Article,
Metabolic Network Topology Reveals Transcriptional Regulatory Signatures of Type 2 Diabetes
PLoS Comput Biol, 6 (4): e1000729+ (Apr 1, 2010)
DOI: 10.1371/journal.pcbi.1000729
Abstract
Type 2 diabetes mellitus (T2DM) is a disorder characterized by both insulin resistance and impaired insulin secretion. Recent transcriptomics studies related to T2DM have revealed changes in expression of a large number of metabolic genes in a variety of tissues. Identification of the molecular mechanisms underlying these transcriptional changes and their impact on the cellular metabolic phenotype is a challenging task due to the complexity of transcriptional regulation and the highly interconnected nature of the metabolic network. In this study we integrate skeletal muscle gene expression datasets with human metabolic network reconstructions to identify key metabolic regulatory features of T2DM. These features include reporter metabolites—metabolites with significant collective transcriptional response in the associated enzyme-coding genes, and transcription factors with significant enrichment of binding sites in the promoter regions of these genes. In addition to metabolites from TCA cycle, oxidative phosphorylation, and lipid metabolism (known to be associated with T2DM), we identified several reporter metabolites representing novel biomarker candidates. For example, the highly connected metabolites NAD+/NADH and ATP/ADP were also identified as reporter metabolites that are potentially contributing to the widespread gene expression changes observed in T2DM. An algorithm based on the analysis of the promoter regions of the genes associated with reporter metabolites revealed a transcription factor regulatory network connecting several parts of metabolism. The identified transcription factors include members of the CREB, NRF1 and PPAR family, among others, and represent regulatory targets for further experimental analysis. Overall, our results provide a holistic picture of key metabolic and regulatory nodes potentially involved in the pathogenesis of T2DM. Type 2 diabetes mellitus is a complex metabolic disease recognized as one of the main threats to human health in the 21st century. Recent studies of gene expression levels in human tissue samples have indicated that multiple metabolic pathways are dysregulated in diabetes and in individuals at risk for diabetes; which of these are primary, or central to disease pathogenesis, remains a key question. Cellular metabolic networks are highly interconnected and often tightly regulated; any perturbations at a single node can thus rapidly diffuse to the rest of the network. Such complexity presents a considerable challenge in pinpointing key molecular mechanisms and biomarkers associated with insulin resistance and type 2 diabetes. In this study, we address this problem by using a methodology that integrates gene expression data with the human cellular metabolic network. We demonstrate our approach by analyzing gene expression patterns in skeletal muscle. The analysis identified transcription factors and metabolites that represent potential targets for therapeutic agents and future clinical diagnostics for type 2 diabetes and impaired glucose metabolism. In a broader perspective, the study provides a framework for analysis of gene expression datasets from complex diseases in the context of changes in cellular metabolism.
