Reconciling Kinetic and Equilibrium Models of Bacterial Transcription

TL;DR

This paper compares seven models of bacterial transcription regulation, demonstrating how equilibrium and kinetic approaches can predict gene expression levels and highlighting the two-state model with burst size distribution as most effective.

Contribution

It introduces and evaluates seven distinct models of the simple-repression motif, clarifying their predictive power and limitations in describing transcriptional regulation.

Findings

Equilibrium models can often predict mean gene expression accurately.

Kinetic models provide insights into variance and distribution of gene expression.

The two-state model with burst size distribution best fits experimental data.

Abstract

The study of transcription remains one of the centerpieces of modern biology with implications in settings from development to metabolism to evolution to disease. Precision measurements using a host of different techniques including fluorescence and sequencing readouts have raised the bar for what it means to quantitatively understand transcriptional regulation. In particular our understanding of the simplest genetic circuit is sufficiently refined both experimentally and theoretically that it has become possible to carefully discriminate between different conceptual pictures of how this regulatory system works. This regulatory motif, originally posited by Jacob and Monod in the 1960s, consists of a single transcriptional repressor binding to a promoter site and inhibiting transcription. In this paper, we show how seven distinct models of this so-called simple-repression motif, based both on equilibrium and kinetic thinking, can be used to derive the predicted levels of gene expression and shed light on the often surprising past success of the equilbrium models. These different models are then invoked to confront a variety of different data on mean, variance and full gene expression distributions, illustrating the extent to which such models can and cannot be distinguished, and suggesting a two-state model with a distribution of burst sizes as the most potent of the seven for describing the simple-repression motif.