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  • Review Article
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Design of gene circuits: lessons from bacteria

Nature Reviews Genetics volume 5, pages 34–42 (2004)Cite this article

Key Points

  • A wealth of knowledge about genetic regulatory circuits motivates us to identify clear patterns in the design of gene circuits and to search for design principles that can explain their natural diversity.

  • Here, we review design principles for the regulation of transcription-factor (TF) expression in elementary gene circuits in bacteria. The design principles resulted from theoretical studies to determine the functional consequences of alternative designs using mathematically controlled comparisons.

  • Negative autoregulation is expected for TFs in systems for which stability, robustness and responsiveness are important.

  • Whether TF expression is expected to increase or decrease in response to an increase in signal depends on several other properties of the gene circuit: whether effector gene expression increases or decreases in response to an increase in signal; whether the TF exerts an activator or repressor mode of control on effector gene expression; and whether the magnitude of the steady-state gain of effector gene expression with signal is high, intermediate or low. The expected change of TF expression in response to signal (increase or decrease) results from considering the most responsive system given constraints that arise when the gain is sufficiently high.

  • To illustrate how the design principles provide a framework for understanding and organizing a large body of data, we assemble and examine a database that incorporates information about 50 TFs in Escherichia coli, resulting in a number of predictions and observations.

  • New experimental methods will enable studies of increasingly complicated gene circuits, which might show even richer patterns of gene-circuit design. Discovery of design principles for gene circuits in all cell types will require not only theoretical and experimental studies of natural systems, but also rigorous analysis of the functional consequences of alternative designs.

Abstract

Researchers are now building synthetic circuits for controlling gene expression and considering practical applications for engineered gene circuits. What can we learn from nature about design principles for gene circuits? A large body of experimental data is now available to test some important theoretical predictions about how gene circuits could be organized, but the data also raise some intriguing new questions.

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Figure 1: Modes of control by a transcription factor in an elementary gene circuit.
Figure 2: Transcriptional regulatory interactions in a gene circuit with a global and a local transcription factor.

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Acknowledgements

This work was supported by the National Institutes of Health and by the Department of Energy. Many thanks to the experimentalists who responded to various questions of ours about the gene circuits they have studied.

Author information

Authors and Affiliations

  1. Computer and Computational Sciences Division, Los Alamos National Laboratory, Los Alamos, 87545, New Mexico, USA

    Michael E. Wall

  2. Bioscience Division, Los Alamos National Laboratory, Los Alamos, 87545, New Mexico, USA

    Michael E. Wall

  3. Theoretical Division, Los Alamos National Laboratory, Los Alamos, 87545, New Mexico, USA

    William S. Hlavacek

  4. Department of Biomedical Engineering, One Shields Avenue, University of California, Davis, 95616, California, USA

    Michael A. Savageau

Authors
  1. Michael E. Wall
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  2. William S. Hlavacek
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  3. Michael A. Savageau
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Correspondence to Michael E. Wall.

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Supplementary information

Related links

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DATABASES

EcoCyc

araC-araBAD

cynR-cynTSX

dsdC-dsdXA

lacI-lacZYA

modEF-modABCD

treR-treBC

trpR-trpLEDCBA

tyrR-(aroF-tyrA)

FURTHER INFORMATION

EcoGene

EcoTFs

RegulonDB

Uri Alon's web site

Glossary

OPERON

A genetic unit or cluster that consists of one or more genes that are transcribed as a unit and are expressed in a coordinated manner.

GENETIC REGULATORY CIRCUIT

Also called a gene circuit. The genes and gene products that are involved in the response to a signal.

DESIGN

The constellation of system components, their specific properties and their pattern of interactions that together determine the integrated behaviour of the system. The term 'structure' might also be used but 'design' is preferred when there is a functional context.

DESIGN PRINCIPLES

General concepts that summarize our understanding of how gene-circuit design relates to gene-circuit function.

BIOREMEDIATION

The use of either naturally occurring or deliberately introduced micro-organisms to consume and break down environmental pollutants.

ELEMENTARY GENE CIRCUIT

A gene circuit in which gene expression is regulated by a single transcription factor in response to a signal under a given set of conditions. When conditions change, however, gene expression might come under the influence of extra regulators.

INDUCIBLE

Describes a gene, the expression of which increases in response to a signal in a given environmental background. An inducible system is one in which the effector transcriptional unit is inducible.

REPRESSIBLE

Describes a gene, the expression of which decreases in response to a signal in a given environmental background. A repressible system is one in which the effector transcriptional unit is repressible.

SIGNAL

A natural molecule that acts directly on the transcription factor to bring about a physiological response.

STABILITY

The ability of a system to return to a steady state after a transient disturbance.

ROBUSTNESS

The ability of a system's steady state to remain unchanged, or not significantly changed, when the structure (that is, the parameter values) of the system significantly changes.

RESPONSIVENESS

The ability of a system to settle quickly into a new steady state after an environmental change.

MODE OF CONTROL

Either positive (activator control) or negative (repressor control) according to whether an increase in the level of the transcription factor (other factors being constant) acts to increase or decrease gene expression.

EFFECTOR GENE

A gene that encodes an enzyme and/or another molecule with an effector function (for example, membrane transport).

MODULAR

A (sub-) system of interacting components is modular if it shows behaviour that is independent of the larger system under certain conditions.

PARAMETER SPACE

A list of values for all N parameters of a model corresponds to a point in an N-dimensional parameter space. A specific system type, as specified by constraints on parameter values, corresponds to a region in parameter space.

EXPRESSION CHARACTERISTIC

A plot of the level of expression versus the level of signal over a range of steady states.

GAIN

If y is the level of enzyme, and x is the level of signal, the gain of the system is defined as δlog y/δlog x (where δ = partial derivative). Gain, according to this definition, is also used interchangeably with the term 'logarithmic gain'. Often, the expression characteristic might be described using the Hill equation, y = (1 + x−n)−1, in which case a representative gain of the system in a log-log plot can be δlog y/δlog x ≈ n.

EXPRESSION CAPACITY

The ratio of maximal to minimal signal-dependent expression levels.

TRANSCRIPTIONAL UNIT

(TU). A DNA sequence that is transcribed as a single polycistronic mRNA, and might encode one or more individual genes.

TRANSCRIPTIONAL ATTENUATION

A decrease in transcription that results from a disengagement of mRNA polymerase from the DNA before reading through a leader sequence. Attenuation is enhanced by an increase in the level of an amino acid that corresponds to codons that are transcribed from the leader sequence.

CRITICAL GAIN

A model-dependent quantity that is used as a reference to determine whether the system gain is high, intermediate or low. The value can be estimated as the total number of molecules of the signal that bind to control transcription-factor interactions near the promoter of the effector transcriptional unit25,28.

HYSTERESIS

A possible attribute of a switch. A switch with hysteresis has a different threshold for the transition from the OFF state to the ON state compared with the transition from the ON state to the OFF state.

NETWORK MOTIF

A common pattern of connections in a network.

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Wall, M., Hlavacek, W. & Savageau, M. Design of gene circuits: lessons from bacteria. Nat Rev Genet 5, 34–42 (2004). https://doi.org/10.1038/nrg1244

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