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Computational design of synthetic regulatory networks from a genetic library to characterize the designability of dynamical behaviors.

ABSTRACT: The engineering of synthetic gene networks has mostly relied on the assembly of few characterized regulatory elements using rational design principles. It is of outmost importance to analyze the scalability and limits of such a design workflow. To analyze the design capabilities of libraries of regulatory elements, we have developed the first automated design approach that combines such elements to search the genotype space associated to a given phenotypic behavior. Herein, we calculated the designability of dynamical functions obtained from circuits assembled with a given genetic library. By designing circuits working as amplitude filters, pulse counters and oscillators, we could infer new mechanisms for such behaviors. We also highlighted the hierarchical design and the optimization of the interface between devices. We dissected the functional diversity of a constrained library and we found that even such libraries can provide a rich variety of behaviors. We also found that intrinsic noise slightly reduces the designability of digital circuits, but it increases the designability of oscillators. Finally, we analyzed the robust design as a strategy to counteract the evolvability and noise in gene expression of the engineered circuits within a cellular background, obtaining mechanisms for robustness through non-linear negative feedback loops.

SUBMITTER: Rodrigo G

PROVIDER: S-EPMC3203596 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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Computational design of synthetic regulatory networks from a genetic library to characterize the designability of dynamical behaviors.

Rodrigo Guillermo G Carrera Javier J Jaramillo Alfonso A

Nucleic acids research 20110824 20

The engineering of synthetic gene networks has mostly relied on the assembly of few characterized regulatory elements using rational design principles. It is of outmost importance to analyze the scalability and limits of such a design workflow. To analyze the design capabilities of libraries of regulatory elements, we have developed the first automated design approach that combines such elements to search the genotype space associated to a given phenotypic behavior. Herein, we calculated the des ...[more]

PMID: 21865275

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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.

Dataset Information

Computational design of synthetic regulatory networks from a genetic library to characterize the designability of dynamical behaviors.

Publications

Computational design of synthetic regulatory networks from a genetic library to characterize the designability of dynamical behaviors.

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