Chromatin as a Coevolutionary Graph: Modeling the Interplay of Replication with Chromatin Dynamics

Modeling DNA replication requires capturing the interplay of multiple biophysical processes and their effects on chromatin structure. We present RepliSage, a multi-scale framework that integrates three key factors: replication timing, loop extrusion, and compartmentalization. Replication forks act as moving barriers that reorganize chromatin during S phase by interfering with loop extrusion. Our approach combines: (1) fork propagation simulated from single-cell replication timing data, (2) Monte Carlo modeling of loop extrusion and epigenetic state transitions, and (3) 3D reconstruction using OpenMM, where loops are modeled as harmonic bonds and epigenetic states drive compartmental interactions. Chromatin is represented as a graph where both the links and the node states change over time. By adjusting model parameters across cell cycle phases, we reproduce known structural transitions and explore how replication stress alters genome organization. This is the first framework to dynamically integrate all three processes for simulating chromatin architecture during the cell cycle.