Post-translational control of gene expression noise by liquid-liquid phase separation

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Noise in transcription and translation causes substantial cell-to-cell variability in protein concentrations across isogenic cells. A key question in biology is how cells manage to function robustly and reliably while their inner workings are often subject to substantial heterogeneity. Previous studies have shown that feedback circuits at the transcriptional level have noise-suppressing properties but their efficacy is often limited by long time delays and they often demand for enormous energy resources to achieve significant noise suppression. In this project, we hypothesize an alternative, post-translational mechanism to suppress gene expression noise based on liquid-liquid phase separation. In phase separating systems, liquid compartments form via demixing of intrinsically disordered proteins as soon as they exceed a certain threshold concentration. In this regime, concentrations outside of the compartments are remarkably homogeneous across cells. This suggests that these compartments could function as buffers that compensate for cell-to-cell variability in protein concentrations. This hypothesis is supported by our preliminary study, where we have demonstrated the suppression of variability via liquid compartments using an artificial gene expression system. However, a demonstration in endogenous systems remains lacking. Here we propose a cross-disciplinary research program, which aims at filling this gap. Our project has the potential to reveal an important novel function of phase separation and may provide a significant leap forward in understanding the mechanisms underlying robust biological behavior.