Stochastic kinetics description of a simple transcription model

We study a stochastic model of transcription kinetics in order to characterize the distributions of transcriptional delay and of elongation rates. Transcriptional delay is the time which elapses between the binding of RNA polymerase to a promoter sequence and its dissociation from the DNA template strand with consequent release of the transcript. Transcription elongation is the process by which the RNA polymerase slides along the template strand. The model considers a DNA template strand with one promoter site and n nucleotide sites, and five types of reaction processes, which we think are key ones in transcription. The chemical master equation is a set of ordinary differential equations in 3n variables, where n is the number of bases in the template. This model is too huge to be handled if n is large. We manage to get a reduced Markov model which has only 2n independent variables and can well approximate the original dynamics. We obtain a number of analytical and numerical results for this model, including delay and transcript elongation rate distributions. Recent studies of single-RNA polymerase transcription by using optical-trapping techniques raise an issue of whether the elongation rates measured in a population are heterogeneous or not. Our model implies that in the cases studied, different RNA polymerase molecules move at different characteristic rates along the template strand. We also discuss the implications of this work for the mathematical modeling of genetic regulatory circuits.

[1]  T. Nagatani The physics of traffic jams , 2002 .

[2]  M. Roussel The Use of Delay Differential Equations in Chemical Kinetics , 1996 .

[3]  D. A. Baxter,et al.  Modeling transcriptional control in gene networks—methods, recent results, and future directions , 2000, Bulletin of mathematical biology.

[4]  J. Hasty,et al.  Translating the noise , 2002, Nature Genetics.

[5]  Paul Smolen,et al.  Effects of macromolecular transport and stochastic fluctuations on dynamics of genetic regulatory systems. , 1999, American journal of physiology. Cell physiology.

[6]  Stephen J. Elledge,et al.  Cell Cycle Checkpoints: Preventing an Identity Crisis , 1996, Science.

[7]  Edward J. Wood,et al.  Biochemistry (3rd ed.) , 2004 .

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

[9]  K. Cooke,et al.  Discrete delay, distributed delay and stability switches , 1982 .

[10]  K. Svoboda,et al.  Fluctuation analysis of motor protein movement and single enzyme kinetics. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[11]  C. A. Thomas,et al.  Electron Microscopic Visualization of Transcription , 1970 .

[12]  O. Miller,et al.  Portrait of a gene , 1969, Journal of cellular physiology.

[13]  Dan ie l T. Gil lespie A rigorous derivation of the chemical master equation , 1992 .

[14]  Yoshihiro Yamanishi,et al.  Comprehensive Analysis of Delay in Transcriptional Regulation Using Expression Profiles , 2003 .

[15]  D. Drew A mathematical model for prokaryotic protein synthesis , 2001, Bulletin of mathematical biology.

[16]  Michael J. Davis,et al.  Geometric Approach to Multiple-Time-Scale Kinetics: A Nonlinear Master Equation Describing Vibration-to-Vibration Relaxation , 2001 .

[17]  Michelle D. Wang,et al.  Sequence-dependent kinetic model for transcription elongation by RNA polymerase. , 2004, Journal of molecular biology.

[18]  P. V. von Hippel,et al.  Reaction pathways in transcript elongation. , 2002, Biophysical chemistry.

[19]  F. Jülicher,et al.  Motion of RNA polymerase along DNA: a stochastic model. , 1998, Biophysical journal.

[20]  T. Elston,et al.  Force generation in RNA polymerase. , 1998, Biophysical journal.

[21]  Donald A Drew,et al.  A mathematical model for elongation of a peptide chain , 2003, Bulletin of mathematical biology.

[22]  N. Monk Oscillatory Expression of Hes1, p53, and NF-κB Driven by Transcriptional Time Delays , 2003, Current Biology.

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

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

[25]  Jeffrey W. Smith,et al.  Stochastic Gene Expression in a Single Cell , 2022 .

[26]  M. Schnitzer,et al.  Statistical kinetics of processive enzymes. , 1995, Cold Spring Harbor symposia on quantitative biology.

[27]  Daniel B. Forger,et al.  Stochastic simulation of the mammalian circadian clock. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[28]  Michael Ruogu Zhang,et al.  Comprehensive identification of cell cycle-regulated genes of the yeast Saccharomyces cerevisiae by microarray hybridization. , 1998, Molecular biology of the cell.

[29]  R. D. Bliss,et al.  Role of feedback inhibition in stabilizing the classical operon. , 1982, Journal of theoretical biology.

[30]  B. Palsson Systems Biology: Transcriptional Regulatory Networks , 2006 .

[31]  C. Bustamante,et al.  Single-molecule study of transcriptional pausing and arrest by E. coli RNA polymerase. , 2000, Science.

[32]  H. Klamut,et al.  The human dystrophin gene requires 16 hours to be transcribed and is cotranscriptionally spliced , 1995, Nature Genetics.

[33]  J. Mahaffy,et al.  Oscillations in a model of repression with external control , 1992, Journal of mathematical biology.

[34]  Marcel Abendroth,et al.  Biological delay systems: Linear stability theory , 1990 .

[35]  M. Chamberlin,et al.  Basic mechanisms of transcript elongation and its regulation. , 1997, Annual review of biochemistry.

[36]  D. A. Baxter,et al.  Frequency selectivity, multistability, and oscillations emerge from models of genetic regulatory systems. , 1998, American journal of physiology. Cell physiology.

[37]  H. Stanley,et al.  Introduction to Phase Transitions and Critical Phenomena , 1972 .

[38]  D. Gillespie A General Method for Numerically Simulating the Stochastic Time Evolution of Coupled Chemical Reactions , 1976 .

[39]  Julian Lewis Autoinhibition with Transcriptional Delay A Simple Mechanism for the Zebrafish Somitogenesis Oscillator , 2003, Current Biology.

[40]  F. W. Schneider,et al.  Computer simulation of T3/T7 phage infection using lag times. , 1987, Biophysical chemistry.

[41]  George H. Weiss,et al.  Stochastic Processes in Chemical Physics: The Master Equation , 1977 .

[42]  P. V. Hippel,et al.  An Integrated Model of the Transcription Complex in Elongation, Termination, and Editing , 1998 .

[43]  Robert Landick,et al.  Diversity in the Rates of Transcript Elongation by Single RNA Polymerase Molecules* , 2004, Journal of Biological Chemistry.

[44]  A. Wightman,et al.  Mathematical Physics. , 1930, Nature.

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

[46]  William Feller,et al.  An Introduction to Probability Theory and Its Applications , 1967 .

[47]  Walter L. Smith Probability and Statistics , 1959, Nature.

[48]  S. Busenberg,et al.  The Effects of Dimension and Size for a Compartmental Model of Repression , 1988 .

[49]  W. McClure,et al.  Rate-limiting steps in RNA chain initiation. , 1980, Proceedings of the National Academy of Sciences of the United States of America.

[50]  Michelle D. Wang,et al.  Single molecule analysis of RNA polymerase elongation reveals uniform kinetic behavior , 2002, Proceedings of the National Academy of Sciences of the United States of America.