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

Modeling DNA replication poses significant challenges due to the intricate interplay of biophysical processes and the need for precise parameter optimization. In this study, we explore the interactions among three key biophysical factors that influence chromatin folding: replication, loop extrusion, and compartmentalization. Replication forks, known to act as barriers to the motion of loop extrusion factors, also correlate with the phase separation of chromatin into A and B compartments. Our approach integrates three components: (1) a numerical model that takes into advantage single-cell replication timing data to simulate replication fork propagation; (2) a stochastic Monte Carlo simulation that captures the interplay between the biophysical factors, with loop extrusion factors binding, unbinding, and extruding dynamically, while CTCF barriers and replication forks act as static and moving barriers, and a Potts Hamiltonian governs the spreading of epigenetic states driving chromatin compartmentalization; and (3) a 3D OpenMM simulation that reconstructs the chromatin’s 3D structure based on the states generated by the stochastic model. To our knowledge, this is the first framework to dynamically integrate and simulate these three biophysical factors, enabling insights into chromatin behavior during replication. Furthermore, we investigate how replication stress alters these dynamics and affects chromatin structure.