Geometric and Topological Chromatin Organization During Progressive Nuclear Confinement

Chromatin spatial organization is commonly described through compaction, contact frequencies, chromosome territories, loops and polymer dynamics, yet these measures do not address how nuclear confinement shapes accessible genome configurations. We introduce the concept of chromatin congestion to describe changes in the geometrically, topologically and mechanically admissible chromatin configurations within a confined nucleus, integrating directional geometric constraints, topological obstruction, stochastic exploration, mechanical deformation and long-range dependence into a common description. We performed stochastic simulations of 480 nuclei across six microchannel widths from 14 to 4 micrometers, keeping chromatin content constant and quantifying collision-free path length, locus displacement, topological encounters, curvature, bending work, perturbation propagation and DNA-damage burden. As confinement progressed, chromatin displacement initially increased, consistent with exploration of the configurations still available, but declined under stronger restriction. Topological encounters, curvature and mechanical work increased, while perturbations extended across progressively larger nuclear regions and were associated with greater damage burden. Our simulations suggest that progressive confinement can drive transition from locally buffered chromatin dynamics to increasingly collective genome behaviour, characterized by stronger spatial interdependence among genomic regions. Potential applications include microfluidic migration experiments, single-cell nuclear phenotyping and the integration of imaging, mechanical and genome-organization measurements.