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Open Access Highly Accessed Methodology article

Modular, rule-based modeling for the design of eukaryotic synthetic gene circuits

Mario Andrea Marchisio1*, Moreno Colaiacovo2, Ellis Whitehead1 and Jörg Stelling1

Author Affiliations

1 ETH Zurich and Swiss Institute of Bioinformatics, D-BSSE, Mattenstrasse 26, Basel 4058, Switzerland

2 CRA-GPG Centro di ricerca per la genomica e la postgenomica animale e vegetale, Consiglio per la Ricerca e la Sperimentazione in Agricoltura, Via San Protaso 302, Fiorenzuola d’Arda (PC) 29017, Italy

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BMC Systems Biology 2013, 7:42  doi:10.1186/1752-0509-7-42

Published: 27 May 2013

Abstract

Background

The modular design of synthetic gene circuits via composable parts (DNA segments) and pools of signal carriers (molecules such as RNA polymerases and ribosomes) has been successfully applied to bacterial systems. However, eukaryotic cells are becoming a preferential host for new synthetic biology applications. Therefore, an accurate description of the intricate network of reactions that take place inside eukaryotic parts and pools is necessary. Rule-based modeling approaches are increasingly used to obtain compact representations of reaction networks in biological systems. However, this approach is intrinsically non-modular and not suitable per se for the description of composable genetic modules. In contrast, the Model Description Language (MDL) adopted by the modeling tool ProMoT is highly modular and it enables a faithful representation of biological parts and pools.

Results

We developed a computational framework for the design of complex (eukaryotic) gene circuits by generating dynamic models of parts and pools via the joint usage of the BioNetGen rule-based modeling approach and MDL. The framework converts the specification of a part (or pool) structure into rules that serve as inputs for BioNetGen to calculate the part’s species and reactions. The BioNetGen output is translated into an MDL file that gives a complete description of all the reactions that take place inside the part (or pool) together with a proper interface to connect it to other modules in the circuit. In proof-of-principle applications to eukaryotic Boolean circuits with more than ten genes and more than one thousand reactions, our framework yielded proper representations of the circuits’ truth tables.

Conclusions

For the model-based design of increasingly complex gene circuits, it is critical to achieve exact and systematic representations of the biological processes with minimal effort. Our computational framework provides such a detailed and intuitive way to design new and complex synthetic gene circuits.

Keywords:
Composable parts; Pools of signal carriers; Gene circuit modular design; Rule-based modeling