Euchromatin Activity Enhances Segregation and Compaction of Heterochromatin in the Cell Nucleus

The large-scale organization of the genome inside the cell nucleus is critical for the cell’s function. Chromatin—the functional form of DNA in cells—serves as a template for active nuclear processes such as transcription, replication, and DNA repair. Chromatin’s spatial organization directly affects its accessibility by ATP-powered enzymes, e.g., RNA polymerase II in the case of transcription. In differentiated cells, chromatin is spatially segregated into compartments—euchromatin and heterochromatin—the former being largely transcriptionally active and loosely packed, the latter containing mostly silent genes and densely compacted. The euchromatin-heterochromatin segregation is crucial for proper genomic function, yet the physical principles behind it are far from understood. Here, we model the nucleus as filled with hydrodynamically interacting active Zimm chains—chromosomes—and investigate how large heterochromatic regions form and segregate from euchromatin through their complex interactions. Each chromosome presents a block copolymer composed of heterochromatic blocks, capable of cross-linking that increases chromatin’s local compaction, and euchromatic blocks, subjected to stochastic force dipoles that capture the microscopic stresses exerted by nuclear ATPases. These active stresses lead to a dynamic self-organization of the genome, with its coherent motions driving some mixing of chromosome territories as well as large-scale heterochromatic segregation through cross-linking of distant genomic regions. We study the stresses and flows that arise in the nucleus during the heterochromatic segregation and identify their signatures in Hi-C proximity maps. Our results reveal the fundamental role of active mechanical processes and hydrodynamic interactions in the kinetics of chromatin compartmentalization and in the emergent large-scale organization of the nucleus.