New Publication: Global transcription regulation of RK2 plasmids: a case study in the combined use of dynamical mathematical models and statistical inference for integration of experimental data and hypothesis exploration.

Today we have published a new article in BMC Systems Biology:

Herman, D., Thomas, C.M. and Stekel, D.J. 2011. Global transcription regulation of RK2 plasmids: a case study in the combined use of dynamical mathematical models and statistical inference for integration of experimental data and hypothesis exploration. BMC Systems Biology 2011, 5:119.

This is Dorota’s first published research article so big congratulations to due to her: a very well-deserved achievement! The paper abstract is:

Background

IncP-1 plasmids are broad host range plasmids that have been found in clinical and environmental bacteria. They often carry genes for antibiotic resistance or catabolic pathways. The archetypal IncP-1 plasmid RK2 is a well-characterized biological system, with a fully sequenced and annotated genome and wide range of experimental measurements. Its central control operon, encoding two global regulators KorA and KorB, is a natural example of a negatively self-regulated operon. To increase our understanding of the regulation of this operon, we have constructed a dynamical mathematical model using Ordinary Differential Equations, and employed a Bayesian inference scheme, Markov Chain Monte Carlo (MCMC) using the Metropolis-Hastings algorithm, as a way of integrating experimental measurements and a priori knowledge. We also compared MCMC and Metabolic Control Analysis (MCA) as approaches for determining the sensitivity of model parameters.

Results

We identified two distinct sets of parameter values, with different biological interpretations, that fit and explain the experimental data. This allowed us to highlight the proportion of repressor protein as dimers as a key experimental measurement defining the dynamics of the system. Analysis of joint posterior distributions led to the identification of correlations between parameters for protein synthesis and partial repression by KorA or KorB dimers, indicating the necessary use of joint posteriors for correct parameter estimation. Using MCA, we demonstrated that the system is highly sensitive to the growth rate but insensitive to repressor monomerization rates in their selected value regions; the latter outcome was also confirmed by MCMC. Finally, by examining a series of model refinements for partial repression by KorA or KorB dimers alone, we showed that a model including partial repression by KorA and KorB was most compatible with existing experimental data.

Conclusions

We have demonstrated that the combination of dynamical mathematical models with Bayesian inference is valuable in integrating diverse experimental data and identifying key determinants and parameters for the IncP-1 central control operon. Moreover, we have shown that Bayesian inference and MCA are complementary methods for identification of sensitive parameters. We propose that this demonstrates generic value in applying this combination of approaches to systems biology dynamical modelling.

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Modelling and Microbiology – Conference at the eScience Institute

Tomorrow is the final meeting at the eScience Institute in Edinburgh: our conference on Modelling and Microbiology. Although I am a co-organizer, I am unable to attend for family reasons. We will be ably represented by Dorota Herman, who will be speaking on Tuesday at 3:05pm.

The entire meeting will be webcast and can be watched here. We have many good speakers, so I am posting the full speaker timetable below.

Monday July 4th

1.45-2 Welcome (Rosalind Allen)

2-3 Robert Austin (Princeton)
Darwin, ecology and the emergence of bacterial resistance: an
attempt at a synthesis

3.30-4.15 Martin Howard (John Innes Centre)
Dissecting the dynamics of low copy number plasmid segregation

4.15–5 Tobias Bollenbach (IST Austria)
Microbial responses to antibiotic combinations

Tuesday July 5th

9.30-10.30 Martin Ackermann (ETH Zuerich)
An evolutionary perspective on phenotypic heterogeneity in bacteria

11-11.45 Peter Lund (Birmingham)
Insights into stress response from laboratory-based evolution

11.45-12.05 Sara Mitri (Oxford)
Social evolution in microbial communities

12.05-12.25 Fatima Drubi (Leiden University)
Do bacteria sporulate as a bet-hedging strategy in stochastic
environments?

2-2.45 Alexander Morozov (Edinburgh)
Self-assembled bacterial rotors

2.45-3.05 Bartlomiej Waclaw (Edinburgh)
Simple models for bacterial evolution with migration

3.05-3.25 Dorota Herman (Birmingham)
Mathematical model for transcriptional regulation of RK2 plasmids and
its evolutional optimisation

3.55-4.40 Jan Kreft (Birmingham)
Individual-based modelling of horizontal gene transfer in chemostats
and biofilms

4.40-5.15 Phil Aldridge (Newcastle)

Continuous control of flagellar gene expression by the s28-FlgM
regulatory circuit in Salmonella enterica

Wednesday July 6th

9.30-10.30 Oskar Hallatschek (MPI Goettingen)
Genetic drift and selection in growing biofilms

11-11.45 Ian Stansfield (Aberdeen)
Negative feedback loops in the translational control of gene
expression

11.45-12.05 Leena Nieminen (Strathclyde)
Modelling metabolic switching in differentiating bacterium
Streptomyces coelicor

12.05-12.25 David Richards (John Innes)
The mechanistic basis of hyphal branching in Streptomyces

2-2.45 Mamen Romano (Aberdeen)
The dynamics of demand and supply in mRNA translation

2.45-3.05 Dominique Chu (Kent)
Optimisation of gene expression resources in bioprocessing host cell
lines

Thursday July 7th

9.30-10.30 John Little (U. Arizona)
Stochastic modelling of the phage lambda regulatory circuit: prophage
induction and stability

11.00-11.45 Francesco Falciani (Birmingham)
A systems biology approach sheds new light on bacterial acid
resistance

11.45-12.30 Kevin Foster (Oxford)
Spatiogenetic structure and cooperation in microbe