Abstract
Nuclear bodies are membraneless condensates that may form via liquid-liquid phase separation. The viscoelastic chromatin network could impact their stability and may hold the key for understanding experimental observations that defy predictions of classical theories. However, quantitative studies on the role of the chromatin network in phase separation have remained challenging. Using a diploid human genome model parameterized with chromosome conformation capture (Hi-C) data, we study the thermodynamics and kinetics of nucleoli formation. Dynamical simulations predict the formation of multiple droplets for nucleolar particles that experience specific interactions with nucleolus-associated domains (NADs). Coarsening dynamics, surface tension, and coalescence kinetics of the simulated droplets are all in quantitative agreement with experimental measurements for nucleoli. Free energy calculations further support that a two-droplet state, often observed for nucleoli in somatic cells, is metastable and separated from the single-droplet state with an entropic barrier. Our study suggests that nucleoli-chromatin interactions facilitate droplets’ nucleation but hinder their coarsening due to the coupled motion between droplets and the chromatin network: as droplets coalesce, the chromatin network becomes increasingly constrained. Therefore, the chromatin network supports a nucleation and arrest mechanism to stabilize the multi-droplet state for nucleoli and possibly for other nuclear bodies.
Highlights
Nuclear bodies are membraneless condensates that may form via liquid-liquid phase separation
We modeled the dynamical process of phase separation that drives nucleoli formation in the presence of the chromatin network
Simulations carried out with coarse-grained nucleolar particles succeeded in producing multiple droplets with dynamical behaviors comparable to nucleoli
Summary
Nuclear bodies are membraneless condensates that may form via liquid-liquid phase separation. Increasing evidence supports that nuclear bodies function as biomolecular condensates formed via liquid-liquid phase separation (LLPS)[4,7,8,9] They exhibit round morphologies and dynamic fluid properties[10,11]. Two nuclear bodies can fuse into larger condensates following growth kinetics with similar scaling behavior as that observed for simple liquids[12,13,14] Their assembly was shown to be concentration-dependent, and the coarsening and growth dynamics can be quantitatively modeled with classical theories of phase separation[15]. Low complexity domains and intrinsically disordered regions are enriched in many of the proteins associated with nuclear bodies[16,17,18,19,20] These features enable non-specific, multivalent interactions that drive the formation of dynamical condensates. Several observations of nuclear bodies appear to defy predictions from classical nucleation and phase separation theories
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