Chromatin heterogeneity modulates nuclear condensate dynamics and phase behavior

The cell nucleus is a soft composite material with a shell-like nuclear cortex enclosing chromatin, comprised of roughly 2 meters of DNA and associated proteins. Assembling on and around chromatin are droplet-like structures known as biomolecular condensates, which form via phase separation, and facilitate vital roles in gene expression. From studies in non-living materials, the driving forces for phase separation are expected to be sensitive to the local mechanical environment, which often exhibits significant spatial heterogeneity. However, the relationship between chromatin heterogeneity and the phase equilibrium and dynamics of nuclear condensates remains unclear. Here, we investigate the interplay between chromatin organization and the formation, dynamics, and size of engineered model condensates and endogenous nuclear bodies in living cells. We demonstrate that decreasing chromatin heterogeneity with epigenetic modifying drugs correlates with decreased mobility of both endogenous and engineered condensates, and is associated with impaired condensate growth and shifts in the binodal phase boundary of engineered condensates. These findings illustrate how the cell nucleus behaves as a heterogeneous composite material with mechanically permissive chromatin micro-environments.