Abstract
The nucleus of eukaryotic cells harbors active and out of equilibrium environments conducive to diverse gene regulatory processes. On a molecular scale, gene regulatory processes take place within hierarchically compartmentalized sub-nuclear bodies. While the impact of nuclear structure on gene regulation is widely appreciated, it has remained much less clear whether and how gene regulation is impacting nuclear order itself. Recently, the liquid–liquid phase separation emerged as a fundamental mechanism driving the formation of biomolecular condensates, including membrane-less organelles, chromatin territories, and transcriptional domains. The transience and environmental sensitivity of biomolecular condensation are strongly suggestive of kinetic gene-regulatory control of phase separation. To better understand kinetic aspects controlling biomolecular phase-separation, we have constructed a minimalist model of the reactive nucleoplasm. The model is based on the Cahn–Hilliard formulation of ternary protein–RNA–nucleoplasm components coupled to non-equilibrium and spatially dependent gene expression. We find a broad range of kinetic regimes through an extensive set of simulations where the interplay of phase separation and reactive timescales can generate heterogeneous multi-modal gene expression patterns. Furthermore, the significance of this finding is that heterogeneity of gene expression is linked directly with the heterogeneity of length-scales in phase-separated condensates.
Highlights
Phase separation is a fundamental mechanism for the emergent order in an ordinary and biological matter [1, 2]
We propose a minimal model of a reactive nucleoplasm (Fig. 1) with an objective to illustrate, in a proof of principle manner; (i) How spatially resolved nonequilibrium reactive en-events generate qualitatively distinct from equilibrium phase behavior and (ii) How the interplay of various kinetic timescales in the system impacts gene expression patterns
Despite the incredible simplicity of the minimal reactive nucleoplasm model, the time course of simulations (Fig. 2-4) has revealed a non-trivial patterning of nucleoplasm which are a dramatic departure from equilibrium thermodynamics of ternary phase separation in the absence of spatially non-uniform reaction-diffusion
Summary
Phase separation is a fundamental mechanism for the emergent order in an ordinary and biological matter [1, 2]. The stickers-and-spacers framework has emerged as a viable model explaining the existence of a broad class of sequence encoded driving forces of disordered proteins which serve as nucleating centers for biomolecular condensates [3, 18]. These newly appreciated abilities of proteins and nucleic acids for forming large-scale liquid bodies is offering fresh avenues for understanding mechanisms of the coordinated action of biomolecules in gene regulation and cellular organization that go beyond single-molecule action. The present work clarifies as a first step the dual nature of nuclear order and gene expression, and provides a useful theoretical framework for understanding equilibrium and non-equilibrium origins of intra-nuclear patterning
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