Evaluation of the performance of mechanisms for noise attenuation in a single-gene expression.

Experiments of synthetic gene regulatory modules and theoretical studies have clarified the stochastic nature of gene expression. The establishment of methods to control the fluctuation in gene expression is an indispensable step to the synthesis of robust and reliable genetic modules. In this study, we evaluate the performances of several major mechanisms to attenuate the fluctuation in a single-gene expression; noise attenuation through the control of the ratio of the transcription rate to the translation one, the interaction between synthesized proteins and background molecules, and an autoregulatory negative feedback. We analytically derive the dependence of the noise intensity on the parameter values related to elementary reaction processes, optimal conditions to attenuate the noise, and the limitation of the attenuation for those mechanisms. Our results can be an important basis for selecting the most efficient combination of the components in the design and synthesis of robust and reliable genetic modules. Furthermore, the knowledge on the performances that we obtain can also play a role in understanding the design principle of the intracellular gene regulatory networks.

[1]  M. Tyers,et al.  From large networks to small molecules. , 2004, Current opinion in chemical biology.

[2]  Kazuyuki Aihara,et al.  Multivariate analysis of noise in genetic regulatory networks. , 2004, Journal of theoretical biology.

[3]  A. Minton,et al.  Influence of excluded volume upon macromolecular structure and associations in 'crowded' media. , 1997, Current opinion in biotechnology.

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

[5]  J. Hopfield,et al.  From molecular to modular cell biology , 1999, Nature.

[6]  U. Alon,et al.  Negative autoregulation speeds the response times of transcription networks. , 2002, Journal of molecular biology.

[7]  Paul Nurse,et al.  Systems biology: Understanding cells , 2003, Nature.

[8]  R. Ellis,et al.  Macromolecular crowding: an important but neglected aspect of the intracellular environment. , 2001 .

[9]  M. Wall,et al.  Design of gene circuits: lessons from bacteria , 2004, Nature Reviews Genetics.

[10]  H. McAdams,et al.  Gene regulation: Towards a circuit engineering discipline , 2000, Current Biology.

[11]  O. Berg A model for the statistical fluctuations of protein numbers in a microbial population. , 1978, Journal of theoretical biology.

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

[13]  S. Shen-Orr,et al.  Network motifs: simple building blocks of complex networks. , 2002, Science.

[14]  J. Collins,et al.  Programmable cells: interfacing natural and engineered gene networks. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[15]  S. Mangan,et al.  Structure and function of the feed-forward loop network motif , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[16]  Z N Oltvai,et al.  Evolutionary conservation of motif constituents in the yeast protein interaction network , 2003, Nature Genetics.

[17]  Ron Weiss,et al.  Genetic circuit building blocks for cellular computation, communications, and signal processing , 2003, Natural Computing.

[18]  L. Serrano,et al.  Engineering stability in gene networks by autoregulation , 2000, Nature.

[19]  R. Weiss,et al.  Directed evolution of a genetic circuit , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[20]  Dan Ferber,et al.  Microbes Made to Order , 2004, Science.

[21]  Kazuyuki Aihara,et al.  How does noise propagate in genetic networks? A new approach to understand stochasticity in genetic networks , 2003, The 2003 Congress on Evolutionary Computation, 2003. CEC '03..

[22]  P. Swain,et al.  Intrinsic and extrinsic contributions to stochasticity in gene expression , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[23]  Michael A. Savageau,et al.  Design principles for elementary gene circuits: Elements, methods, and examples. , 2001, Chaos.

[24]  T. Kepler,et al.  Stochasticity in transcriptional regulation: origins, consequences, and mathematical representations. , 2001, Biophysical journal.

[25]  C. Rao,et al.  Control, exploitation and tolerance of intracellular noise , 2002, Nature.

[26]  Farren J. Isaacs,et al.  Prediction and measurement of an autoregulatory genetic module , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[27]  A. Ninfa,et al.  Development of Genetic Circuitry Exhibiting Toggle Switch or Oscillatory Behavior in Escherichia coli , 2003, Cell.

[28]  Jesper Tegnér,et al.  Systems biology is taking off. , 2003, Genome research.

