Network-based analysis of transcriptional profiles from chemical perturbations experiments

Abstract

Background: Methods for inference and comparison of biological networks are emerging as powerful tools for the identification of groups of tightly connected genes whose activity may be altered during disease progression or due to chemical perturbations. Connectivity-based comparisons help identify aggregate changes that would be difficult to detect with differential analysis methods comparing individual genes. Methods: In this study, we describe a pipeline for network comparison and its application to the analysis of gene expression datasets from chemical perturbation experiments, with the goal of elucidating the modes of actions of the profiled perturbations. We apply our pipeline to the analysis of the DrugMatrix and the TG-GATEs, two of the largest toxicogenomics resources available, containing gene expression measurements for model organisms exposed to hundreds of chemical compounds with varying carcinogenicity and genotoxicity. Results: Starting from chemical-specific transcriptional networks inferred from these data, we show that the proposed comparative analysis of their associated networks identifies groups of chemicals with similar functions and similar carcinogenicity/genotoxicity profiles. We also show that the in-silico annotation by pathway enrichment analysis of the gene modules with a significant gain or loss of connectivity for specific groups of compounds can reveal molecular pathways significantly associated with the chemical perturbations and their likely modes of action. Conclusions: The proposed pipeline for transcriptional network inference and comparison is highly reproducible and allows grouping chemicals with similar functions and carcinogenicity/genotoxicity profiles. In the context of drug discovery or drug repositioning, the methods presented here could help assign new functions to novel or existing drugs, based on the similarity of their associated network with those built for other known compounds. Additionally, the method has broad applicability beyond the uses here described and could be used as an alternative or as a complement to standard approaches of differential gene expression analysis.