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Noise-induced Min phenotypes in E. coli
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology. (Ehrenberg)
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology. (Ehrenberg)
2006 (English)In: PloS Computational Biology, ISSN 1553-734X, E-ISSN 1553-7358, Vol. 2, no 6, 637-648 p.Article in journal (Refereed) Published
Abstract [en]

The spatiotemporal oscillations of the Escherichia coli proteins MinD and MinE direct cell division to the region between the chromosomes. Several quantitative models of the Min system have been suggested before, but no one of them accounts for the behavior of all documented mutant phenotypes. We analyzed the stochastic reaction-diffusion kinetics of the Min proteins for several E. coli mutants and compared the results to the corresponding deterministic mean-field description. We found that wild-type (wt) and filamentous (ftsZ(-)) cells are well characterized by the mean-field model, but that a stochastic model is necessary to account for several of the characteristics of the spherical (rodA(-)) and phospathedylethanolamide-deficient (PE-) phenotypes. For spherical cells, the mean-field model is bistable, and the system can get trapped in a non-oscillatory state. However, when the intrinsic noise is considered, only the experimentally observed oscillatory behavior remains. The stochastic model also reproduces the change in oscillation directions observed in the spherical phenotype and the occasional gliding of the MinD region along the inner membrane. For the PE- mutant, the stochastic model explains the appearance of randomly localized and dense MinD clusters as a nucleation phenomenon, in which the stochastic kinetics at low copy number causes local discharges of the high MinD(ATP) to MinD(ADP) potential. We find that a simple five-reaction model of the Min system can explain all documented Min phenotypes, if stochastic kinetics and three-dimensional diffusion are accounted for. Our results emphasize that local copy number fluctuation may result in phenotypic differences although the total number of molecules of the relevant species is high.

Place, publisher, year, edition, pages
2006. Vol. 2, no 6, 637-648 p.
National Category
Biological Sciences
URN: urn:nbn:se:uu:diva-18951DOI: 10.1371/journal.pcbi.0020080ISI: 000239494000016PubMedID: 16846247OAI: oai:DiVA.org:uu-18951DiVA: diva2:46723
Available from: 2006-11-24 Created: 2006-11-24 Last updated: 2016-04-21Bibliographically approved
In thesis
1. Modelling Approaches to Molecular Systems Biology
Open this publication in new window or tab >>Modelling Approaches to Molecular Systems Biology
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Systembiologisk modellering på molekylär nivå
Abstract [en]

Implementation and analysis of mathematical models can serve as a powerful tool in understanding how intracellular processes in bacteria affect the bacterial phenotype. In this thesis I have implemented and analysed models of a number of different parts of the bacterium E. coli in order to understand these types of connections. I have also developed new tools for analysis of stochastic reaction-diffusion models.

Resistance mutations in the E. coli ribosomes make the bacteria less susceptible to treatment with the antibiotic drug erythromycin compared to bacteria carrying wildtype ribosomes. The effect is dependent on efficient drug efflux pumps. In the absence of pumps for erythromycin, there is no difference in growth between wildtype and drug target resistant bacteria. I present a model explaining this unexpected phenotype, and also give the conditions for its occurrence.

Stochastic fluctuations in gene expression in bacteria, such as E. coli, result in stochastic fluctuations in biosynthesis pathways. I have characterised the effect of stochastic fluctuations in the parallel biosynthesis pathways of amino acids. I show how the average protein synthesis rate decreases with an increasing number of fluctuating amino acid production pathways. I further show how the cell can remedy this problem by using sensitive feedback control of transcription, and by optimising its expression levels of amino acid biosynthetic enzymes.

The pole-to-pole oscillations of the Min-proteins in E. coli are required for accurate mid-cell division. The phenotype of the Min-oscillations is altered in three different mutants: filamentous cells, round cells and cells with changed membrane lipid composition. I have shown that the wildtype and mutant phenotypes can be explained using a stochastic reaction-diffusion model.

In E. coli, the transcription elongation rate on the ribosmal RNA operon increases with increasing transcription initiation rate. In addition, the polymerase density varies along the ribosomal RNA operons. I present a DNA sequence dependent model that explains the transcription elongation rate speed-up, and also the density variation along the ribosomal operons. Both phenomena are explained by the RNA polymerase backtracking on the DNA.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2010. 57 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 785
stochastic reaction-diffuion kinetics, antibiotic drugs, efflux pumps, amino acid biosynthesis, Min-system, rRNA operon, transcription
National Category
Biochemistry and Molecular Biology
Research subject
Biology with specialization in Molecular Biotechnology
urn:nbn:se:uu:diva-132864 (URN)978-91-554-7941-1 (ISBN)
Public defence
2010-12-16, B21, BMC, Husargatan 3, Uppsala, 13:00 (English)
Felaktigt tryckt som Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology 715Available from: 2010-11-24 Created: 2010-10-27 Last updated: 2011-03-21Bibliographically approved

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