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Microfluidic devices for measuring gene network dynamics in single cells

Key Points

  • This Review examines the ways in which microfluidic devices have helped to reveal the dynamics of gene regulation and intracellular signalling.

  • Gene regulatory networks often operate through highly dynamic processes that cannot be studied by stationary measurements.

  • Microfluidic devices can trap cells for long periods of time, which allows time-lapse imaging of single cells. When these devices are combined with fluorescent reporters, the time-dependent activity of a network can be measured.

  • New designs for microfludic devices allow the growth environments of cellular populations to be perturbed in non-trivial ways, such as through the creation of spatial gradients or temporal waves of chemical concentrations.

  • Mathematical models that have been created from data obtained through time-lapse fluorescence microscopy have revealed novel functions of gene networks and new regulatory pathways.

  • Multicellular and multispecies studies have also been conducted using microfluidic devices that have been designed for research in intercellular signalling.

  • It is hoped that these new technologies will eventually help to identify techniques that can more accurately model genetic regulatory networks.

Abstract

The dynamics governing gene regulation have an important role in determining the phenotype of a cell or organism. From processing extracellular signals to generating internal rhythms, gene networks are central to many time-dependent cellular processes. Recent technological advances now make it possible to track the dynamics of gene networks in single cells under various environmental conditions using microfluidic 'lab-on-a-chip' devices, and researchers are using these new techniques to analyse cellular dynamics and discover regulatory mechanisms. These technologies are expected to yield novel insights and allow the construction of mathematical models that more accurately describe the complex dynamics of gene regulation.

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Figure 1: A microfluidic device for monitoring Escherichia coli.
Figure 2: The Tesla microchemostat.
Figure 3: Microfluidic trapping devices designed for the long-term acquisition of single-cell data.
Figure 4: A microfluidic device designed for generating concentration gradients.
Figure 5: The microfluidic 'dial-a-wave' device.
Figure 6: Temporal driving with microfluidic chips to test mathematical models.

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Acknowledgements

We would like to thank O. Mondragon and S. Cookson for initial literature searches, and B. Baumgartner for thorough readings of the drafts. This work was supported by the National Institute of General Medical Sciences of the National Institutes of Health (GMO79333).

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Correspondence to Matthew R. Bennett.

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Glossary

Intrinsic noise

Random, stochastic fluctuations in gene expression caused by a small number of reactants interacting in a finite volume.

Extrinsic noise

Fluctuations in gene expression that are not caused by intrinsic noise.

Time-lapse fluorescence microscopy

The repeated imaging of fluorescent markers using microscopy over a period of time, thus allowing a movie of the dynamics of gene expression or signalling networks to be obtained.

Bacterial persistence

Similar to antibiotic resistance, bacterial persistence is the phenomenon by which a fraction of a genetically homogeneous bacterial colony will survive antibiotic treatment but retain antibiotic sensitivity following regrowth.

Polydimethylsiloxane

An optically clear organic polymer that is commonly used for soft lithography.

Stochastic

Probabilistic; governed by chance.

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Bennett, M., Hasty, J. Microfluidic devices for measuring gene network dynamics in single cells. Nat Rev Genet 10, 628–638 (2009). https://doi.org/10.1038/nrg2625

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