Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Long-range temporal coordination of gene expression in synthetic microbial consortia

Nature Chemical Biology volume 15, pages 1102–1109 (2019)Cite this article

Subjects

This article has been updated

Abstract

Synthetic microbial consortia have an advantage over isogenic synthetic microbes because they can apportion biochemical and regulatory tasks among the strains. However, it is difficult to coordinate gene expression in spatially extended consortia because the range of signaling molecules is limited by diffusion. Here, we show that spatio-temporal coordination of gene expression can be achieved even when the spatial extent of the consortium is much greater than the diffusion distance of the signaling molecules. To do this, we examined the dynamics of a two-strain synthetic microbial consortium that generates coherent oscillations in small colonies. In large colonies, we find that temporally coordinated oscillations across the population depend on the presence of an intrinsic positive feedback loop that amplifies and propagates intercellular signals. These results demonstrate that synthetic multicellular systems can be engineered to exhibit coordinated gene expression using only transient, short-range coupling among constituent cells.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Dynamics of the two-strain oscillator in large microfluidic devices.
Fig. 2: Comparison of the dynamics of different circuit topologies in the compact and extended microfluidic devices.
Fig. 3: The mathematical model reproduces the experimentally observed spatio-temporal dynamics exhibited by the four regulatory architectures.
Fig. 4: Positive feedback changes the response to incoming signals.
Fig. 5: Intracellular positive feedback promotes synchronization between reciprocally coupled consortia.
Fig. 6: Experimental estimation of the phase difference maps.

Similar content being viewed by others

Data availability

The datasets generated and analyzed during the current study are available from the corresponding authors upon reasonable request.

Code availability

The code generated during the current study is available from the corresponding authors upon reasonable request.

Change history

  • 10 December 2019

    In the version of this article originally published, the contents of the ‘Supplementary Information’ PDF file were missing. The Supplementary Information PDF should contain Supplementary Tables 1–3 and Supplementary Figures 1–10. The error has been corrected.

References

  1. Gardner, T. S., Cantor, C. R. & Collins, J. J. Construction of a genetic toggle switch in Escherichia coli. Nature 403, 339–342 (2000).

    Article  CAS  Google Scholar 

  2. Atkinson, M. R., Savageau, M. A., Myers, J. T. & Ninfa, A. J. Development of genetic circuitry exhibiting toggle switch or oscillatory behavior in Escherichia coli. Cell 113, 597–607 (2003).

    Article  CAS  Google Scholar 

  3. Elowitz, M. B. & Leibler, S. A synthetic oscillatory network of transcriptional regulators. Nature 403, 335–338 (2000).

    Article  CAS  Google Scholar 

  4. Stricker, J. et al. A fast, robust and tunable synthetic gene oscillator. Nature 456, 516–519 (2008).

    Article  CAS  Google Scholar 

  5. Tigges, M., Marquez-Lago, T. T., Stelling, J. & Fussenegger, M. A tunable synthetic mammalian oscillator. Nature 457, 309–312 (2009).

    Article  CAS  Google Scholar 

  6. Moon, T. S., Lou, C. B., Tamsir, A., Stanton, B. C. & Voigt, C. A. Genetic programs constructed from layered logic gates in single cells. Nature 491, 249–253 (2012).

    Article  CAS  Google Scholar 

  7. Shis, D. L., Hussain, F., Meinhardt, S., Swint-Kruse, L. & Bennett, M. R. Modular, multi-input transcriptional logic gating with orthogonal Lacl/GaIR family chimeras. ACS Synth. Biol. 3, 645–651 (2014).

    Article  CAS  Google Scholar 

  8. Brenner, K., You, L. C. & Arnold, F. H. Engineering microbial consortia: a new frontier in synthetic biology. Trends Biotechnol. 26, 483–489 (2008).

    Article  CAS  Google Scholar 

  9. Miller, M. B. & Bassler, B. L. Quorum sensing in bacteria. Ann. Rev. Microbiol 55, 165–199 (2001).

    Article  CAS  Google Scholar 

  10. Brenner, K., Karig, D. K., Arnold, F. H. & Weiss, R. Engineered bidirectional communication mediates a consensus in a microbial biofilm consortium. Proc. Natl Acad. Sci. USA 104, 17300–17304 (2007).

    Article  CAS  Google Scholar 

  11. Balagadde, F. K. et al. A synthetic Escherichia coli predator-prey ecosystem. Mol. Syst. Biol. 4, 187 (2008).

    Article  Google Scholar 

  12. Danino, T., Mondragon-Palomino, O., Tsimring, L. & Hasty, J. A synchronized quorum of genetic clocks. Nature 463, 326–330 (2010).

    Article  CAS  Google Scholar 

  13. Chen, Y., Kim, J. K., Hirning, A. J., Josić, K. & Bennett, M. R. Emergent genetic oscillations in synthetic microbial consortia. Science 349, 986–989 (2015).

    Article  CAS  Google Scholar 

  14. Payne, S. et al. Temporal control of self-organized pattern formation without morphogen gradients in bacteria. Mol. Syst. Biol. 9, 697 (2013).

    Article  CAS  Google Scholar 

  15. Basu, S., Gerchman, Y., Collins, C. H., Arnold, F. H. & Weiss, R. A synthetic multicellular system for programmed pattern formation. Nature 434, 1130–1134 (2005).

    Article  CAS  Google Scholar 

  16. You, L. C., Cox, R. S., Weiss, R. & Arnold, F. H. Programmed population control by cell–cell communication and regulated killing. Nature 428, 868–871 (2004).

    Article  CAS  Google Scholar 

  17. Tamsir, A., Tabor, J. J. & Voigt, C. A. Robust multicellular computing using genetically encoded NOR gates and chemical ‘wires’. Nature 469, 212–215 (2011).

    Article  CAS  Google Scholar 

  18. Prindle, A. et al. A sensing array of radically coupled genetic ‘biopixels’. Nature 481, 39–44 (2012).

    Article  CAS  Google Scholar 

  19. Volfson, D., Cookson, S., Hasty, J. & Tsimring, L. S. Biomechanical ordering of dense cell populations. Proc. Natl Acad. Sci. USA 105, 15346–15351 (2008).

    Article  Google Scholar 

  20. Winkle, J. J., Igoshin, O. A., Bennett, M. R., Josić, K. & Ott, W. Modeling mechanical interactions in growing populations of rod-shaped bacteria. Phys. Biol. 14, 055001 (2017).

    Article  Google Scholar 

  21. Karamched, B. R. et al. Moran model of spatial alignment in microbial colonies. Phys. D. 7, 1834–1843 (2019).

    Google Scholar 

  22. Alnahhas, R. N. et al. Spatiotemporal dynamics of synthetic microbial consortia in microfluidic devices. ACS Synth. Biol. 8, 2051–2058 (2019).

    Article  CAS  Google Scholar 

  23. Shinomoto, S. & Kuramoto, Y. Phase-transitions in active rotator systems. Prog. Theor. Phys. 75, 1105–1110 (1986).

    Article  Google Scholar 

  24. Taylor, A. F., Tinsley, M. R., Wang, F., Huang, Z. Y. & Showalter, K. Dynamical quorum sensing and synchronization in large populations of chemical oscillators. Science 323, 614–617 (2009).

    Article  CAS  Google Scholar 

  25. Ermentrout, G. B. & Kopell, N. Frequency plateaus in a chain of weakly coupled oscillators. Siam J. Math. Anal. 15, 215–237 (1984).

    Article  Google Scholar 

  26. Kim, J. K., Kilpatrick, Z. P., Bennett, M. R. & Josić, K. Molecular mechanisms that regulate the coupled period of the mammalian circadian clock. Biophys. J. 106, 2071–2081 (2014).

    Article  CAS  Google Scholar 

  27. Gelens, L., Anderson, G. A. & Ferrell, J. E. Jr. Spatial trigger waves: positive feedback gets you a long way. Mol. Biol. Cell 25, 3486–3493 (2014).

    Article  Google Scholar 

  28. Cao, Y., Lopatkin, A. & You, L. Elements of biological oscillations in time and space. Nat. Struct. Mol. Biol. 23, 1030–1034 (2016).

    Article  CAS  Google Scholar 

  29. Goldbeter, A., Gerard, C., Gonze, D., Leloup, J. C. & Dupont, G. Systems biology of cellular rhythms. FEBS Lett. 586, 2955–2965 (2012).

    Article  CAS  Google Scholar 

  30. Parent, C. A. & Devreotes, P. N. A cell’s sense of direction. Science 284, 765–770 (1999).

    Article  CAS  Google Scholar 

  31. De Palo, G., Yi, D. & Endres, R. G. A critical-like collective state leads to long-range cell communication in dictyostelium discoideum aggregation. PLoS Biol. 15, e1002602 (2017).

    Article  Google Scholar 

  32. McMains, V. C., Liao, X. H. & Kimmel, A. R. Oscillatory signaling and network responses during the development of dictyostelium discoideum. Ageing Res. Rev. 7, 234–248 (2008).

