title: Modelling and analysis of a gene-regulatory feed-forward loop with basal expression of the second regulator.
abstract: Efficient adaptation strategies to changing environmental conditions are essential for bacteria to survive and grow. Fundamental restructuring of their metabolism is usually mediated by corresponding gene regulation. Here, often several different environmental stimuli have to be integrated into a reasonable, energy-efficient response. Fast fluctuations and overshooting have to be filtered out. The gene regulatory network for the anaerobic adaptation of the pathogenic bacterium Pseudomonas aeruginosa is organized as a feed-forward loop (FFL), which is a three-gene network motif composed of two transcription factors (Anr for oxygen, NarxL for nitrate) and one target (Nar for nitrate reductase). The upstream transcription factor (Anr) induces the downstream transcription factor (NarXL). Both regulators act together positively by inducing the target (Nar) via a direct and indirect regulation path (coherent type-1 FFL). Since full promoter activity is only achieved when both transcription factors are present the target operon is expressed with a delay. Thus, in response to environmental stimuli (oxygen, nitrate), signals are mediated and processed in a way that short pulses are filtered out. In this study we analyze a special kind of FFL called FFLk by means of a family of ordinary differential equation models. The secondary FFL regulator (NarXL) is expressed constitutively but further induced in the presence of the upstream stimuli. This FFL modification has substantial influence on the response time and cost-benefit ratio mediated by environmental fluctuations. In order to find conditions where this regulatory network motif might be beneficial, we analyzed various models and environments. We describe the observed evolutional advantage of FFLk and its role in environmental adaptation and pathogenicity.
authors.affiliation: Institute of Microbiology and Braunschweig Integrated Centre of Systems Biology, Technische Universität Braunschweig, Spielmannstr. 7, D-38106 Braunschweig, Germany.
authors.forename: Louisa
authors.initials: L
authors.lastname: Roselius
authors.affiliation: Institute of Computational Mathematics, Pockelsstr. 14, Technische Universität Braunschweig, D-38106 Braunschweig, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Langemann
authors.affiliation: Centre for Mathematical Sciences, Technische Universitat München, Boltzmannstr. 3, D-85747 Garching/Munich, Germany; Institute of Computational Biology, Helmholtz Zentrum München - German Research Center for Environmental Health, Ingolstädter Landstr. 1, D-85764 Neuherberg, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Müller
authors.affiliation: Institute of Computational Biology, Helmholtz Zentrum München - German Research Center for Environmental Health, Ingolstädter Landstr. 1, D-85764 Neuherberg, Germany.
authors.forename: Burkhard A
authors.initials: BA
authors.lastname: Hense
authors.affiliation: Institute of Microbiology and Braunschweig Integrated Centre of Systems Biology, Technische Universität Braunschweig, Spielmannstr. 7, D-38106 Braunschweig, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Filges
authors.affiliation: Institute of Microbiology and Braunschweig Integrated Centre of Systems Biology, Technische Universität Braunschweig, Spielmannstr. 7, D-38106 Braunschweig, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Jahn
authors.affiliation: Institute of Microbiology and Braunschweig Integrated Centre of Systems Biology, Technische Universität Braunschweig, Spielmannstr. 7, D-38106 Braunschweig, Germany. Electronic address: r.muench@tu-bs.de.
authors.forename: Richard
authors.initials: R
authors.lastname: Münch
mesh_terms: D000220:Adaptation, Biological / Q000235:genetics / Q000502:physiology*; D000693:Anaerobiosis; D003362:Cost-Benefit Analysis; D004777:Environment; D053263:Gene Regulatory Networks / Q000502:physiology*; D008954:Models, Biological; D011550:Pseudomonas aeruginosa / Q000235:genetics / Q000502:physiology*
keywords: Energy metabolism; Environmental adaptation; Gene regulation; Mathematical modelling