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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

Analysis of the ‘89ADEGs’ with the ACUMENTA literature lab demonstrated an enriched of the keratinocyte differentiation pathway.Keratinocytes are known to play a major role in barrier function in AD due to their location in the epidermis. DEGs associated with the keratinocyte differentiation pathway have been shown. The biological functions of these genes were related to cellular movement, barrier functions, signaling as well as cellular development and function. The genes making the strongest contribution are shown in the inner ring starting at the 12 o’clock position and descending in a clockwise direction and outward in the order of contribution to the association to keratinocyte differentiation pathway. Thus LOR accounts for the largest share of the gene set's association with the keratinocyte differentiation pathway, followed by FLG then KRT16 and so on. The gene in this diagram contributing the least to the gene set's association with the keratinocyte differentiation pathway is AOP9.
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pone.0144316.g006: Analysis of the ‘89ADEGs’ with the ACUMENTA literature lab demonstrated an enriched of the keratinocyte differentiation pathway.Keratinocytes are known to play a major role in barrier function in AD due to their location in the epidermis. DEGs associated with the keratinocyte differentiation pathway have been shown. The biological functions of these genes were related to cellular movement, barrier functions, signaling as well as cellular development and function. The genes making the strongest contribution are shown in the inner ring starting at the 12 o’clock position and descending in a clockwise direction and outward in the order of contribution to the association to keratinocyte differentiation pathway. Thus LOR accounts for the largest share of the gene set's association with the keratinocyte differentiation pathway, followed by FLG then KRT16 and so on. The gene in this diagram contributing the least to the gene set's association with the keratinocyte differentiation pathway is AOP9.

Mentions: Analysis of the 89ADGES with the ACUMENTA (www.acumenta.com) revealed that the keratinocyte differentiation pathway was the most significantly enriched pathway (p = <0.0006). The genes associated with the keratinocyte differentiation pathway (36 out of the 89 signature genes) are shown in Fig 6. Many of these genes involved in barrier function [10, 32–34]. These results strongly indicate that AD is associated with a defect in the keratinocyte differentiation pathway, which is consistent with down-regulation of terminal differentiation proteins. The contributing genes for the keratinocyte pathway, ranked by the number of the corresponding publications, were LOR (44%), FLG (42%), KRT16 (4.5%), S100A7 (2%), C1orf46 (1.4%), DEFB4A (0.6%) and SERPINB4 (0.5%) [35].


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)

Analysis of the ‘89ADEGs’ with the ACUMENTA literature lab demonstrated an enriched of the keratinocyte differentiation pathway.Keratinocytes are known to play a major role in barrier function in AD due to their location in the epidermis. DEGs associated with the keratinocyte differentiation pathway have been shown. The biological functions of these genes were related to cellular movement, barrier functions, signaling as well as cellular development and function. The genes making the strongest contribution are shown in the inner ring starting at the 12 o’clock position and descending in a clockwise direction and outward in the order of contribution to the association to keratinocyte differentiation pathway. Thus LOR accounts for the largest share of the gene set's association with the keratinocyte differentiation pathway, followed by FLG then KRT16 and so on. The gene in this diagram contributing the least to the gene set's association with the keratinocyte differentiation pathway is AOP9.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0144316.g006: Analysis of the ‘89ADEGs’ with the ACUMENTA literature lab demonstrated an enriched of the keratinocyte differentiation pathway.Keratinocytes are known to play a major role in barrier function in AD due to their location in the epidermis. DEGs associated with the keratinocyte differentiation pathway have been shown. The biological functions of these genes were related to cellular movement, barrier functions, signaling as well as cellular development and function. The genes making the strongest contribution are shown in the inner ring starting at the 12 o’clock position and descending in a clockwise direction and outward in the order of contribution to the association to keratinocyte differentiation pathway. Thus LOR accounts for the largest share of the gene set's association with the keratinocyte differentiation pathway, followed by FLG then KRT16 and so on. The gene in this diagram contributing the least to the gene set's association with the keratinocyte differentiation pathway is AOP9.
Mentions: Analysis of the 89ADGES with the ACUMENTA (www.acumenta.com) revealed that the keratinocyte differentiation pathway was the most significantly enriched pathway (p = <0.0006). The genes associated with the keratinocyte differentiation pathway (36 out of the 89 signature genes) are shown in Fig 6. Many of these genes involved in barrier function [10, 32–34]. These results strongly indicate that AD is associated with a defect in the keratinocyte differentiation pathway, which is consistent with down-regulation of terminal differentiation proteins. The contributing genes for the keratinocyte pathway, ranked by the number of the corresponding publications, were LOR (44%), FLG (42%), KRT16 (4.5%), S100A7 (2%), C1orf46 (1.4%), DEFB4A (0.6%) and SERPINB4 (0.5%) [35].

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