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.

RNA chain length and stoichiometry govern surface tension and stability of protein-RNA condensates

“…Theoretical models ( Choi et al., 2020a ; Ruff et al., 2018 ; Zeng et al., 2020 ; Pappu, 2020 ; Lin et al., 2020 ; Huihui and Ghosh, 2020 ), molecular simulations ( Shea et al., 2021 ; Regy et al., 2020 ; Dignon et al., 2020 ; Ruff et al., 2018 ; Choi et al., 2019 ), and field theoretical simulations ( Pal et al., 2021 ; McCarty et al., 2019 ; Laghmach and Potoyan, 2020 ) of biomolecular phase transitions have emerged to play an increasingly important role alongside experiments in shedding light on the sequence-encoded driving forces as well as biophysical and material properties of condensates. One of the emerging theoretical frameworks from these studies is the stickers-and-spacers framework ( Choi et al., 2020a , 2020b ; Brangwynne et al., 2015 ; Chong and Mir, 2021 ) inspired from the field of associative polymers.…”