Illuminating the link between nuclear geometry and chromatin structure dynamics through 4D nucleus modeling

Eukaryotic nucleus confines nearly meter-long polymeric chromatin folding chains within its micron-sized membrane bounds while remaining dynamic and accessible for gene regulation. The chromatin structures in the nucleus form through microphase separation of epigenetically decorated chromatin types. The 3D structures and dynamical aspects of chromatin is believed to be strongly coupled with genetic processes. Investigating the principles underlying the nuclear architectures and dynamics could pave the way to identifying the relationship between chromatin structures, gene expression, and regulation machinery. The chromatin capture and imaging techniques have revealed a much more dynamic and stochastic nature of chromatin structures which is reminiscent of multiphase fluid behavior. The recent findings show that the nuclear geometry and presence of membrane-bound lamina globally shapes nuclear architectures and dynamical aspects of chromatin organization. The link between nuclear geometry and the dynamics of phase-separated chromatin domains is imperative to be considered for revealing features of the nucleus and its biological functions. Here, we present a mesoscale liquid model of the nucleus called MELON-4D, which describes the state of the nucleus as a mixture of incompressible multiphase liquid-like chromatin types. Our model disentangles the complex interplay of nuclear geometry and driving forces that contribute to the emergent patterns of chromatin organization and dynamics. Our results indicate that the liquid-liquid phase separation, together with surface tension effects, are sufficient to recapitulate much of the structural and dynamical aspects of nuclear chromatin architectures along the life cycle of cells. We also shed light on the dynamical heterogeneity and coherent motions of chromatin compartments which are fully captured by an interplay of micro-phase separation of chromatin types and lamina binding.