A Three Stage Integrative Pathway Search (TIPS©) framework to identify toxicity relevant genes and pathways
1 Department of Chemical Engineering and Materials Science, Michigan State University, East Lansing, MI 48824, USA
2 Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824, USA
3 Department of Computer Science and Engineering, Michigan State University, East Lansing, MI 48824, USA
4 MetagenX LLC. Okemos, MI, 48864, USA
5 Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824, USA
6 National Institute on Alcohol Abuse and Alcoholism (NIAAA/NIH), 5625 Fishers Lane, Rockville, MD 20851, USA
BMC Bioinformatics 2007, 8:202 doi:10.1186/1471-2105-8-202Published: 14 June 2007
The ability to obtain profiles of gene expressions, proteins and metabolites with the advent of high throughput technologies has advanced the study of pathway and network reconstruction. Genome-wide network reconstruction requires either interaction measurements or large amount of perturbation data, often not available for mammalian cell systems. To overcome these shortcomings, we developed a Three Stage Integrative Pathway Search (TIPS©) approach to reconstruct context-specific active pathways involved in conferring a specific phenotype, from limited amount of perturbation data. The approach was tested on human liver cells to identify pathways that confer cytotoxicity.
This paper presents a systems approach that integrates gene expression and cytotoxicity profiles to identify a network of pathways involved in free fatty acid (FFA) and tumor necrosis factor-α (TNF-α) induced cytotoxicity in human hepatoblastoma cells (HepG2/C3A). Cytotoxicity relevant genes were first identified and then used to reconstruct a network using Bayesian network (BN) analysis. BN inference was used subsequently to predict the effects of perturbing a gene on the other genes in the network and on the cytotoxicity. These predictions were subsequently confirmed through the published literature and further experiments.
The TIPS© approach is able to reconstruct active pathways that confer a particular phenotype by integrating gene expression and phenotypic profiles. A web-based version of TIPS© that performs the analysis described herein can be accessed at http://www.egr.msu.edu/tips webcite.