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首页> 外文期刊>Archives of Toxicology >MPTP's pathway of toxicity indicates central role of transcription factor SP1.
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MPTP's pathway of toxicity indicates central role of transcription factor SP1.

机译:MPTP的毒性途径表明转录因子SP1的核心作用。

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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.
机译:从转录组数据得出毒性途径仍然是一项艰巨的任务。我们探索使用加权基因相关网络分析(WGCNA)从小鼠MPTP毒性的小型微阵列研究中提取初始网络。五个模块具有统计学意义;通过功能和捕获的与神经退行性疾病相关的途径,分析了每个模块的分子签名数据库的化学和遗传扰动子集中的基因签名,以及过度代表的转录因子结合位点和WGCNA簇状探针。分析所得网络中的转录因子候选物,通过文本挖掘缩小与疾病模型的相关性,然后将其与大规模相互作用的FANTOM4数据库组合以生成遗传调控网络。丰富了与帕金森氏病相关的转录因子的模块。转录因子显着改善了给定组件中可以连接的基因数量。对于每个模块,到目前为止,具有最高数量相互作用的转录因子是SP1,并且它也具有大量相互作用的实验证据。该分析既捕获了MPTP毒性的许多已知生物学信息,又提出了一些有待进一步研究的候选人。此外,分析强烈暗示SP1在协调细胞对MPTP毒性的反应中起着核心作用。

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