    Article  CAS  Google Scholar 

  33. Chang, J. B. & Ferrell, J. E. Jr. Mitotic trigger waves and the spatial coordination of the xenopus cell cycle. Nature 500, 603–607 (2013).

    Article  CAS  Google Scholar 

  34. Antle, M. C. & Silver, R. Orchestrating time: arrangements of the brain circadian clock. Trends Neurosci. 28, 145–151 (2005).

    Article  CAS  Google Scholar 

  35. Abel, J. H. et al. Functional network inference of the suprachiasmatic nucleus. Proc. Natl Acad. Sci. USA 113, 4512–4517 (2016).

    Article  CAS  Google Scholar 

  36. Myung, J. et al. GABA-mediated repulsive coupling between circadian clock neurons in the SCN encodes seasonal time. Proc. Natl Acad. Sci. USA 112, E3920–E3929 (2015).

    Article  CAS  Google Scholar 

  37. Takahashi, J. S. Transcriptional architecture of the mammalian circadian clock. Nat. Rev. Genet. 18, 164–179 (2017).

    Article  CAS  Google Scholar 

  38. Li, X. et al. Synchronization measurement of multiple neuronal populations. J. Neurophysiol. 98, 3341–3348 (2007).

    Article  Google Scholar 

  39. Pai, A. & You, L. C. Optimal tuning of bacterial sensing potential. Mol. Syst. Biol. 5, 286 (2009).

    Article  Google Scholar 

  40. Hussain, F. et al. Engineered temperature compensation in a synthetic genetic clock. Proc. Natl Acad. Sci. USA 111, 972–977 (2014).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was funded by the National Institutes of Health and the National Sciences Foundation through the joint NSF-National Institutes of General Medical Sciences Mathematical Biology Program grant nos. R01GM104974 (M.R.B. and K.J.), DMS-1662290 (M.R.B.) and DMS-1662305 (K.J.); the NSF grant no. DBI-1707400 (K.J.); the National Institutes of Health grant no. R01GM117138 (M.R.B. and K.J.); the Robert A. Welch Foundation grant no. C-1729 (M.R.B.); the Hamill Foundation (M.R.B.); the National Research Foundation of Korea grant no. 2016 RICIB 3008468 (J.K.K.), EWon fellowship (J.K.K.) and the TJ Park Science Fellowship of POSCO TJ Park Foundation (J.K.K.).

Author information

Author notes

  1. Ye Chen

    Present address: Department of Bioengineering, Massachusetts Institute of Technology, Boston, MA, USA

  2. These authors contributed equally: Jae Kyoung Kim, Ye Chen.

Authors and Affiliations

  1. Department of Mathematics, Korean Advanced Institute of Science and Technology, Daejeon, South Korea

    Jae Kyoung Kim

  2. Department of Biosciences, Rice University, Houston, TX, USA

    Ye Chen, Andrew J. Hirning, Razan N. Alnahhas, Krešimir Josić & Matthew R. Bennett

  3. Department of Mathematics, University of Houston, Houston, TX, USA

    Krešimir Josić

  4. Department of Biology and Biochemistry, University of Houston, Houston, TX, USA

    Krešimir Josić

  5. Department of Bioengineering, Rice University, Houston, TX, USA

    Matthew R. Bennett

Authors
  1. Jae Kyoung Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ye Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Andrew J. Hirning
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Razan N. Alnahhas
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Krešimir Josić
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Matthew R. Bennett
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

J.K.K. performed the computational modeling and mathematical analysis. Y.C. performed the molecular biology. Y.C., A.J.H. and R.N.A. performed the microscopy experiments. A.J.H. designed and fabricated the microfluidic devices. J.K.K., Y.C. and K.J. analyzed the data. J.K.K., Y.C., K.J. and M.R.B. conceived the project. M.R.B. supervised the project. All authors wrote the manuscript.

Corresponding authors

Correspondence to Jae Kyoung Kim, Krešimir Josić or Matthew R. Bennett.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Information

Supplementary Tables 1–3 and Supplementary Figures 1–10.

Reporting Summary

Supplementary Video 1

Synchronous oscillations within a consortium.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kim, J.K., Chen, Y., Hirning, A.J. et al. Long-range temporal coordination of gene expression in synthetic microbial consortia. Nat Chem Biol 15, 1102–1109 (2019). https://doi.org/10.1038/s41589-019-0372-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41589-019-0372-9

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing