Predicting the dynamic behavior of a large network from that of the composing modules is a central problem in systems and synthetic biology. Yet, this predictive ability is still largely missing because modules display context-dependent behavior. One cause of context-dependence is retroactivity, a phenomenon similar to loading that influences in non-trivial ways the dynamic performance of a module upon connection to other modules. Here, we establish an analysis framework for gene transcription networks that explicitly accounts for retroactivity. Specifically, a module's key properties are encoded by three retroactivity matrices: internal, scaling, and mixing retroactivity. All of them have a physical interpretation and can be computed from macroscopic parameters (dissociation constants and promoter concentrations) and from the modules' topology. The internal retroactivity quantifies the effect of intramodular connections on an isolated module's dynamics. The scaling and mixing retroactivity establish how intermodular connections change the dynamics of connected modules. Based on these matrices and on the dynamics of modules in isolation, we can accurately predict how loading will affect the behavior of an arbitrary interconnection of modules. We illustrate implications of internal, scaling, and mixing retroactivity on the performance of recurrent network motifs, including negative autoregulation, combinatorial regulation, two-gene clocks, the toggle switch, and the single-input motif. We further provide a quantitative metric that determines how robust the dynamic behavior of a module is to interconnection with other modules. This metric can be employed both to evaluate the extent of modularity of natural networks and to establish concrete design guidelines to minimize retroactivity between modules in synthetic systems.
Biological modules are inherently context-dependent as the input/output behavior of a module often changes upon connection with other modules. One source of context-dependence is retroactivity, a loading phenomenon by which a downstream system affects the behavior of an upstream system upon interconnection. This fact renders it difficult to predict how modules will behave once connected to each other. In this paper, we propose a general modeling framework for gene transcription networks to accurately predict how retroactivity affects the dynamic behavior of interconnected modules, based on salient physical properties of the same modules in isolation. We illustrate how our framework predicts surprising and counter-intuitive dynamic properties of naturally occurring network structures, which cannot be captured by existing models of the same dimension. We describe implications of our findings on the bottom-up approach to designing synthetic circuits, and on the top-down approach to identifying functional modules in natural networks, revealing trade-offs between robustness to interconnection and dynamic performance. Our framework carries substantial conceptual analogies with electrical network theory based on equivalent representations. We believe that the framework we have proposed, also based on equivalent network representations, can be similarly useful for the analysis and design of biological networks.