MPTP’s Pathway of Toxicity Indicates Central Role of Transcription Factor SP1

Abstract

Deriving a Pathway of Toxicity from transcriptomic data remains a challenging task. We explore the use of weighted gene correlation network analysis (WGCNA) to extract an initial network from a small microarray study of MPTP toxicity in mice. Five modules were statistically significant; each module was analyzed for gene signatures in the Chemical and Genetic Perturbation subset of the Molecular Signatures Database as well as for over-represented transcription factor binding sites and WGCNA clustered probes by function and captured pathways relevant to neurodegenerative disorders. The resulting network was analyzed for transcription factor candidates, which were narrowed down via text-mining for relevance to the disease model, and then combined with the large-scale interaction FANTOM4 database to generate a genetic regulatory network. Modules were enriched for transcription factors relevant to Parkinson’s disease. Transcription factors significantly improved the number of genes that could be connected in a given component. For each module, the transcription factor that had, by far, the highest number of interactions was SP1, and it also had substantial experimental evidence of interactions. This analysis both captures much of the known biology of MPTP toxicity and suggests several candidates for further study. Furthermore, the analysis strongly suggests that SP1 plays a central role in coordinating the cellular response to MPTP toxicity.

Metabolomic network analysis of estrogen-stimulated MCF-7 cells: a comparison of overrepresentation analysis, quantitative enrichment analysis and pathway analysis versus metabolite network analysis

“…This approach, however, is only as useful as the quality of the databases and the reproducibility of the data used - for transcriptomics this may cover a significant portion of the data, but it likely leaves relevant gaps for toxicology, as shown in our previous work (Maertens et al, 2015) and (Pendse et al, in preparation). Metabolomics, on the other hand, has a relatively underdeveloped database infrastructure, and owing to inconsistent or incomplete pathway annotation may miss key information.…”

The need for strategic development of safety sciences

“…CAAT, with one of the authors (TH) as principal investigator, promotes the use of advanced-omics and high-throughput technologies and supports the implementation of knowledge-based frameworks such as Pathways of Toxicity and Adverse Outcome Pathways (Hartung and McBride, 2011) and thus plays a key role in implementing the NAS Tox21 vision. A key goal of the Human Toxome Project is the development of tools for identification of pathways of toxicity (Kleensang et al, 2014) from multi-omics technologies (Maertens et al 2015Pendse et al, 2016) to feed into a systems toxicology approach (Hartung et al, 2012). The combination of orthogonal omics technologies has the advantage that the tremendous signal/noise problem of any omics technology is overcome.…”

Cellular resilience

“…Workflows like those suggested earlier (Maertens et al, 2015), however, can help derive candidate pathways from such untargeted characterizations, and from our experience, WGCNA analysis represents a key tool for overcoming the aforementioned shortcomings. Targeted follow-up measurements, transcription factor analysis and qualification of results by linguistic search engines and systematic literature reviews, also help.…”

“…This becomes even more complex if we see a population of cells, different cell types interacting, or then the organ functions they form and their systemic interaction in the organism. As a further complication, living organisms react to their In the second project (Maertens et al, 2015), we analyzed microarray data derived from brains from MPTP treated mice (Miller et al, 2004) and carried out weighted gene correlation network analysis (WGCNA), supported by text mining, and other systems-level technologies to construct a genetic a regulatory network for MPTP toxicity. The paper was discussed in two guest editorials (Rahnenführer and Leist, 2015;Andersen et al, 2015).…”