A Three Stage Integrative Pathway Search (TIPS©) framework to identify toxicity relevant genes and pathways

<p>Abstract</p> <p>Background</p> <p>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 (<it>TIPS</it>^©) 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.</p> <p>Results</p> <p>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.</p> <p>Conclusion</p> <p>The <it>TIPS</it>^©approach is able to reconstruct active pathways that confer a particular phenotype by integrating gene expression and phenotypic profiles. A web-based version of <it>TIPS</it>^©that performs the analysis described herein can be accessed at <url>http://www.egr.msu.edu/tips</url>.</p

A Three Stage Integrative Pathway Search () framework to identify toxicity relevant genes and pathways-6

<p><b>Copyright information:</b></p><p>Taken from "A Three Stage Integrative Pathway Search () framework to identify toxicity relevant genes and pathways"</p><p>http://www.biomedcentral.com/1471-2105/8/202</p><p>BMC Bioinformatics 2007;8():202-202.</p><p>Published online 14 Jun 2007</p><p>PMCID:PMC1906836.</p><p></p>ated fatty acid (oleate). * significantly higher in palmitate, p < 0.01 by t-test. BSA: control, Ole: oleate treatment, Palm: palmitate treatment

A Three Stage Integrative Pathway Search () framework to identify toxicity relevant genes and pathways-5

<p><b>Copyright information:</b></p><p>Taken from "A Three Stage Integrative Pathway Search () framework to identify toxicity relevant genes and pathways"</p><p>http://www.biomedcentral.com/1471-2105/8/202</p><p>BMC Bioinformatics 2007;8():202-202.</p><p>Published online 14 Jun 2007</p><p>PMCID:PMC1906836.</p><p></p>0.01 by t-test. H: control, P: palmitate treatment, O: oleate treatment, L: linoleate treatment

A Three Stage Integrative Pathway Search () framework to identify toxicity relevant genes and pathways-4

<p><b>Copyright information:</b></p><p>Taken from "A Three Stage Integrative Pathway Search () framework to identify toxicity relevant genes and pathways"</p><p>http://www.biomedcentral.com/1471-2105/8/202</p><p>BMC Bioinformatics 2007;8():202-202.</p><p>Published online 14 Jun 2007</p><p>PMCID:PMC1906836.</p><p></p>NF-α for 24 and 48 hours. X-axis labels indicate the TNF-α concentration in ng/ml and the medium employed in each condition. Data expressed as averages of nine samples +/- s.d. from three independent experiments. , Significant medium effect, P < 0.05 relative to control (BSA medium with no TNF-α); , Significant TNF-α effect within a treatment, P < 0.05 compared to corresponding medium with no TNF-α exposure. TNF-α concentrations are in ng/ml

A Three Stage Integrative Pathway Search () framework to identify toxicity relevant genes and pathways-1

<p><b>Copyright information:</b></p><p>Taken from "A Three Stage Integrative Pathway Search () framework to identify toxicity relevant genes and pathways"</p><p>http://www.biomedcentral.com/1471-2105/8/202</p><p>BMC Bioinformatics 2007;8():202-202.</p><p>Published online 14 Jun 2007</p><p>PMCID:PMC1906836.</p><p></p>0.01 by t-test. H: control, P: palmitate treatment, O: oleate treatment, L: linoleate treatment

A Three Stage Integrative Pathway Search () framework to identify toxicity relevant genes and pathways-3

<p><b>Copyright information:</b></p><p>Taken from "A Three Stage Integrative Pathway Search () framework to identify toxicity relevant genes and pathways"</p><p>http://www.biomedcentral.com/1471-2105/8/202</p><p>BMC Bioinformatics 2007;8():202-202.</p><p>Published online 14 Jun 2007</p><p>PMCID:PMC1906836.</p><p></p>d subset of genes. The network provides an overview of the factors and pathways involved in regulating cytotoxicity. The nodes discussed in the paper are highlighted in red. Microsoft Visio was used to generate the Figure

A Three Stage Integrative Pathway Search () framework to identify toxicity relevant genes and pathways-0

<p><b>Copyright information:</b></p><p>Taken from "A Three Stage Integrative Pathway Search () framework to identify toxicity relevant genes and pathways"</p><p>http://www.biomedcentral.com/1471-2105/8/202</p><p>BMC Bioinformatics 2007;8():202-202.</p><p>Published online 14 Jun 2007</p><p>PMCID:PMC1906836.</p><p></p>NF-α for 24 and 48 hours. X-axis labels indicate the TNF-α concentration in ng/ml and the medium employed in each condition. Data expressed as averages of nine samples +/- s.d. from three independent experiments. , Significant medium effect, P < 0.05 relative to control (BSA medium with no TNF-α); , Significant TNF-α effect within a treatment, P < 0.05 compared to corresponding medium with no TNF-α exposure. TNF-α concentrations are in ng/ml