title: Coherent feedforward transcriptional regulatory motifs enhance drug resistance.
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.
authors.affiliation: Department of Physics, University of Ottawa, 150 Louis Pasteur, Ottawa, Ontario, Canada K1N 6N5 and Ottawa Institute of Systems Biology, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Charlebois
authors.affiliation: Department of Systems Biology-Unit 950, University of Texas MD Anderson Cancer Center, 7435 Fannin Street, Houston, Texas 77054, USA.
authors.forename: Gábor
authors.initials: G
authors.lastname: Balázsi
authors.affiliation: Department of Physics, University of Ottawa, 150 Louis Pasteur, Ottawa, Ontario, Canada K1N 6N5 and Ottawa Institute of Systems Biology, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5 and Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5.
authors.forename: Mads
authors.initials: M
authors.lastname: Kærn
mesh_terms: D000220:Adaptation, Biological; D003198:Computer Simulation; D004351:Drug Resistance / Q000502:physiology*; D025461:Feedback, Physiological; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D053263:Gene Regulatory Networks; D056084:Genetic Fitness; D008954:Models, Biological; D011157:Population Dynamics; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000502:physiology; D013269:Stochastic Processes