Application of Comparative Transcriptional Genomics to Identify Molecular Targets for Pediatric IBD.
Application of Comparative Transcriptional Genomics to Identify Molecular Targets for Pediatric IBD.
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DOI：
10.3389/fimmu.2015.00165
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发表时间：
2015
影响因子：
7.3
通讯作者：
Kevil CG
中科院分区：
文献类型：
--
作者：
Fang K;Grisham MB;Kevil CG
小鼠结肠炎实验模型已被广泛用于分析炎症性肠病（IBD）发展过程中发生的分子事件。然而，尚不确定实验模型在多大程度上再现了人类IBD的特征。这主要是由于缺乏精确的方法来直接和全面地比较小鼠和人类炎症结肠组织在分子水平上的差异。在这里，我们使用两组儿童IBD和两种小鼠结肠炎模型的全局基因表达模式来直接比较小鼠和人类IBD的基因组特征。通过比较两组儿童IBD微阵列数据，我们发现83个基因在儿童克罗恩病和溃疡性结肠炎之间以相似的方式差异表达。趋化因子（C-C motif）配体2 （CCL2）基因的上调定位于IBD易感位点17q12，表明我们的比较研究可以揭示已知的与IBD的遗传关联。通过比较小儿IBD和实验性结肠炎微阵列数据，我们发现它们之间的共同特征包括：(1)CXCL9和S100A8上调；(2)细胞因子-细胞因子受体通路失调；(3) IRF1和IRF2转录结合位点在上调基因的启动子区域过度表达，HNF1A和Lhx3转录结合位点在下调基因的启动子区域过度表达。总之，本研究提供了不同儿童IBD人群与不同结肠炎模型之间转录组变化的综合观点。这些发现揭示了几个新的分子靶点在结肠炎调节方面的进一步研究。
Experimental models of colitis in mice have been used extensively for analyzing the molecular events that occur during inflammatory bowel disease (IBD) development. However, it is uncertain to what extent the experimental models reproduce features of human IBD. This is largely due to the lack of precise methods for direct and comprehensive comparison of mouse and human inflamed colon tissue at the molecular level. Here, we use global gene expression patterns of two sets of pediatric IBD and two mouse models of colitis to obtain a direct comparison of the genome signatures of mouse and human IBD. By comparing the two sets of pediatric IBD microarray data, we found 83 genes were differentially expressed in a similar manner between pediatric Crohn’s disease and ulcerative colitis. Up-regulation of the chemokine (C–C motif) ligand 2 (CCL2) gene that maps to 17q12, a confirmed IBD susceptibility loci, indicates that our comparison study can reveal known genetic associations with IBD. In comparing pediatric IBD and experimental colitis microarray data, we found common signatures amongst them including: (1) up-regulation of CXCL9 and S100A8; (2) cytokine–cytokine receptor pathway dysregulation; and (3) over-represented IRF1 and IRF2 transcription binding sites in the promoter region of up-regulated genes, and HNF1A and Lhx3 binding sites were over-represented in the promoter region of the down-regulated genes. In summary, this study provides a comprehensive view of transcriptome changes between different pediatric IBD populations in comparison with different colitis models. These findings reveal several new molecular targets for further study in the regulation of colitis.
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