Gene regulation in continuous cultures: A unified theory for bacteria and yeasts

TL;DR

This paper extends a minimal enzyme induction and dilution model to continuous microbial cultures, explaining substrate consumption patterns and growth behaviors across bacteria and yeasts without invoking specific regulatory mechanisms.

Contribution

It demonstrates that dilution effects alone can explain observed growth patterns and provides a bifurcation diagram linking batch and continuous culture behaviors.

Findings

Dilution explains enzymatic trends previously attributed to specific regulation.

The bifurcation diagram accurately predicts substrate and enzyme levels at various conditions.

Numerical simulations match experimental data across different microbes and growth conditions.

Abstract

During batch growth on mixtures of two growth-limiting substrates, microbes consume the substrates either sequentially or simultaneously. These growth patterns are manifested in all types of bacteria and yeasts. The ubiquity of these growth patterns suggests that they are driven by a universal mechanism common to all microbial species. In previous work, we showed that a minimal model accounting only for enzyme induction and dilution explains the phenotypes observed in batch cultures of various wild-type and mutant/recombinant cells. Here, we examine the extension of the minimal model to continuous cultures. We show that: (1) Several enzymatic trends, usually attributed to specific regulatory mechanisms such as catabolite repression, are completely accounted for by dilution. (2) The bifurcation diagram of the minimal model for continuous cultures, which classifies the substrate consumption pattern at any given dilution rate and feed concentrations, provides a a precise explanation for the empirically observed correlation between the growth patterns in batch and continuous cultures. (3) Numerical simulations of the model are in excellent agreement with the data. The model captures the variation of the steady state substrate concentrations, cell densities, and enzyme levels during the single- and mixed-substrate growth of bacteria and yeasts at various dilution rates and feed concentrations. (4) This variation is well-approximated by simple analytical expressions that furnish physical insights into the steady states of continuous cultures. The minimal model provides a framework for quantitating the effect of regulatory mechanisms. We illustrate this by analyzing several data sets from the literature.