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

Mario Marchisio,Moreno Colaiacovo,Jörg Stelling,Ellis Whitehead

doi:10.1186/1752-0509-7-42

Abstract

BackgroundThe 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.ResultsWe 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.ConclusionsFor 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.

Highlights

The modular design of synthetic gene circuits via composable parts (DNA segments) and pools of signal carriers has been successfully applied to bacterial systems
We aim at giving part descriptions that are useful for synthetic biology applications and do not pursue an exhaustive representation of all the possible interactions that govern transcription and translation in eukaryotes
Despite the power of a rule-based modeling approach, one has to find a proper trade-off between model granularity and available knowledge in order to obtain a meaningful model that can predict synthetic gene circuit dynamics and performance

Summary

Introduction

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. Rule-based modeling approaches are increasingly used to obtain compact representations of reaction networks in biological systems. This approach is intrinsically non-modular and not suitable per se for the description of composable genetic modules. Bacterial synthetic gene circuits can be designed in an electronic fashion by wiring together Standard Biological Parts and pools of signal carriers [1]. Org/), Standard Biological Parts are DNA segments such as promoters, ribosome binding sites (RBS), coding regions, small RNAs, and terminators (see Figure 1). In analogy with RNA polymerases, their flux

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