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Coherent feedforward transcriptional regulatory motifs enhance drug resistance

Daniel A. Charlebois1,2,*, Gábor Balázsi3, and Mads Kærn1,2,4,†

  • 1Department of Physics, University of Ottawa, 150 Louis Pasteur, Ottawa, Ontario, Canada K1N 6N5
  • 2Ottawa Institute of Systems Biology, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5
  • 3Department of Systems Biology-Unit 950, University of Texas MD Anderson Cancer Center, 7435 Fannin Street, Houston, Texas 77054, USA
  • 4Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5

  • *daniel.charlebois@uottawa.ca
  • †mkaern@uottawa.ca
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Phys. Rev. E 89, 052708 – Published 14 May, 2014

DOI: https://doi.org/10.1103/PhysRevE.89.052708

Abstract

Fluctuations in gene expression give identical cells access to a spectrum of phenotypes that can serve as a transient, nongenetic basis for natural selection by temporarily increasing drug resistance. In this study, we demonstrate using mathematical modeling and simulation that certain gene regulatory network motifs, specifically coherent feedforward loop motifs, can facilitate the development of nongenetic resistance by increasing cell-to-cell variability and the time scale at which beneficial phenotypic states can be maintained. Our results highlight how regulatory network motifs enabling transient, nongenetic inheritance play an important role in defining reproductive fitness in adverse environments and provide a selective advantage subject to evolutionary pressure.

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Outline

Information

Phys. Rev. E 89, 052708– Published 14 May, 2014
  • Received 28 November 2013
  • Revised 2 February 2014

©2014 American Physical Society

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