Fluctuations in DNA Packing Density Drive the Spatial Segregation between Euchromatin and Heterochromatin

In the crowded eukaryotic nucleus, euchromatin and heterochromatin segregate into distinct compartments, a phenomenon often attributed to homotypic interactions mediated by liquid liquid phase separation of chromatin associated proteins. Here, we revisit genome compartmentalization by examining the role of in vivo DNA packing density fluctuations driven by ATP dependent chromatin remodelers. Leveraging DNA accessibility data, we develop a polymer based model that captures these fluctuations and successfully reproduces genome wide compartment patterns observed in HiC data, without invoking homotypic interactions. Further analysis reveals that density fluctuations in a crowded nuclear environment elevate the system energy, while euchromatin heterochromatin segregation facilitates energy dissipation, offering a thermodynamic advantage for spontaneous compartment formation. These findings suggest that euchromatin heterochromatin segregation may arise through a non equilibrium, self organizing process, providing new insights into genome organization.