Landscapes and nonequilibrium fluctuations of eukaryotic gene regulation

TL;DR

This paper investigates how different timescales of chromatin state changes and protein production influence eukaryotic gene regulation, revealing complex nonequilibrium dynamics and hysteresis effects through stochastic modeling.

Contribution

It introduces a stochastic model that captures the impact of nonadiabatic chromatin transitions on gene regulation dynamics, highlighting the role of timescale differences.

Findings

Slow chromatin transitions significantly affect gene regulation.

Circular probability currents indicate maximum entropy production in nonadiabatic regimes.

Hysteresis emerges when chromatin state changes precede transcription changes.

Abstract

Understanding the interplay among processes that occur over different timescales is a challenging issue in the physics of systems regulation. In gene regulation, the timescales for changes in chromatin states can differ from those for changes in the concentration of product protein, raising questions about how to understand their coupled dynamics. In this study, we examine the effects of these different timescales on eukaryotic gene regulation using a stochastic model that describes the landscapes and probability currents of nonequilibrium fluctuations.This model shows that slow, nonadiabatic transitions of chromatin states significantly impact gene-regulation dynamics. The simulated circular flow of the probability currents indicates a maximum entropy production when the rates of chromatin-state transitions are low in the intensely nonadiabatic regime. In the mildly nonadiabatic regime, this circular flow fosters hysteresis, suggesting that changes in chromatin states precede changes in transcription activity. Furthermore, calculations using a model of a circuit involving three core genes in mouse embryonic stem cells illustrate how the timescale difference can tune fluctuations in individual genes. These findings highlight the rich effects of nonadiabatic chromatin-state transitions on gene regulation in eukaryotic cells.