Abstract

Significance Human DNA is 2 m long and is folded into a 10-μm-sized cellular nucleus. Experiments have revealed two major features of genome organization: Segregation of alternating active and inactive regions into compartments, and formation of compacted local domains. These were hypothesized to be formed by different mechanisms: Compartments can be formed by microphase separation and domains by active, motor-driven, loop extrusion. Here, we integrate these mechanisms into a polymer model and show that their interplay coherently explains diverse experimental data for wild-type and mutant cells. Our results provide a framework for the interpretation of chromosome organization in cellular phenotypes and highlight that chromatin is a complex, active matter shaped by an interplay of phase segregation and loop extrusion.