Synchronizing genetic relaxation oscillators by intercell signaling

The ability to design and construct synthetic gene regulatory networks offers the prospect of studying issues related to cellular function in a simplified context; such networks also have many potential applications in biotechnology. A synthetic network exhibiting oscillatory behavior has recently been constructed [Elowitz, M. B. & Leibler, S. (2000) Nature (London) 403, 335–338]. It has also been shown that a natural bacterial quorum-sensing mechanism can be used in a synthetic system to communicate a signal between two populations of cells, such that receipt of the signal causes expression of a target gene [Weiss, R. & Knight, T. F. (2000) in DNA6: Sixth International Meeting on DNA-Based Computers, June 13–17, 2000, Leiden, The Netherlands]. We propose a synthetic gene network in Escherichia coli which combines these two features: the system acts as a relaxation oscillator and uses an intercell signaling mechanism to couple the oscillators and induce synchronous oscillations. We model the system and show that the proposed coupling scheme does lead to synchronous behavior across a population of cells. We provide an analytical treatment of the synchronization process, the dominant mechanism of which is “fast threshold modulation.”

[1]  J. Rogers.  Chaos , 1876, Molecular Vibrations.

[2]  J. Monod,et al.  Genetic regulatory mechanisms in the synthesis of proteins. , 1961, Journal of molecular biology.

[3]  M. Savageau.  Comparison of classical and autogenous systems of regulation in inducible operons , 1974, Nature.

[4]  W. Reznikoff,et al.  Genetic regulation: the Lac control region. , 1975, Science.

[5]  B. Bainbridge,et al.  Genetics , 1981, Experientia.

[6]  M. Rosenberg,et al.  Purification and properties of a transcriptional activator. The cII protein of phage lambda. , 1982, The Journal of biological chemistry.

[7]  J. Sambrook,et al.  Molecular Cloning: A Laboratory Manual , 2001 .

[8]  M. Rosenberg,et al.  Bacteriophage λ protein cII binds promoters on the opposite face of the DNA helix from RNA polymerase , 1983, Nature.

[9]  M. Shih,et al.  Role of cII protein in stimulating transcription initiation at the lambda PRE promoter. Enhanced formation and stabilization of open complexes. , 1984, Journal of molecular biology.

[10]  E. Greenberg,et al.  Diffusion of autoinducer is involved in regulation of the Vibrio fischeri luminescence system , 1985, Journal of bacteriology.

[11]  H. Sambrook.  Molecular cloning : a laboratory manual. Cold Spring Harbor, NY , 1989 .

[12]  Michael I. Jordan,et al.  Advances in Neural Information Processing Systems 30 , 1995 .

[13]  T. Baldwin,et al.  The Vibrio fischeri LuxR protein is capable of bidirectional stimulation of transcription and both positive and negative regulation of the luxR gene , 1991, Journal of bacteriology.

[14]  R Thomas,et al.  Dynamical behaviour of biological regulatory networks--I. Biological role of feedback loops and practical use of the concept of the loop-characteristic state. , 1995, Bulletin of mathematical biology.

[15]  Deliang Wang,et al.  Global competition and local cooperation in a network of neural oscillators , 1995 .

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

[17]  N. Kopell,et al.  Anti-phase solutions in relaxation oscillators coupled through excitatory interactions , 1995, Journal of mathematical biology.

[18]  Nancy Kopell,et al.  Waves and synchrony in networks of oscillators of relaxation and non-relaxation type , 1995 .

[19]  Margret I. Moré,et al.  Enzymatic Synthesis of a Quorum-Sensing Autoinducer Through Use of Defined Substrates , 1996, Science.

[20]  E. Greenberg,et al.  Census and consensus in bacterial ecosystems: the LuxR-LuxI family of quorum-sensing transcriptional regulators. , 1996, Annual review of microbiology.

[21]  L. Glass,et al.  Chaos in high-dimensional neural and gene networks , 1996 .

[22]  M. Kessel,et al.  Proteolysis of the phage λ CII regulatory protein by FtsH (HflB) of Escherichia coli , 1997, Molecular microbiology.

[23]  D. Wolf,et al.  On the relationship between genomic regulatory element organization and gene regulatory dynamics. , 1998, Journal of theoretical biology.

[24]  R. Sauer,et al.  The ClpXP and ClpAP proteases degrade proteins with carboxy-terminal peptide tails added by the SsrA-tagging system. , 1998, Genes & development.

[25]  A. Goldbeter,et al.  A Model for Circadian Rhythms in Drosophila Incorporating the Formation of a Complex between the PER and TIM Proteins , 1998, Journal of biological rhythms.

[26]  A. Arkin,et al.  Stochastic kinetic analysis of developmental pathway bifurcation in phage lambda-infected Escherichia coli cells. , 1998, Genetics.

[27]  P. Hardin,et al.  Interlocked feedback loops within the Drosophila circadian oscillator. , 1999, Science.

[28]  J. Tyson,et al.  A simple model of circadian rhythms based on dimerization and proteolysis of PER and TIM. , 1999, Biophysical journal.

[29]  B. Bassler.  How bacteria talk to each other: regulation of gene expression by quorum sensing. , 1999, Current opinion in microbiology.

[30]  Gary M. Dunny,et al.  Cell-cell signaling in bacteria , 1999 .

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

[32]  S. Leibler,et al.  Biological rhythms: Circadian clocks limited by noise , 2000, Nature.

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

[34]  T. Ziv,et al.  Proteolysis of Bacteriophage λ CII byEscherichia coli FtsH (HflB) , 2000, Journal of bacteriology.

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

[36]  F R Adler,et al.  How to make a biological switch. , 2000, Journal of theoretical biology.

[37]  D. A. Baxter,et al.  Mathematical Modeling of Gene Networks , 2000, Neuron.

[38]  J. Keener,et al.  A mathematical model for quorum sensing in Pseudomonas aeruginosa , 2001, Bulletin of mathematical biology.

[39]  Jeff Hasty,et al.  Designer gene networks: Towards fundamental cellular control. , 2001, Chaos.

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

[41]  Farren J. Isaacs,et al.  Computational studies of gene regulatory networks: in numero molecular biology , 2001, Nature Reviews Genetics.

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

[43]  Nancy Kopell,et al.  Rapid synchronization through fast threshold modulation , 1993, Biological Cybernetics.