Network motifs in the transcriptional regulation network of Escherichia coli (original) (raw)

Nature Genetics volume 31, pages 64–68 (2002)Cite this article

Abstract

Little is known about the design principles1,2,3,4,5,6,7,8,9,10 of transcriptional regulation networks that control gene expression in cells. Recent advances in data collection and analysis2,11,12, however, are generating unprecedented amounts of information about gene regulation networks. To understand these complex wiring diagrams1,2,3,4,5,6,7,8,9,10,13, we sought to break down such networks into basic building blocks2. We generalize the notion of motifs, widely used for sequence analysis, to the level of networks. We define 'network motifs' as patterns of interconnections that recur in many different parts of a network at frequencies much higher than those found in randomized networks. We applied new algorithms for systematically detecting network motifs to one of the best-characterized regulation networks, that of direct transcriptional interactions in Escherichia coli3,6. We find that much of the network is composed of repeated appearances of three highly significant motifs. Each network motif has a specific function in determining gene expression, such as generating temporal expression programs and governing the responses to fluctuating external signals. The motif structure also allows an easily interpretable view of the entire known transcriptional network of the organism. This approach may help define the basic computational elements of other biological networks.

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

Access options

Subscribe to this journal

Receive 12 print issues and online access

$209.00 per year

only $17.42 per issue

Buy this article

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

Additional access options:

Similar content being viewed by others

References

  1. Bray, D. Protein molecules as computational elements in living cells. Nature 376, 307–312 (1995).
    Article CAS Google Scholar
  2. Hartwell, L.H., Hopfield, J.J., Leibler, S. & Murray, A.W. From molecular to modular cell biology. Nature 402, C47–52 (1999).
    Article CAS Google Scholar
  3. Thieffry, D., Huerta, A.M., Perez-Rueda, E. & Collado-Vides, J. From specific gene regulation to genomic networks: a global analysis of transcriptional regulation in Escherichia coli. Bioessays 20, 433–440 (1998).
    Article CAS Google Scholar
  4. McAdams, H.H. & Arkin, A. Simulation of prokaryotic genetic circuits. Annu. Rev. Biophys. Biomol. Struct. 27, 199–224 (1998).
    Article CAS Google Scholar
  5. McAdams, H.H. & Shapiro, L. Circuit simulation of genetic networks. Science 269, 650–656 (1995).
    Article CAS Google Scholar
  6. Savageau, M. & Neidhart, F.C. Regulation beyond the operon. in Escherichia coli and Salmonella: Cellular and Molecular Biology (ed. Neidhart, F.C.) 1310–1324 (American Society for Microbiology, Washington D.C., 1996).
    Google Scholar
  7. Strogatz, S.H. Exploring complex networks. Nature 410, 268–276 (2001).
    Article CAS Google Scholar
  8. Rao, C.V. & Arkin, A.P. Control motifs for intracellular regulatory networks. Annu. Rev. Biomed. Eng. 3, 391–419 (2001).
    Article CAS Google Scholar
  9. Kauffman, S.A. Metabolic stability and epigenesis in randomly constructed genetic nets. J. Theor. Biol. 22, 437–467 (1969).
    Article CAS Google Scholar
  10. Barabasi, A.L. & Albert, R. Emergence of scaling in random networks. Science 286, 509–512 (1999).
    Article CAS Google Scholar
  11. Hughes, J.D., Estep, P.W., Tavazoie, S. & Church, G.M. Computational identification of _cis_-regulatory elements associated with groups of functionally related genes in Saccharomyces cerevisiae. J. Mol. Biol. 296, 1205–1214 (2000).
    Article CAS Google Scholar
  12. Hartemink, A.J., Gifford, D.K., Jaakkola, T.S. & Young, R.A. Using graphical models and genomic expression data to statistically validate models of genetic regulatory networks. Pac. Symp. Biocomput., 422–433 (2001).
  13. Newman, M.E., Strogatz, S.H. & Watts, D.J. Random graphs with arbitrary degree distributions and their applications. Phys. Rev. E 64, 026118 (2001).
    Article CAS Google Scholar
  14. Salgado, H. et al. RegulonDB (version 3.2): transcriptional regulation and operon organization in Escherichia coli K-12. Nucleic Acids Res. 29, 72–74 (2001).
    Article CAS Google Scholar
  15. Schleif, R. Regulation of the L-arabinose operon of Escherichia coli. Trends Genet. 16, 559–565 (2000).
    Article CAS Google Scholar
  16. Hengge-Aronis, R. Survival of hunger and stress: the role of rpoS in early stationary phase gene regulation in E. coli. Cell 72, 165–168 (1993).
    Article CAS Google Scholar
  17. Yuh, C.H., Bolouri, H. & Davidson, E.H., Genomic _cis_-regulatory logic: experimental and computational analysis of a sea urchin gene. Science 279, 1896–1902 (1998).
    Article CAS Google Scholar
  18. Kalir, S. et al. Ordering genes in a flagella pathway by analysis of expression kinetics from living bacteria. Science 292, 2080–2083 (2001).
    Article CAS Google Scholar
  19. Jeong, H., Tombor, B., Albert, R., Oltvai, Z.N. & Barabasi, A.L. The large-scale organization of metabolic networks. Nature 407, 651–654 (2000).
    Article CAS Google Scholar
  20. Duda, R.O. & Hart, P.E. Pattern Classification and Scene Analysis (Wiley, New York, 1973).
    Google Scholar
  21. Kannan, R., Tetali, P. & Vempala, S., Markov-chain algorithms for generating bipartite graphs and tournaments. Random Structures and Algorithms 14, 293–308 (1999).
    Article Google Scholar

Download references

Acknowledgements

We thank J. Collado-Vides and the RegulonDB team for making their invaluable database available. We thank A. Arkin, H.C. Berg, J. Doyle, M. Elowitz, S. Leibler, S. Quake, J. Shapiro, M.G. Surette, B. Shilo, E. Winfree and all members of our lab for discussions. This work was supported by the Israel Science Foundation and the Minerva Foundation.

Author information

Authors and Affiliations

  1. Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, 76100, Israel
    Shai S. Shen-Orr, Shmoolik Mangan & Uri Alon
  2. Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot, 76100, Israel
    Ron Milo & Uri Alon

Authors

  1. Shai S. Shen-Orr
  2. Ron Milo
  3. Shmoolik Mangan
  4. Uri Alon

Corresponding author

Correspondence toUri Alon.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Rights and permissions

About this article

Cite this article

Shen-Orr, S., Milo, R., Mangan, S. et al. Network motifs in the transcriptional regulation network of Escherichia coli.Nat Genet 31, 64–68 (2002). https://doi.org/10.1038/ng881

Download citation

This article is cited by