A Protocol for the Construction and Curation of Genome-Scale Integrated Metabolic and Regulatory Network Models

Genome-scale metabolic network models have been widely used over the last decade and have been shown to successfully predict the metabolic behavior of many organisms. Yet the complexity of metabolic regulation often limits the accuracy of these models. Integrative modeling approaches have recently been developed that combine metabolic and regulatory networks, thereby expanding the capabilities and accuracy of genome-scale modeling. This chapter provides a guide to reconstruct and curate such integrated network models. Specifically, this protocol describes the PROM (Probabilistic Regulation of Metabolism) and GEMINI (Gene Expression and Metabolism Integrated for Network Inference) approaches. PROM is an automated method for the construction of integrated metabolic and transcriptional regulatory network models, while the GEMINI approach curates the integrated network models using transcriptomics and phenomics data. GEMINI represents the first attempt at applying well-established curation tools that exist for metabolic networks to be applied for curating regulatory networks. The integrated network models generated by these approaches enable the mechanistic integration of diverse biological data and can identify novel strategies to engineer cellular metabolism.