial distance relations. Chromatin compaction and expansion are seen in response to epigenetic spreading through methylation and acetylation reactions, respectively, which agrees with experimental STORM imaging observations. We can also predict 3D chromatin reorganization in response to changing chromatin-lamin interactions. Lastly, we expose our system to changing stimuli and find that the genomic domains show memory-like features. The simplicity of the dynamics, along with our use of biological inputs, is a significant step forward in understanding how chromatin dynamics affect both short-term (immediate response) and long-term (memory) cellular behavior.