Stochastic Gene Expression Modeling with Hill Function for Switch-Like Gene Responses

Gene expression models play a key role to understand the mechanisms of gene regulation whose aspects are grade and switch-like responses. Though many stochastic approaches attempt to explain the gene expression mechanisms, the Gillespie algorithm which is commonly used to simulate the stochastic models requires additional gene cascade to explain the switch-like behaviors of gene responses. In this study, we propose a stochastic gene expression model describing the switch-like behaviors of a gene by employing Hill functions to the conventional Gillespie algorithm. We assume eight processes of gene expression and their biologically appropriate reaction rates are estimated based on published literatures. We observed that the state of the system of the toggled switch model is rarely changed since the Hill function prevents the activation of involved proteins when their concentrations stay below a criterion. In ScbA-ScbR system, which can control the antibiotic metabolite production of microorganisms, our modified Gillespie algorithm successfully describes the switch-like behaviors of gene responses and oscillatory expressions which are consistent with the published experimental study.

[1]  Darren J. Wilkinson Stochastic Modelling for Systems Biology , 2006 .

[2]  D. A. Baxter,et al.  Modeling Circadian Oscillations with Interlocking Positive and Negative Feedback Loops , 2001, The Journal of Neuroscience.

[3]  M. Elowitz,et al.  Functional roles for noise in genetic circuits , 2010, Nature.

[4]  Erol Gelenbe,et al.  Random Neural Networks with Multiple Classes of Signals , 1999, Neural Computation.

[5]  A. Arkin,et al.  Stochastic mechanisms in gene expression. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

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

[7]  Michal Linial,et al.  Using Bayesian Networks to Analyze Expression Data , 2000, J. Comput. Biol..

[8]  E. Gelenbe Search in unknown random environments. , 2010, Physical review. E, Statistical, nonlinear, and soft matter physics.

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

[10]  Nicolas E. Buchler,et al.  Nonlinear protein degradation and the function of genetic circuits. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[11]  Sarika Mehra,et al.  A Bistable Gene Switch for Antibiotic Biosynthesis: The Butyrolactone Regulon in Streptomyces coelicolor , 2008, PloS one.

[12]  H. Erickson,et al.  Kinetics of protein-protein association explained by Brownian dynamics computer simulation. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

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

[14]  Erol Gelenbe G-Networks with Signals and Batch Removal , 1993 .

[15]  Erol Gelenbe,et al.  Steady-state solution of probabilistic gene regulatory networks. , 2007, Physical review. E, Statistical, nonlinear, and soft matter physics.

[16]  Erol Gelenbe,et al.  G-networks with multiple classes of signals and positive customers , 1998, Eur. J. Oper. Res..

[17]  D. Volfson,et al.  Delay-induced stochastic oscillations in gene regulation. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[18]  Jin Wang,et al.  Potential landscape and flux framework of nonequilibrium networks: Robustness, dissipation, and coherence of biochemical oscillations , 2008, Proceedings of the National Academy of Sciences.

[19]  M. Bibb,et al.  Purification and Structural Determination of SCB1, a γ-Butyrolactone That Elicits Antibiotic Production inStreptomyces coelicolor A3(2)* , 2000, The Journal of Biological Chemistry.

[20]  P. Swain,et al.  Strategies for cellular decision-making , 2009, Molecular systems biology.

[21]  Erol Gelenbe,et al.  Network of interacting synthetic molecules in steady state , 2008, Proceedings of the Royal Society A: Mathematical, Physical and Engineering Sciences.

[22]  Erol Gelenbe,et al.  Stability of Product Form G-Networks , 1992 .

[23]  P. Ao Global view of bionetwork dynamics: adaptive landscape. , 2009, Journal of genetics and genomics = Yi chuan xue bao.

[24]  Erol Gelenbe,et al.  Probabilistic models of computer systems—Part I (exact results) , 1976, Acta Informatica.

[25]  Eriko Takano,et al.  A bacterial hormone (the SCB1) directly controls the expression of a pathway‐specific regulatory gene in the cryptic type I polyketide biosynthetic gene cluster of Streptomyces coelicolor , 2005, Molecular microbiology.

[26]  G. Balázsi,et al.  Negative autoregulation linearizes the dose–response and suppresses the heterogeneity of gene expression , 2009, Proceedings of the National Academy of Sciences.

[27]  Korbinian Strimmer,et al.  Learning causal networks from systems biology time course data: an effective model selection procedure for the vector autoregressive process , 2007, BMC Bioinformatics.

[28]  J. Matthews,et al.  The power of two: protein dimerization in biology. , 2004, Trends in biochemical sciences.

[29]  Erol Gelenbe,et al.  Anomaly detection in gene expression via stochastic models of gene regulatory networks , 2009, BMC Genomics.

[30]  Vahid Shahrezaei,et al.  Analytical distributions for stochastic gene expression , 2008, Proceedings of the National Academy of Sciences.

[31]  Daniel T Gillespie,et al.  Stochastic simulation of chemical kinetics. , 2007, Annual review of physical chemistry.

[32]  M. Caruthers,et al.  Binding of synthetic lactose operator DNAs to lactose represessors. , 1977, Proceedings of the National Academy of Sciences of the United States of America.

[33]  Erol Gelenbe,et al.  G-Networks Based Two Layer Stochastic Modeling of Gene Regulatory Networks with Post-Translational Processes , 2011 .

[34]  M. Thattai,et al.  Intrinsic noise in gene regulatory networks , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[35]  Jorge Chahine,et al.  Configuration-dependent diffusion can shift the kinetic transition state and barrier height of protein folding , 2007, Proceedings of the National Academy of Sciences.

[36]  E. Gelenbe Genetic algorithms with analytical solution , 1996 .

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

[38]  D. Dubnau,et al.  Noise in Gene Expression Determines Cell Fate in Bacillus subtilis , 2007, Science.

[39]  Erol Gelenbe,et al.  Probabilistic models of computer systems , 1976, SIGMETRICS '76.