Switching off: the phenotypic transition to the uninduced state of the lactose uptake pathway

TL;DR

This paper investigates the stochastic mechanisms behind the transition of the lac-operon in E. coli from an induced to an uninduced state, combining detailed computational modeling with experimental data to understand the stability and transition rates of gene regulation states.

Contribution

The study introduces a minimal model capturing the transition to the uninduced state, highlighting the roles of repressor dynamics and stochastic fluctuations, and compares it with detailed simulations and experiments.

Findings

Transition rate to uninduced state is extremely low (<2×10⁻⁹ per minute).

The transition to the uninduced state can be modeled as a 2D diffusive barrier crossing.

Repressor binding/unbinding and fluctuations are key to phenotypic switching.

Abstract

The lactose uptake-pathway of E. coli is a paradigmatic example of multistability in gene-regulatory circuits. In the induced state of the lac-pathway, the genes comprising the lac-operon are transcribed, leading to the production of proteins which import and metabolize lactose. In the uninduced state, a stable repressor-DNA loop frequently blocks the transcription of the lac-genes. Transitions from one phenotypic state to the other are driven by fluctuations, which arise from the random timing of the binding of ligands and proteins. This stochasticity affects transcription and translation, and ultimately molecular copy numbers. Our aim is to understand the transition from the induced to the uninduced state of the lac-operon. We use a detailed computational model to show that repressor-operator binding/unbinding, fluctuations in the total number of repressors, and inducer-repressor binding/unbinding all play a role in this transition. Based on the timescales on which these processes operate, we construct a minimal model of the transition to the uninduced state and compare the results with simulations and experimental observations. The induced state turns out to be very stable, with a transition rate to the uninduced state lower than $2 \times 10^{-9}$ per minute. In contrast to the transition to the induced state, the transition to the uninduced state is well described in terms of a 2D diffusive system crossing a barrier, with the diffusion rates emerging from a model of repressor unbinding.