Effects of chromatin phase separation on the morphology of eukaryotic cell nucleus*

Anomalies in the shape of the eukaryotic cell nucleus are typical hallmarks of a variety of diseases, including progeria, many cancer types, and even chronological aging. One of the significant contributors to the nuclear shape is the chromatin polymer confined inside the micron-sized elastic nucleus. However, the polymer-physical mechanisms of this relationship need to be better understood. Using coarse-grained random tri-block copolymers and an elastic-shell model that can capture conventional chromatin organization while maintaining the mechanical deformability of the cell nucleus, we focus on how chromatin (micro)phase separation can affect nuclear morphology. Scanning biologically relevant volume fractions, polymer-polymer interactions, and polymer-shell interactions reveals that polymer compaction (effective Flory parameter) could be a major driver of nuclear shape. When the polymer and shell interact strongly, the nuclear shape deforms, shape fluctuations arise, and the nuclear shape deviates from the spherical shape in simulations. Low polymer volume fractions favor abnormal nuclear shape as the polymer-induced pressure decreases. Altogether, our simulations suggest that nuclear-scale distribution of the copolymer genome can lead to misshapen nuclei, possibly determining the nuclear morphology along with nuclear lamina components and cytoskeletal forces