[29]  Kazuyuki Aihara,et al.  Noise-reduction through interaction in gene expression and biochemical reaction processes. , 2004, Journal of theoretical biology.

[30]  J. Raser,et al.  Control of Stochasticity in Eukaryotic Gene Expression , 2004, Science.

[31]  Mads Kærn,et al.  Noise in eukaryotic gene expression , 2003, Nature.

[32]  W. Fontana,et al.  Small Numbers of Big Molecules , 2002, Science.

[33]  U. Alon,et al.  Detailed map of a cis-regulatory input function , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[34]  M. Ehrenberg,et al.  Random signal fluctuations can reduce random fluctuations in regulated components of chemical regulatory networks. , 2000, Physical review letters.

[35]  Jeremy D. Glasner,et al.  Genome-Scale Analysis of the Uses of the Escherichia coli Genome: Model-Driven Analysis of Heterogeneous Data Sets , 2003, Journal of bacteriology.

[36]  Uri Alon,et al.  Using a Quantitative Blueprint to Reprogram the Dynamics of the Flagella Gene Network , 2004, Cell.

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

[38]  E. Shapiro,et al.  An autonomous molecular computer for logical control of gene expression , 2004, Nature.

[39]  Ertugrul M. Ozbudak,et al.  Multistability in the lactose utilization network of Escherichia coli , 2004, Nature.

[40]  U Alon,et al.  Generation of oscillations by the p53-Mdm2 feedback loop: a theoretical and experimental study. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[41]  A. Kierzek,et al.  The Effect of Transcription and Translation Initiation Frequencies on the Stochastic Fluctuations in Prokaryotic Gene Expression* , 2001, The Journal of Biological Chemistry.

[42]  B. Palsson,et al.  The evolution of molecular biology into systems biology , 2004, Nature Biotechnology.

[43]  A. Fulton,et al.  How crowded is the cytoplasm? , 1982, Cell.

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

[45]  William A. Wells Rewiring the cell , 2004, The Journal of Cell Biology.

[46]  J. Collins,et al.  Inferring Genetic Networks and Identifying Compound Mode of Action via Expression Profiling , 2003, Science.

[47]  Nicola J. Rinaldi,et al.  Transcriptional Regulatory Networks in Saccharomyces cerevisiae , 2002, Science.

[48]  C Jayaprakash,et al.  The role of dimerization in noise reduction of simple genetic networks. , 2003, Journal of theoretical biology.

[49]  Edda Klipp,et al.  Systems Biology , 1994 .

[50]  N. Kampen,et al.  Stochastic processes in physics and chemistry , 1981 .

[51]  Michael L Simpson,et al.  Rewiring the cell: synthetic biology moves towards higher functional complexity. , 2004, Trends in biotechnology.

[52]  R. Lindner,et al.  Effects of dextran on the self-association of human spectrin. , 1995, Biophysical chemistry.

[53]  Jeff Hasty,et al.  Engineered gene circuits , 2002, Nature.

[54]  H. Kitano Systems Biology: A Brief Overview , 2002, Science.

[55]  C M Dobson,et al.  Effects of macromolecular crowding on protein folding and aggregation , 1999, The EMBO journal.

[56]  D. Gillespie Exact Stochastic Simulation of Coupled Chemical Reactions , 1977 .

[57]  M. Elowitz,et al.  Protein Mobility in the Cytoplasm ofEscherichia coli , 1999, Journal of bacteriology.

[58]  U. Alon,et al.  Assigning numbers to the arrows: Parameterizing a gene regulation network by using accurate expression kinetics , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[59]  G. Shivashankar,et al.  Tracking operator state fluctuations in gene expression in single cells. , 2004, Biophysical journal.

[60]  S. Shen-Orr,et al.  Network motifs in the transcriptional regulation network of Escherichia coli , 2002, Nature Genetics.

[61]  M. Thattai,et al.  Attenuation of noise in ultrasensitive signaling cascades. , 2002, Biophysical journal.

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

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

[64]  Uri Alon,et al.  Dynamics of the p53-Mdm2 feedback loop in individual cells , 2004, Nature Genetics.