Liquid-liquid phase separation induces stochastic oscillations in gene regulation

Area of Science:

• Biochemistry
• Systems Biology
• Molecular Biology

Background:

• Rhythmic gene expression is crucial for physiological processes.
• Protein compartmentalization via liquid-liquid phase separation (LLPS) is implicated in regulating these dynamics.
• The precise mechanisms linking LLPS to oscillatory behavior remain largely unknown.

Purpose of the Study:

• To develop a minimal model investigating how LLPS influences gene expression rhythms.
• To elucidate the feedback mechanisms between LLPS and oscillatory dynamics.
• To provide a quantitative framework for understanding LLPS-rhythm coupling.

Main Methods:

• Development of a minimal two-phase gene-expression model.
• Analysis of protein synthesis, partitioning between dilute and dense phases, and repression of production.
• Investigation in both deterministic and stochastic regimes using power spectral density and autocorrelation functions.

Main Results:

• In the deterministic limit, LLPS alone does not generate sustained oscillations but creates damped transients.
• Nonlinear partitioning and timescale separation between phase separation and protein turnover are key.
• In the stochastic regime, intrinsic noise amplifies near-focus dynamics into noise-sustained, near-periodic fluctuations.

Conclusions:

• LLPS can reshape oscillatory signatures by encoding and filtering temporal signals.
• The interplay between noise and LLPS dynamics generates characteristic rhythmic behavior.
• This work offers a framework for interpreting LLPS-rhythm coupling and engineering biomolecular systems.