Liquid–liquid phase separation driven compartmentalization of reactive nucleoplasm

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.

Liquid-Liquid Phase Separation: Unraveling the Enigma of Biomolecular Condensates in Microbial Cells

“…Using the surface effect, cells can utilize additional components that can only be dissolved in droplets to prevent droplets from Ostwald ripening ( Webster and Cates, 1998 ; Zwicker et al, 2015 ; Bressloff, 2020 ). Currently, frameworks have been proposed for studying the non-equilibrium dynamics of the dense cellular aggregates, facilitating the link between phase separation and the gene regulatory processes inside the nucleus ( Yamamoto et al, 2020 ; Kuan et al, 2021 ; Laghmach and Potoyan, 2021 ).…”

Chromatin Conformation in Development and Disease

“…It has also been proposed that the outer edge of phase-separation droplets acts as a barrier that proteins could not pass through ( Strom et al, 2017 ), despite the quick recovery of CDK9-mCherry signal after photo-bleaching, suggesting that CDK9-mCherry is constantly recruited to the stably positioned transcription factories ( Ghamari et al, 2013 ), Chromatin compartmentalization might be the reason that activating transcription factors are not present in B compartments ( Laghmach and Potoyan, 2021 ). Phase separation could explain several confusing observations, like how transcriptional activation occurs without direct physical contact between enhancers and promoters through eRNAs ( Cai et al, 2020 ), or multi-enhancer and multi-promoter contacts ( Li G. et al, 2012 ; Jin et al, 2013 ), or simultaneous regulation of more than one gene by a single enhancer ( Fukaya et al, 2016 ).…”

The intertwined physics of active chemical reactions and phase separation

“…Chemical reactions provide additional control via rate-controlling enzymes, which can be localized precisely. Such spatial control over reactions can determine resulting patterns [126,127] and localize droplets [128,129]. Finally, the interplay between bulk and surface dynamics implies a prominent role of geometry, which was described in detail for traditional reaction-diffusion systems, like the Min oscillations [130,131], but could also control droplets, e.g., at the origin-of-life [132].…”