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  • Review Article
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Phenotypic variation in bacteria: the role of feedback regulation

Nature Reviews Microbiology volume 4, pages 259–271 (2006)Cite this article

Key Points

  • Even under laboratory conditions, bacteria often show a high degree of phenotypic variability — cells within an isogenic population displaying variable expression patterns.

  • Positive feedback within a regulatory network has the potential to generate multistationarity — the possibility of a cell to switch between states.

  • Bistability or multistability is the occurrence of two or more distinguishable phenotypes within the isogenic population. The ratio of cells within a specific cell state depends on the intrinsic properties of the switch and is often influenced and modulated by environmental signals.

  • It was found that the molecular mechanism underlying phenotypic variation in a number of adaptive bacterial responses, such as competence and sporulation in Bacillus subtilis, is based on positive feedback.

  • Many of the observed — but still unexplained — variable phenotypes reported within bacterial research are likely to originate from the feedback structure within the regulatory pathway.

  • Phenotypic variability is a way to increase the fitness of the population, especially under fluctuating environmental conditions.

Abstract

To survive in rapidly changing environmental conditions, bacteria have evolved a diverse set of regulatory pathways that govern various adaptive responses. Recent research has reinforced the notion that bacteria use feedback-based circuitry to generate population heterogeneity in natural situations. Using artificial gene networks, it has been shown that a relatively simple 'wiring' of a bacterial genetic system can generate two or more stable subpopulations within an overall genetically homogeneous population. This review discusses the ubiquity of these processes throughout nature, as well as the presumed molecular mechanisms responsible for the heterogeneity observed in a selection of bacterial species.

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Figure 1: Bistability in the lactose-utilization network.
Figure 2: Bistability in competence and sporulation of Bacillus subtilis.
Figure 3: Survival of variable phenotypes under selective pressure.

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Acknowledgements

W.K.S. and J.W.V. were supported by grants from the Netherlands Organization of Scientific Research, Earth and Life Sciences (NWO-ALW) and Technology Foundation (NWO-STW), respectively. We thank B. Buttaro (Temple University School of Medicine, Philadelphia, USA) for allowing us to cite unpublished work, J. Guespin for helpful comments on the manuscript and L. Hamoen for stimulating discussions. We apologize to colleagues whose work was not cited fully due to space restrictions.

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  1. Molecular Genetics Group, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Kerklaan 30, NN Haren, 9751, The Netherlands

    Wiep Klaas Smits, Oscar P. Kuipers & Jan-Willem Veening

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  1. Wiep Klaas Smits
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Correspondence to Oscar P. Kuipers.

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DATABASES

Entrez Genome

Bacteriophage λ

Entrez Genome Project

Bacillus subtilis

Escherichia coli

Mycobacterium tuberculosis

Myxococcus xanthus

Pseudomonas aeruginosa

Saccharomyces cerevisiae

Salmonella enterica serovar Typhimurium

Staphylococcus aureus

Streptococcus mutans

Streptococcus pneumoniae

Streptococcus pyogenes

FURTHER INFORMATION

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Glossary

Phenotypic variation

Cells within an isogenic population that show variable expression patterns.

Epigenetic

Any heritable change in gene expression that is not caused by a change in DNA sequence.

Multistationarity

The possibility of the existence of two (or more) stationary states of gene expression between which individual cells can switch.

Bistability

Situation in which two stable states coexist among cells within a population.

Multistability

The existence of two (or more) distinct phenotypes within an isogenic population owing to multistationarity.

Feedback-based multistability

(FBM). The existence of two or more distinct subpopulations in a culture, based on the presence of positive or negative feedback in the underlying regulatory network.

Graded response

Expression of a gene in direct correlation with the intracellular levels of its regulator.

Gratuitous inducer

Compounds that bind to, and inactivate, a repressor without being metabolized by the induced enzymes.

Hysteresis

Situation in which the switch from one state to the other requires a force unequal to that required for the reverse transition.

Binary

Exhibiting an 'on' and 'off' state.

Phase plane

Solution of a system of differential equations plotted in a two-dimensional plane.

ComK

Master regulator for competence development in Bacillus subtilis.

Monomodal

Demonstrating a single Gaussian distribution.

Toggle switch

A bistable switch formed by double-negative feedback.

Bacteriocin

Bacterially produced, small, heat-stable peptide that is active against other bacteria and to which the producer has a specific immunity mechanism. Bacteriocins can have a narrow or broad target spectrum.

Spo0A

Master regulator for sporulation in Bacillus subtilis.

Flow cytometry

A technique that measures the fluorescence of individual cells as they pass through a laser beam.

Noise

Part of a signal or parameter that is a deviation from the true value.

Alarmone

Signalling molecule produced in response to nutritional and/or physicochemical stress

Finite number effect

The effect that fewer molecules lead to increased noise levels.

Intrinsic noise

Noise inherent to the biochemical process of gene expression (transcription and translation).

Extrinsic noise

Noise due to fluctuations in other cellular components required for gene expression in a cell (such as polymerase and regulators).

Transcriptional reinitiation

Repeated rounds of transcription from a single mRNA, without dissociation of the transcription machinery.

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Smits, W., Kuipers, O. & Veening, JW. Phenotypic variation in bacteria: the role of feedback regulation. Nat Rev Microbiol 4, 259–271 (2006). https://doi.org/10.1038/nrmicro1381

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