Russian Journal of Genetics

, Volume 46, Issue 5, pp 536–540

Phenotypic switching of Escherichia coli cells containing cyclic digenic systems with negative feedback upon changes in cultivation conditions

Genetics of Microorganisms


One of the mechanisms for the epigenetic control of cell phenotypes is based on switching the functioning regimes of bistable gene networks, which can maintain the two alternative levels of gene expression under the same conditions. Cyclic digenic systems with negative feedback represent an example of a simple bistable gene network. Cells carrying artificial cyclic digenic systems on plasmids inherit each alternative phenotype upon exponential growth on rich medium during several cell generations. The action of specific inducers is necessary for switching. In this work, the impact of changes in cell cultivation conditions on the phenotypic composition of the clonal Escherichia coli cell population containing artificial cyclic digenic systems with negative feedback was studied. Phenotypes differ with respect to the expression level of marker proteins: β-galactosidase and GFP. Slow growth on a medium containing little-available carbon sources was shown to cause the transition from the phenotype Lac to Lac+ in the absence of inducers. Phenotypic switching cannot be explained by transcriptional activation of the lactose operon, because 80 ± 15% of cells inherit the acquired phenotype after replating bacteria on rich medium. Inheritance of the phenotype Lac in batch culture depends on the medium and duration of cultivation. Dynamics of changes in the activity of β-galactosidase and culture fluorescence suggests that a decrease in the level of metabolism resulted in the switch of these cyclic systems from bistable to monostable functioning regime, which corresponds to the Lac+ phenotype with respect to the ratio of regulatory proteins. Thus, the instability of growth conditions may cause phenotypic heterogeneity in the clonal population of cells containing bistable gene networks.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Kaern, M., Elston, T.C., Blake, W.J., and Collins, J.J., Stochasticity in Gene Expression: From Theories to Phenotypes, Nat. Rev. Genet., 2005, vol. 6, pp. 451–464.CrossRefPubMedGoogle Scholar
  2. 2.
    Elowitz, M.B., Levine, A.J., Siggia, E.D., and Swain, P.S., Stochastic Gene Expression in a Single Cell, Science, 2002, vol. 297, pp. 1183–1186.CrossRefPubMedGoogle Scholar
  3. 3.
    Chen, L., Wang, R., Kobayashi, T.J., and Aihara, K., Dynamics of Gene Regulatory Networks with Cell Division Cycle, Phys. Rev., 2004, E 70: 011909.Google Scholar
  4. 4.
    Veening, J.W., Smits, W.K., and Kuipers, O.P., Bistability, Epigenetics, and Bet-Hedging in Bacteria, Annu. Rev. Microbiol., 2008, vol. 62, pp. 193–210.CrossRefPubMedGoogle Scholar
  5. 5.
    Sekerina, O.A. and Chemerilova, V.I., On the Adaptive Nature of the Dissociation Process in Bacillus thuringiensis, Mikrobiologiya, 2003, vol. 72, no. 5, pp. 689–694.Google Scholar
  6. 6.
    Babu, M.M. and Teichmann, S.A., Evolution of Transcription Factors and the Gene Regulatory Network in Escherichia coli, Nucleic Acids Res., 2003, vol. 31, pp. 1234–1244.CrossRefGoogle Scholar
  7. 7.
    Churaev, R.N., The Frame of Non-Canonical Theory of Heredity: From Genes to Epigenes, Zh. Obshch. Biol., 2005, vol. 66, no. 2, pp. 99–122.PubMedGoogle Scholar
  8. 8.
    Angeli, D., Ferrell, J.E., Sontag, Jr.D., and Sontag, E.D., Detection of Multistability, Bifurcations, and Hysteresis in a Large Class of Biological Positive-Feedback Systems, Proc. Natl. Acad. Sci. USA, 2004, vol. 101, pp. 1822–1827.CrossRefPubMedGoogle Scholar
  9. 9.
    Gardner, T.S., Cantor, C.R., and Collins, J.J., Construction of a Genetic Toggle Switch in Escherichia coli, Nature, 2000, vol. 403, pp. 339–342.CrossRefPubMedGoogle Scholar
  10. 10.
    Tchuraev, R.N., Stupak, E.E., Stupak, I.V., and Galimzyanov, A.V., A New Epigene Property: Metastable Epigenotypes, Dokl. Akad. Nauk, 2006, vol. 406, no. 4, pp. 570–573.Google Scholar
  11. 11.
    Kobayashi, H., Kaern, M., Araki, M., et al., Programmable Cells: Interfacing Natural and Engineered Gene Networks, Proc. Natl. Acad. Sci. USA, 2004, vol. 101, pp. 8414–8419.CrossRefPubMedGoogle Scholar
  12. 12.
    Miller, J.H., Experiments in Molecular Genetics, Cold Spring Harbor: Cold Spring Harbor Laboratories, 1972.Google Scholar
  13. 13.
    Khmel, I.A., Regulation of Expression of Bacterial Genes in the Absence of Active Cell Growth, Russ. J. Genet., 2005, vol. 41, no. 9, pp. 968–984.CrossRefGoogle Scholar
  14. 14.
    Kuo, J-T., Chang, Y-J., and Tseng, C-P., Growth Rate Regulation of lac Operon Expression in Escherichia coli Is Cyclic AMP Dependent, FEBS Lett., 2003, vol. 553, pp. 397–402.CrossRefPubMedGoogle Scholar
  15. 15.
    Lanzer, M. and Bujard, H., Promoters Largely Determine the Efficiency of Repressor Action, Proc. Natl. Acad. Sci. USA, 1988, vol. 85, pp. 8973–8977.CrossRefPubMedGoogle Scholar
  16. 16.
    Kashiwagi, A., Urabe, I., Kaneko, K., and Yomo, T., Adaptive Response of a Gene Network to Environmental Changes by Fitness-Induced Attractor Selection, PLoS ONE, 2006, vol. 1, no. 1, p. e49.CrossRefPubMedGoogle Scholar

Copyright information

© Pleiades Publishing, Ltd. 2010

Authors and Affiliations

  1. 1.Establishment of the Russian Academy of Sciences Institute of Biology of the Ufa Research Centre of the RASUfaRussia

Personalised recommendations