Multiple Transcriptome Data Analysis Reveals Biologically Relevant Atopic Dermatitis Signature Genes and Pathways.
Multiple Transcriptome Data Analysis Reveals Biologically Relevant Atopic Dermatitis Signature Genes and Pathways.
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DOI：
10.1371/journal.pone.0144316
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Mersha TB
中科院分区：
文献类型：
--
作者：
Ghosh D;Ding L;Sivaprasad U;Geh E;Biagini Myers J;Bernstein JA;Khurana Hershey GK;Mersha TB
一些研究已经确定了特应性皮炎(AD)与正常皮肤相比差异表达的基因。然而，不同群体报道的差异表达基因(Deg)也有相当大的差异，AD的确切原因仍不完全清楚。使用基于排名的方法，我们分析了来自五个不同微阵列研究的基因表达数据，总共包括127个样本和超过250,000个转录本。在这些研究中，包括Flg基因在内的89个AD基因表达特征被鉴定为一致的失调。使用支持向量机，我们表明，‘89ADGES’区分AD和正常皮肤的预测准确率为98%。这些基因的功能注释表明，它们在免疫反应(如β防御素、微精原蛋白)、角质形成细胞分化/表皮发育(如Flg、Corin、AQP、LOR、KRT16)、炎症(如IL37、IL27RA、CCL18)和脂代谢(如AKR1B10、FAD7、FAR2)中发挥作用。随后，我们使用定量聚合酶链式反应在小鼠模型中验证了签名基因的子集。利用生物信息学方法，我们在89个签名基因中确定了角质形成细胞途径的过度表达(P=0.0006)。角质形成细胞位于表皮中，在屏障功能中发挥着重要作用。我们的结果表明，除了免疫介导的途径外，皮肤屏障途径，如角质形成细胞分化途径，在AD的发病中起着关键作用。更好地了解角质形成细胞在AD中的作用对于开发针对该疾病的新的“屏障疗法”将是重要的。
Several studies have identified genes that are differentially expressed in atopic dermatitis (AD) compared to normal skin. However, there is also considerable variation in the list of differentially expressed genes (DEGs) reported by different groups and the exact cause of AD is still not fully understood. Using a rank-based approach, we analyzed gene expression data from five different microarray studies, comprising a total of 127 samples and more than 250,000 transcripts. A total of 89 AD gene expression signatures ‘89ADGES’, including FLG gene, were identified to show dysregulation consistently across these studies. Using a Support Vector Machine, we showed that the ‘89ADGES’ discriminates AD from normal skin with 98% predictive accuracy. Functional annotation of these genes implicated their roles in immune responses (e.g., betadefensin, microseminoprotein), keratinocyte differentiation/epidermal development (e.g., FLG, CORIN, AQP, LOR, KRT16), inflammation (e.g., IL37, IL27RA, CCL18) and lipid metabolism (e.g., AKR1B10, FAD7, FAR2). Subsequently, we validated a subset of signature genes using quantitative PCR in a mouse model. Using a bioinformatic approach, we identified keratinocyte pathway over-represented (P = <0.0006) among the 89 signature genes. Keratinocytes are known to play a major role in barrier function due to their location in the epidermis. Our result suggests that besides immune- mediated pathway, skin barrier pathways such as the keratinocyte differentiation pathway play a key role in AD pathogenesis. A better understanding of the role of keratinocytes in AD will be important for developing novel “barrier therapy” for this disease.