Computational analysis of 3D genome organization and its effect on nuclear morphology and mechanics

Abstract

Several disorders, including progeria, cancer, and Emery-Dreifuss muscular dystrophy, share abnormalities in eukaryotic cells' nuclear structure and mechanics. One of the contributors to nuclear morphology and mechanics is the chromatin filling the 10-micron elastic nucleus. The polymer physics principles behind the relationship between chromatin and nuclear morphology and its mechanics need to be clarified. To elucidate this relationship between chromatin and polymer and nuclear morphology and mechanics, we concentrate on chromatin phase separation utilizing a coarse-grained polymer model encapsulated in an elastic shell. Our approach can capture the conventional and inverted nucleus organization while allowing nuclear deformability. Heterochromatin can be one of the key determinants of the nuclear shape by revealed by examining heterochromatin heterochromatin interactions, as well as the interaction between chromatin and lamina inspecting through the biologically relevant volume fractions. The simulations showed that the heterochromatin-nuclear shell interactions influence the variation in the nuclear shape fluctuations, thus leading to nuclear deformations. The interplay between heterochromatin-heterochromatin interactions and its interaction with the nuclear shell plays a role in phase separation and nuclear shape fluctuations. Higher heterochromatin concentration resulted in abnormal morphology in lower volume fraction, in contrast to some experiments suggesting the opposite trend. The volume fraction exhibits a suppressing effect on the nuclear shape fluctuations in all examinations of heterochromatin interactions. Additionally, the tethering and crosslinking of the heterochromatin provide a chromatin-based stiffness to the nuclear shell revealed by force-strain relationships. Altogether, our results imply that chromatin, mainly heterochromatin, considerably contributes to nuclear morphology and mechanics.