Chromatin phase separation and nuclear shape fluctuations are correlated in a polymer model of the nucleus

Abnormalities in the shapes of mammalian cell nuclei are hallmarks of a variety of diseases, including progeria, muscular dystrophy, and various cancers. Experiments have shown that there is a causal relationship between chromatin organization and nuclear morphology. Decreases in heterochromatin levels, perturbations to heterochromatin organization, and increases in euchromatin levels all lead to misshapen nuclei, which exhibit deformations, such as nuclear blebs and nuclear ruptures. However, the polymer physical mechanisms of how chromatin governs nuclear shape and integrity are poorly understood. To investigate how heterochromatin and euchromatin, which are thought to microphase separate in vivo , govern nuclear morphology, we implemented a composite coarse-grained polymer and elastic shell model. By varying chromatin volume fraction (density), heterochromatin levels and structure, and heterochromatin-lamina interactions, we show how the spatial organization of chromatin polymer phases within the nucleus could perturb nuclear shape in some scenarios. Increasing the volume fraction of chromatin in the cell nucleus stabilizes the nuclear lamina against large fluctuations. However, surprisingly, we find that increasing heterochromatin levels or heterochromatin-lamina interactions enhances nuclear shape fluctuations in our simulations by a "wetting"-like interaction. In contrast, shape fluctuations are largely insensitive to the internal structure of the heterochromatin, such as the presence or absence of chromatin-chromatin crosslinks. Therefore, our simulations suggest that heterochromatin accumulation at the nuclear periphery could perturb nuclear morphology in a nucleus or nuclear region that is sufficiently soft, while stabilization of the nucleus via heterochromatin likely occurs through mechanisms other than chromatin microphase organization.