RepliSage: A Stochastic Graph-Based Framework for 3D Chromatin Modeling Across the Cell Cycle

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.