School of Agriculture and Biology, Department of Animal Sciences, Shanghai Jiao Tong University, Shanghai, Peoples' Republic of China.
Mamm Genome. 2011 Dec;22(11-12):703-13. doi: 10.1007/s00335-011-9359-x. Epub 2011 Oct 14.
The mutation of the Wilson's disease protein ATP7B has been widely used to study the direct link between hepatic high copper and development of liver pathology. Several studies have used gene expression profiling of high-copper effects to identify the key genes in the process, but few focused on the involved pathways and the coexpression patterns of associated pathways. We used a microarray data set from the public database library of GEO (Gene Expression Omnibus), which is associated with liver transcriptome in the early stages of copper accumulation in the mouse model of Wilson's disease under Atp7b knockout. To be more powerful than conventional single-gene methods in the study of complex diseases, we applied gene set enrichment analysis (GSEA) on the data sets and performed candidate transcription factors selection. As a result, 16 upregulated pathways such as tryptophan metabolism and cell cycle and 15 downregulated pathways such as TCA cycle and PPAR signaling pathway were identified as high-copper-responsive target pathways in Atp7b knockout mouse liver, and most of them had not been reported on previously. Finally, coexpression networks of related pathways were constructed with the significant core genes and transcription factors such as SREBP1 and PPARG. The results of our study may help us better understand the molecular mechanisms of high-copper effects in mice liver in genome-wide.
Wilson 病蛋白 ATP7B 的突变已被广泛用于研究肝内高铜与肝病理发展之间的直接联系。有几项研究使用高铜效应的基因表达谱分析来确定该过程中的关键基因，但很少关注相关途径以及相关途径的共表达模式。我们使用了来自 GEO（基因表达综合数据库）公共数据库库的微阵列数据集，该数据集与 Wilson 病小鼠模型中铜蓄积早期的肝转录组有关，该模型在 Atp7b 敲除下。为了在复杂疾病的研究中比传统的单基因方法更强大，我们在数据集上应用了基因集富集分析（GSEA）并进行了候选转录因子选择。结果，鉴定出 16 个上调途径，如色氨酸代谢和细胞周期，以及 15 个下调途径，如 TCA 循环和 PPAR 信号通路，作为 Atp7b 敲除小鼠肝中高铜反应的靶途径，其中大多数以前没有报道过。最后，用显著的核心基因和转录因子（如 SREBP1 和 PPARG）构建了相关途径的共表达网络。我们的研究结果可能有助于我们更全面地了解高铜对小鼠肝脏的分子机制。
