Stochastic dynamics of genetic networks: modelling and parameter identification

MOTIVATION Identification of regulatory networks is typically based on deterministic models of gene expression. Increasing experimental evidence suggests that the gene regulation process is intrinsically random. To ensure accurate and thorough processing of the experimental data, stochasticity must be explicitly accounted for both at the modelling stage and in the design of the identification algorithms. RESULTS We propose a model of gene expression in prokaryotes where transcription is described as a probabilistic event, whereas protein synthesis and degradation are captured by first-order deterministic kinetics. Based on this model and assuming that the network of interactions is known, a method for estimating unknown parameters, such as synthesis and binding rates, from the outcomes of multiple time-course experiments is introduced. The method accounts naturally for sparse, irregularly sampled and noisy data and is applicable to gene networks of arbitrary size. The performance of the method is evaluated on a model of nutrient stress response in Escherichia coli.

[1]  Rolf Wagner,et al.  Transcription Regulation in Prokaryotes , 2000 .

[2]  Linda R. Petzold,et al.  Stochastic Modeling of Gene Regulatory Networks y , 2005 .

[3]  John Lygeros,et al.  Subtilin Production by Bacillus Subtilis: Stochastic Hybrid Models and Parameter Identification , 2008, IEEE Transactions on Automatic Control.

[4]  Panagiotis Kouretas,et al.  Stochastic Hybrid Modeling of Biochemical Processes , 2006 .

[5]  Johan Paulsson,et al.  Models of stochastic gene expression , 2005 .

[6]  Linda R. Petzold,et al.  Stochastic modelling of gene regulatory networks , 2005 .

[7]  J. Hespanha,et al.  Stochastic models for chemically reacting systems using polynomial stochastic hybrid systems , 2005 .

[8]  Ming-Jing Hwang,et al.  An analytical rate expression for the kinetics of gene transcription mediated by dimeric transcription factors. , 2007, Journal of biochemistry.

[9]  A. Arkin,et al.  It's a noisy business! Genetic regulation at the nanomolar scale. , 1999, Trends in genetics : TIG.

[10]  E. Cox,et al.  Real-Time Kinetics of Gene Activity in Individual Bacteria , 2005, Cell.

[11]  A. Keller,et al.  Model genetic circuits encoding autoregulatory transcription factors. , 1995, Journal of theoretical biology.

[12]  Hidde de Jong,et al.  Modeling and Simulation of Genetic Regulatory Systems: A Literature Review , 2002, J. Comput. Biol..

[13]  Junbin Gao,et al.  Simulated maximum likelihood method for estimating kinetic rates in gene expression , 2007, Bioinform..

[14]  Ertugrul M. Ozbudak,et al.  Regulation of noise in the expression of a single gene , 2002, Nature Genetics.

[15]  P. Swain,et al.  Stochastic Gene Expression in a Single Cell , 2002, Science.

[16]  M. Groudine,et al.  Enhancers increase the probability but not the level of gene expression. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[17]  S Zeiser,et al.  Simulation of genetic networks modelled by piecewise deterministic Markov processes. , 2008, IET systems biology.

[18]  M. Ko,et al.  A stochastic model for gene induction. , 1991, Journal of theoretical biology.

[19]  John Lygeros,et al.  Parameter identification for stochastic hybrid systems using randomized optimization: A case study on subtilin production by Bacillus subtilis , 2008 .

[20]  N. Friedman,et al.  Stochastic protein expression in individual cells at the single molecule level , 2006, Nature.

[21]  B. Séraphin,et al.  Positive feedback in eukaryotic gene networks: cell differentiation by graded to binary response conversion , 2001, The EMBO journal.

[22]  Lennart Ljung,et al.  System Identification: Theory for the User , 1987 .

[23]  J Timmer,et al.  Parameter estimation in stochastic biochemical reactions. , 2006, Systems biology.

[24]  Carmen G. Moles,et al.  Parameter estimation in biochemical pathways: a comparison of global optimization methods. , 2003, Genome research.

[25]  D. Wilkinson,et al.  Bayesian Inference for Stochastic Kinetic Models Using a Diffusion Approximation , 2005, Biometrics.

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

[27]  D. Gillespie,et al.  Stochastic Modeling of Gene Regulatory Networks † , 2005 .

[28]  J. Hasty,et al.  Dynamics of single-cell gene expression , 2006, Molecular systems biology.

[29]  A. Jazwinski Stochastic Processes and Filtering Theory , 1970 .

[30]  K. Kohn Molecular interaction maps as information organizers and simulation guides. , 2001, Chaos.