A Simple Model to Control Growth Rate of Synthetic E. coli during the Exponential Phase: Model Analysis and Parameter Estimation

We develop and analyze a model of a minimal synthetic gene circuit, that describes part of the gene expression machinery in Escherichia coli, and enables the control of the growth rate of the cells during the exponential phase. This model is a piecewise non-linear system with two variables (the concentrations of two gene products) and an input (an inducer). We study the qualitative dynamics of the model and the bifurcation diagram with respect to the input. Moreover, an analytic expression of the growth rate during the exponential phase as function of the input is derived. A relevant problem is that of identifiability of the parameters of this expression supposing noisy measurements of exponential growth rate. We present such an identifiability study that we validate in silico with synthetic measurements.

[1]  Frédéric Grognard,et al.  Piecewise-Linear Models of Genetic Regulatory Networks: Theory and Example , 2007 .

[2]  D. Schneider,et al.  Qualitative simulation of the carbon starvation response in Escherichia coli. , 2006, Bio Systems.

[3]  T. Ferenci,et al.  The relationship between external glucose concentration and cAMP levels inside Escherichia coli: implications for models of phosphotransferase-mediated regulation of adenylate cyclase. , 1997, Microbiology.

[4]  Jean Lévine,et al.  Advances in the Theory of Control, Signals and Systems with Physical Modeling , 2011 .

[5]  H. Bremer Modulation of Chemical Composition and Other Parameters of the Cell by Growth Rate , 1999 .

[6]  J. Monod The Growth of Bacterial Cultures , 1949 .

[7]  Shankar Mukherji,et al.  Synthetic biology: understanding biological design from synthetic circuits , 2009, Nature Reviews Genetics.

[8]  H. D. Jong,et al.  Qualitative simulation of genetic regulatory networks using piecewise-linear models , 2004, Bulletin of mathematical biology.

[9]  M. Elowitz,et al.  A synthetic oscillatory network of transcriptional regulators , 2000, Nature.

[10]  D. E. Goldberg,et al.  Genetic Algorithms in Search , 1989 .

[11]  H. D. Jong,et al.  Piecewise-linear Models of Genetic Regulatory Networks: Equilibria and their Stability , 2006, Journal of mathematical biology.

[12]  Ursula Klingmüller,et al.  Structural and practical identifiability analysis of partially observed dynamical models by exploiting the profile likelihood , 2009, Bioinform..

[13]  L. You,et al.  Emergent bistability by a growth-modulating positive feedback circuit. , 2009, Nature chemical biology.

[14]  J. Banga,et al.  Structural Identifiability of Systems Biology Models: A Critical Comparison of Methods , 2011, PloS one.

[15]  Eric Walter,et al.  QUALITATIVE AND QUANTITATIVE IDENTIFIABILITY ANALYSIS OF NONLINEAR CHEMICAL KINETIC MODELS , 1989 .

[16]  Jean-Luc Gouzé,et al.  Piecewise Affine Models of Regulatory Genetic Networks: Review and Probabilistic Interpretation , 2010 .

[17]  A. G. Marr,et al.  Growth rate of Escherichia coli. , 1991, Microbiological reviews.

[18]  Andreas Kremling,et al.  Correlation between Growth Rates, EIIACrr Phosphorylation, and Intracellular Cyclic AMP Levels in Escherichia coli K-12 , 2007, Journal of bacteriology.

[19]  G. Yagil,et al.  On the relation between effector concentration and the rate of induced enzyme synthesis. , 1971, Biophysical journal.

[20]  A. Danchin,et al.  The regulation of Enzyme IIAGlc expression controls adenylate cyclase activity in Escherichia coli , 2022 .

[21]  Uri Alon,et al.  Proteome Half-Life Dynamics in Living Human Cells , 2011, Science.

[22]  A. Ronald Gallant,et al.  Seemingly unrelated nonlinear regressions , 1975 .

[23]  Mads Kaern,et al.  The engineering of gene regulatory networks. , 2003, Annual review of biomedical engineering.

[24]  Ahmad S. Khalil,et al.  Synthetic biology: applications come of age , 2010, Nature Reviews Genetics.

[25]  T. Hwa,et al.  Growth Rate-Dependent Global Effects on Gene Expression in Bacteria , 2009, Cell.

[26]  J. Collins,et al.  Construction of a genetic toggle switch in Escherichia coli , 2000, Nature.

[27]  P. Cochat,et al.  Et al , 2008, Archives de pediatrie : organe officiel de la Societe francaise de pediatrie.

[28]  Aleksej F. Filippov,et al.  Differential Equations with Discontinuous Righthand Sides , 1988, Mathematics and Its Applications.

[29]  J. Stelling,et al.  A tunable synthetic mammalian oscillator , 2009, Nature.

[30]  J. Gouzé,et al.  A class of piecewise linear differential equations arising in biological models , 2002 .

[31]  A. Danchin,et al.  The regulation of Enzyme IIA(Glc) expression controls adenylate cyclase activity in Escherichia coli. , 2002, Microbiology.

[32]  E. Andrianantoandro,et al.  Synthetic biology: new engineering rules for an emerging discipline , 2006, Molecular systems biology.

[33]  Hidde de Jong,et al.  Genetic Network Analyzer: qualitative simulation of genetic regulatory networks , 2003, Bioinform..

[34]  T. Hwa,et al.  Interdependence of Cell Growth and Gene Expression: Origins and Consequences , 2010, Science.

[35]  David E. Goldberg,et al.  Genetic Algorithms in Search Optimization and Machine Learning , 1988 .

[36]  Eric Walter,et al.  Identification of Parametric Models: from Experimental Data , 1997 .