Four-Dimensional Mesoscale Liquid Model of Nucleus Resolves Chromatin's Radial Organization.

Recent advances chromatin capture, imaging techniques, and polymer modeling have dramatically enhanced quantitative understanding of chromosomal folding. However, the dynamism inherent in genome architectures due to physical and biochemical forces and their impact on nuclear architecture and cellular functions remains elusive. While imaging of chromatin in four dimensions is becoming more common, there is a conspicuous lack of physics-based computational tools appropriate for revealing the forces that shape nuclear architecture and dynamics. To this end, we have developed a multiphase liquid model of the nucleus, which can resolve chromosomal territories, compartments, and nuclear lamina using a physics-based and data-informed free-energy function. The model enables rapid hypothesis-driven prototyping of nuclear dynamics in four dimensions, thereby facilitating comparison with whole nucleus imaging experiments. As an application, we model the Drosophila nucleus and map phase diagram of various possible nuclear morphologies. We shed light on the interplay of adhesive and cohesive interactions which give rise to distinct radial organization seen in conventional, inverted, and senescent nuclear architectures. The results also show the highly dynamic nature of the radial organization, the disruption of which leads to significant variability in domain coarsening dynamics and consequently variability of chromatin architecture. The model also highlights the impact of oblate nuclear geometry and heterochromatin-subtype interactions on the global chromatin architecture and local asymmetry of chromatin compartments.