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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

Major steps in the analysis of transcriptome data.Five individual datasets, obtained from GEO, were first normalized and quality-checked using hierarchical cluster analysis (HCA) and principal component analysis (PCA), and differentially expressed genes (DEGs; fold change ≥ 1.5) were identified from each dataset. Genes differentially regulated between AD and non-AD controls in at least 3 out of 5 datasets (common dataset ratio ≥ 0.6), were ranked by fold-change. Ingenuity Pathway Analysis (IPA) were conducted for network analysis and ACUMENTA for pathway analysis, and Support Vector Machine and discriminant analysis were used to discriminate and predict membership of AD patients from healthy controls.
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pone.0144316.g001: Major steps in the analysis of transcriptome data.Five individual datasets, obtained from GEO, were first normalized and quality-checked using hierarchical cluster analysis (HCA) and principal component analysis (PCA), and differentially expressed genes (DEGs; fold change ≥ 1.5) were identified from each dataset. Genes differentially regulated between AD and non-AD controls in at least 3 out of 5 datasets (common dataset ratio ≥ 0.6), were ranked by fold-change. Ingenuity Pathway Analysis (IPA) were conducted for network analysis and ACUMENTA for pathway analysis, and Support Vector Machine and discriminant analysis were used to discriminate and predict membership of AD patients from healthy controls.

Mentions: To explore genes and pathways related to AD, gene expression analysis was done using AD datasets originated from five independent studies [4, 10–13]. First, we analyzed individual datasets obtained from publicly accessible databases to determine DEGs with fold changes ≥1.5 [6]. The DEGs consistently present in individual datasets were identified and arranged based on p values [6]. Our DEGs were then clustered by their functions to identify the most affected pathways related to AD. Data collection and analysis steps have been summarized in Fig 1.


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)

Major steps in the analysis of transcriptome data.Five individual datasets, obtained from GEO, were first normalized and quality-checked using hierarchical cluster analysis (HCA) and principal component analysis (PCA), and differentially expressed genes (DEGs; fold change ≥ 1.5) were identified from each dataset. Genes differentially regulated between AD and non-AD controls in at least 3 out of 5 datasets (common dataset ratio ≥ 0.6), were ranked by fold-change. Ingenuity Pathway Analysis (IPA) were conducted for network analysis and ACUMENTA for pathway analysis, and Support Vector Machine and discriminant analysis were used to discriminate and predict membership of AD patients from healthy controls.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0144316.g001: Major steps in the analysis of transcriptome data.Five individual datasets, obtained from GEO, were first normalized and quality-checked using hierarchical cluster analysis (HCA) and principal component analysis (PCA), and differentially expressed genes (DEGs; fold change ≥ 1.5) were identified from each dataset. Genes differentially regulated between AD and non-AD controls in at least 3 out of 5 datasets (common dataset ratio ≥ 0.6), were ranked by fold-change. Ingenuity Pathway Analysis (IPA) were conducted for network analysis and ACUMENTA for pathway analysis, and Support Vector Machine and discriminant analysis were used to discriminate and predict membership of AD patients from healthy controls.
Mentions: To explore genes and pathways related to AD, gene expression analysis was done using AD datasets originated from five independent studies [4, 10–13]. First, we analyzed individual datasets obtained from publicly accessible databases to determine DEGs with fold changes ≥1.5 [6]. The DEGs consistently present in individual datasets were identified and arranged based on p values [6]. Our DEGs were then clustered by their functions to identify the most affected pathways related to AD. Data collection and analysis steps have been summarized in Fig 1.

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