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Multiple Transcriptome Data Analysis Reveals Biologically Relevant Atopic Dermatitis Signature Genes and Pathways.

Ghosh D, Ding L, Sivaprasad U, Geh E, Biagini Myers J, Bernstein JA, Khurana Hershey GK, Mersha TB - PLoS ONE (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Division of Immunology, Allergy & Rheumatology, Department of Internal Medicine, University of Cincinnati, Cincinnati, United States of America.

ABSTRACT
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.

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Related in: MedlinePlus

Hierarchical clustering and principal component analysis.Hierarchical cluster analysis (panel A) and principal component analysis (Panel B) are shown. HCA which is based on the means for all individuals from AD and control individuals was used to obtain similarities among individuals according to their correlation measures across all expression values of 89 gene datasets. Branch height represents dissimilarity. Note that, AD samples differ in branch length from controls. Sample-based principal component analysis (PCA) analysis of the entire AD and control samples are shown. The first PC accounted for more than double the variance of the second PC. The contribution of the first two PCs in classifying AD and control samples are presented.
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pone.0144316.g002: Hierarchical clustering and principal component analysis.Hierarchical cluster analysis (panel A) and principal component analysis (Panel B) are shown. HCA which is based on the means for all individuals from AD and control individuals was used to obtain similarities among individuals according to their correlation measures across all expression values of 89 gene datasets. Branch height represents dissimilarity. Note that, AD samples differ in branch length from controls. Sample-based principal component analysis (PCA) analysis of the entire AD and control samples are shown. The first PC accounted for more than double the variance of the second PC. The contribution of the first two PCs in classifying AD and control samples are presented.

Mentions: Fig 2 shows unsupervised hierarchical cluster analysis (HCA) (panel A) and Principal component analysis (Panel B) of the datasets. In HCA, euclidean distance and complete linkage were used to obtain similarities/dissimilarities among sets of individuals according to their expression values of all 89 genes. Branch height represents dissimilarity. As expected, samples were clustered into two groups: AD patients versus healthy individuals. Principal component analysis (PCA) of the entire AD and control samples are shown in Fig 2 (Panel B). The first PC accounted for more than double the variance of the second PC. Further analysis using principal component scatter plot showed that the first two PCs contributed to 60–80% of the total variation in AD. Fig 3 shows log average fold-changes of expression of 89DEGs plotted against p-value ranks. Result shows that the top significant genes belong to keratinocyte differentiation, cell morphology as well as some innate immune genes, which were consistently down-regulated.


Multiple Transcriptome Data Analysis Reveals Biologically Relevant Atopic Dermatitis Signature Genes and Pathways.

Ghosh D, Ding L, Sivaprasad U, Geh E, Biagini Myers J, Bernstein JA, Khurana Hershey GK, Mersha TB - PLoS ONE (2015)

Hierarchical clustering and principal component analysis.Hierarchical cluster analysis (panel A) and principal component analysis (Panel B) are shown. HCA which is based on the means for all individuals from AD and control individuals was used to obtain similarities among individuals according to their correlation measures across all expression values of 89 gene datasets. Branch height represents dissimilarity. Note that, AD samples differ in branch length from controls. Sample-based principal component analysis (PCA) analysis of the entire AD and control samples are shown. The first PC accounted for more than double the variance of the second PC. The contribution of the first two PCs in classifying AD and control samples are presented.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4696650&req=5

pone.0144316.g002: Hierarchical clustering and principal component analysis.Hierarchical cluster analysis (panel A) and principal component analysis (Panel B) are shown. HCA which is based on the means for all individuals from AD and control individuals was used to obtain similarities among individuals according to their correlation measures across all expression values of 89 gene datasets. Branch height represents dissimilarity. Note that, AD samples differ in branch length from controls. Sample-based principal component analysis (PCA) analysis of the entire AD and control samples are shown. The first PC accounted for more than double the variance of the second PC. The contribution of the first two PCs in classifying AD and control samples are presented.
Mentions: Fig 2 shows unsupervised hierarchical cluster analysis (HCA) (panel A) and Principal component analysis (Panel B) of the datasets. In HCA, euclidean distance and complete linkage were used to obtain similarities/dissimilarities among sets of individuals according to their expression values of all 89 genes. Branch height represents dissimilarity. As expected, samples were clustered into two groups: AD patients versus healthy individuals. Principal component analysis (PCA) of the entire AD and control samples are shown in Fig 2 (Panel B). The first PC accounted for more than double the variance of the second PC. Further analysis using principal component scatter plot showed that the first two PCs contributed to 60–80% of the total variation in AD. Fig 3 shows log average fold-changes of expression of 89DEGs plotted against p-value ranks. Result shows that the top significant genes belong to keratinocyte differentiation, cell morphology as well as some innate immune genes, which were consistently down-regulated.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Division of Immunology, Allergy & Rheumatology, Department of Internal Medicine, University of Cincinnati, Cincinnati, United States of America.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus