PPARa siRNA-Treated Expression Profiles Uncover the Causal Sufficiency Network for Compound-Induced Liver Hypertrophy

ABSTRACT: Approaches for discovering mechanisms of action and for identifying molecular biomarkers in biomedical research are evolving today, as the growing symbiosis with computational sciences becomes more widely appreciated than ever. In fact, the combination of various new technologies has been pushing forward both frontiers. Here, we present an example of the combined use of in vivo siRNA knock-down technology, genome-wide gene expression profiling, and computational reasoning to unveil regulatory causal relationships and the sufficiency network of identified genes for compound-induced toxicity. Unlike previously reported approaches, our method requires only one targeted perturbation for genome-wide de novo pathway discovery. Hence, our method can be directly applied to animal models in which it is still technically challenging to perform genome-wide genetic perturbation or RNAi screening. The independent application of our derived model to compounds with unrelated mechanisms of action suggests the existence of a universal molecular module that mediates liver hypertrophy. The resulting sufficiency network for induction of liver hypertrophy will have an immediate impact on the progress of toxicogenomics. When combined with phenotypic evaluation, our approach should help to unleash the full potential of siRNAs in systematically unveiling the molecular mechanisms of biological events. Keywords: Regulatory pathway discovery by In vivo transcription modification

ORGANISM(S): Mus musculus

PROVIDER: GSE6622 | GEO | 2007/01/20

SECONDARY ACCESSION(S): PRJNA98849

REPOSITORIES: GEO