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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

Top biological networks identified using IPA connecting several DEGs for (a) lesional and non-lesional combined (b) lesional (c) non-lesional AD.Lipid genes, protease genes and immune-related ‘nodal genes’, controlling several DEGs, are located at the center of the networks. Solid lines represent direct and established regulatory functions, while dotted lines represent indirect roles.
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pone.0144316.g005: Top biological networks identified using IPA connecting several DEGs for (a) lesional and non-lesional combined (b) lesional (c) non-lesional AD.Lipid genes, protease genes and immune-related ‘nodal genes’, controlling several DEGs, are located at the center of the networks. Solid lines represent direct and established regulatory functions, while dotted lines represent indirect roles.

Mentions: Analysis of 89ADGES using IPA generated three different gene networks Fig 5A: dermatological diseases and conditions, Fig 5B: cellular growth and proliferation, and Fig 5C: metabolic disease; The networks had several genes involved in epidermal barrier, inflammation and immunity, anti-oxidant and lipid metabolism (see discussionsection). Similar analysis has been done for lesional (Fig 5D) and non-lesional (Fig 5E) datasets. The biological functions of these genes were related to skin development and function, cell-mediated immune response, hematology/immune cell trafficking and organ morphology (Table 2).


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)

Top biological networks identified using IPA connecting several DEGs for (a) lesional and non-lesional combined (b) lesional (c) non-lesional AD.Lipid genes, protease genes and immune-related ‘nodal genes’, controlling several DEGs, are located at the center of the networks. Solid lines represent direct and established regulatory functions, while dotted lines represent indirect roles.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0144316.g005: Top biological networks identified using IPA connecting several DEGs for (a) lesional and non-lesional combined (b) lesional (c) non-lesional AD.Lipid genes, protease genes and immune-related ‘nodal genes’, controlling several DEGs, are located at the center of the networks. Solid lines represent direct and established regulatory functions, while dotted lines represent indirect roles.
Mentions: Analysis of 89ADGES using IPA generated three different gene networks Fig 5A: dermatological diseases and conditions, Fig 5B: cellular growth and proliferation, and Fig 5C: metabolic disease; The networks had several genes involved in epidermal barrier, inflammation and immunity, anti-oxidant and lipid metabolism (see discussionsection). Similar analysis has been done for lesional (Fig 5D) and non-lesional (Fig 5E) datasets. The biological functions of these genes were related to skin development and function, cell-mediated immune response, hematology/immune cell trafficking and organ morphology (Table 2).

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