Dataset Information

A method for the generation of standardized qualitative dynamical systems of regulatory networks.

ABSTRACT:

Background

Modeling of molecular networks is necessary to understand their dynamical properties. While a wealth of information on molecular connectivity is available, there are still relatively few data regarding the precise stoichiometry and kinetics of the biochemical reactions underlying most molecular networks. This imbalance has limited the development of dynamical models of biological networks to a small number of well-characterized systems. To overcome this problem, we wanted to develop a methodology that would systematically create dynamical models of regulatory networks where the flow of information is known but the biochemical reactions are not. There are already diverse methodologies for modeling regulatory networks, but we aimed to create a method that could be completely standardized, i.e. independent of the network under study, so as to use it systematically.

Results

We developed a set of equations that can be used to translate the graph of any regulatory network into a continuous dynamical system. Furthermore, it is also possible to locate its stable steady states. The method is based on the construction of two dynamical systems for a given network, one discrete and one continuous. The stable steady states of the discrete system can be found analytically, so they are used to locate the stable steady states of the continuous system numerically. To provide an example of the applicability of the method, we used it to model the regulatory network controlling T helper cell differentiation.

Conclusion

The proposed equations have a form that permit any regulatory network to be translated into a continuous dynamical system, and also find its steady stable states. We showed that by applying the method to the T helper regulatory network it is possible to find its known states of activation, which correspond the molecular profiles observed in the precursor and effector cell types.

SUBMITTER: Mendoza L

PROVIDER: S-EPMC1440308 | biostudies-literature | 2006 Mar

REPOSITORIES: biostudies-literature

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Publications

A method for the generation of standardized qualitative dynamical systems of regulatory networks.

Mendoza Luis L Xenarios Ioannis I

Theoretical biology & medical modelling 20060316

<h4>Background</h4>Modeling of molecular networks is necessary to understand their dynamical properties. While a wealth of information on molecular connectivity is available, there are still relatively few data regarding the precise stoichiometry and kinetics of the biochemical reactions underlying most molecular networks. This imbalance has limited the development of dynamical models of biological networks to a small number of well-characterized systems. To overcome this problem, we wanted to d ...[more]

PMID: 16542429

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Project description:BACKGROUND: Qualitative dynamics of small gene regulatory networks have been studied in quite some details both with synchronous and asynchronous analysis. However, both methods have their drawbacks: synchronous analysis leads to spurious attractors and asynchronous analysis lacks computational efficiency, which is a problem to simulate large networks. We addressed this question through the analysis of a major biosynthesis pathway. Indeed the cholesterol synthesis pathway plays a pivotal role in dislypidemia and, ultimately, in cancer through intermediates such as mevalonate, farnesyl pyrophosphate and geranyl geranyl pyrophosphate, but no dynamic model of this pathway has been proposed until now. RESULTS: We set up a computational framework to dynamically analyze large biological networks. This framework associates a classical and computationally efficient synchronous Boolean analysis with a newly introduced method based on Markov chains, which identifies spurious cycles among the results of the synchronous simulation. Based on this method, we present here the results of the analysis of the cholesterol biosynthesis pathway and its physiological regulation by the Sterol Response Element Binding Proteins (SREBPs), as well as the modeling of the action of statins, inhibitor drugs, on this pathway. The in silico experiments show the blockade of the cholesterol endogenous synthesis by statins and its regulation by SREPBs, in full agreement with the known biochemical features of the pathway. CONCLUSION: We believe that the method described here to identify spurious cycles opens new routes to compute large and biologically relevant models, thanks to the computational efficiency of synchronous simulation. Furthermore, to the best of our knowledge, we present here the first dynamic systems biology model of the human cholesterol pathway and several of its key regulatory control elements, hoping it would provide a good basis to perform in silico experiments and confront the resulting properties with published and experimental data. The model of the cholesterol pathway and its regulation, along with Boolean formulae used for simulation are available on our web site http://Bioinformaticsu613.free.fr. Graphical results of the simulation are also shown online. The SBML model is available in the BioModels database http://www.ebi.ac.uk/biomodels/ with submission ID: MODEL0568648427.

Project description:Genetic regulatory networks (GRNs) regulate the flow of genetic information from the genome to expressed messenger RNAs (mRNAs) and thus are critical to controlling the phenotypic characteristics of cells. Numerous methods exist for profiling mRNA transcript levels and identifying protein-DNA binding interactions at the genome-wide scale. These enable researchers to determine the structure and output of transcriptional regulatory networks, but uncovering the complete structure and regulatory logic of GRNs remains a challenge. The field of GRN inference aims to meet this challenge using computational modeling to derive the structure and logic of GRNs from experimental data and to encode this knowledge in Boolean networks, Bayesian networks, ordinary differential equation (ODE) models, or other modeling frameworks. However, most existing models do not incorporate dynamic transcriptional data since it has historically been less widely available in comparison to “static” transcriptional data. We report the development of an evolutionary algorithm-based ODE modeling approach that integrates kinetic transcription data and the theory of attractor dynamics analysis to infer GRN architecture and regulatory logic. Our method outperformed six leading GRN inference methods, all of which do not incorporate kinetic transcriptional data in predicting regulatory connections among TFs when applied to a small-scale engineered synthetic GRN in S. cerevisiae. Moreover, we have shown the potential of our method to predict unknown transcription profiles that would be produced upon genetic perturbation of the GRN governing a two-state phenotypic switch in C. albicans. We established an iterative refinement strategy to facilitate candidate selection for experimentation and the experimental results in turn provide validation or improvement for the model. In this way, our GRN inference approach can expedite the development of a sophisticated mathematical model that accurately describes the structure and dynamics of the in vivo GRN.

Dataset Information

A method for the generation of standardized qualitative dynamical systems of regulatory networks.

Background

Results

Conclusion

Publications

A method for the generation of standardized qualitative dynamical systems of regulatory networks.

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