Dataset Information

Promoter DNA methylation contributes to human ?-defensin-1 deficiency in atopic dermatitis.

ABSTRACT: Atopic dermatitis (AD) is a chronic inflammatory skin disease caused by epidermal barrier dysfunction and dysregulation of innate and adaptive immunity. Epigenetic regulation of human ?-defensin-1 (HBD-1) might be associated with a variety of defects in the innate immune system during AD pathogenesis. We investigated the possible mechanism of decreased HBD-1 gene expression in AD and demonstrated the restoration of HBD-1 transcription in undifferentiated normal human epidermal keratinocyte cells after treatment with a DNA methyltransferase inhibitor. We also conducted an in vitro methylated reporter assay using a reporter containing 14 CpG sites. Methylation of the 14 CpG sites within the HBD-1 5' region resulted in an approximately 86% reduction in promoter activity and affected HBD-1 transcriptional regulation. We then compared methylation frequencies at CpG 3 and CpG 4 between non-lesional and lesional epidermis samples of patients with severe AD and between these paired tissues and healthy control epidermis from normal volunteers without AD history. Bisulfite pyrosequencing data showed significantly higher methylation frequencies at the CpG 3 and 4 sites in AD lesional samples than in non-lesional AD skin and normal skin samples (P?

SUBMITTER: Noh YH

PROVIDER: S-EPMC6138329 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Promoter DNA methylation contributes to human β-defensin-1 deficiency in atopic dermatitis.

Noh Yoo-Hun YH Lee Jaehyouk J Seo Seong Joon SJ Myung Soon Chul SC

Animal cells and systems 20180524 3

Atopic dermatitis (AD) is a chronic inflammatory skin disease caused by epidermal barrier dysfunction and dysregulation of innate and adaptive immunity. Epigenetic regulation of human β-defensin-1 (HBD-1) might be associated with a variety of defects in the innate immune system during AD pathogenesis. We investigated the possible mechanism of decreased HBD-1 gene expression in AD and demonstrated the restoration of HBD-1 transcription in undifferentiated normal human epidermal kera ...[more]

PMID: 30460095

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Project description:Dedicator of cytokinesis 8 deficiency is an autosomal recessive primary immune deficiency disease belonging to the group of hyperimmunoglobulinemia E syndrome (HIES). The clinical phenotype of dedicator of cytokinesis 8 (DOCK8) deficiency, characterized by allergic manifestations, increased infections, and increased IgE levels, overlaps with the clinical presentation of atopic dermatitis (AD). Despite the identification of metabolomics and cytokine biomarkers, distinguishing between the two conditions remains clinically challenging. The present study used a label-free untargeted proteomics approach using liquid-chromatography mass spectrometry with network pathway analysis to identify the differentially regulated serum proteins and the associated metabolic pathways altered between the groups. Serum samples from DOCK8 (n = 10), AD (n = 9) patients and healthy control (Ctrl) groups (n = 5) were analyzed. Based on the proteomics profile, the PLS-DA score plot between the three groups showed a clear group separation and sample clustering (R2 = 0.957, Q2 = 0.732). Significantly differentially abundant proteins (p < 0.05, FC cut off 2) were identified between DOCK8-deficient and AD groups relative to Ctrl (n = 105, and n = 109) and between DOCK8-deficient and AD groups (n = 85). Venn diagram analysis revealed a differential regulation of 24 distinct proteins from among the 85 between DOCK8-deficient and AD groups, including claspin, haptoglobin-related protein, immunoglobulins, complement proteins, fibulin, and others. Receiver-operating characteristic curve (ROC) analysis identified claspin and haptoglobin-related protein, as potential biomarkers with the highest sensitivity and specificity (AUC = 1), capable of distinguishing between patients with DOCK8 deficiency and AD. Network pathway analysis between DOCK8-deficiency and AD groups revealed that the identified proteins centered around the dysregulation of ERK1/2 signaling pathway. Herein, proteomic profiling of DOCK8-deficiency and AD groups was carried out to determine alterations in the proteomic profiles and identify a panel of the potential proteomics biomarker with possible diagnostic applications. Distinguishing between DOCK8-deficiency and AD will help in the early initiation of treatment and preventing complications.

Project description:Bi-allelic mutations in the dedicator of cytokinesis 8 (DOCK8) are responsible for a rare autosomal recessive primary combined immunodeficiency syndrome, characterized by atopic dermatitis, elevated serum Immunoglobulin E (IgE) levels, recurrent severe cutaneous viral infections, autoimmunity, and predisposition to malignancy. The molecular link between DOCK8 deficiency and atopic skin inflammation remains unknown. Severe atopic dermatitis (AD) and DOCK8 deficiency share some clinical symptoms, including eczema, eosinophilia, and increased serum IgE levels. Increased serum IgE levels are characteristic of, but not specific to allergic diseases. Herein, we aimed to study the metabolomic profiles of DOCK8-deficient and AD patients for potential disease-specific biomarkers using chemical isotope labeling liquid chromatography-mass spectrometry (CIL LC-MS). Serum samples were collected from DOCK8-deficient (n = 10) and AD (n = 9) patients. Metabolomics profiling using CIL LC-MS was performed on patient samples and compared to unrelated healthy controls (n = 33). Seven metabolites were positively identified, distinguishing DOCK8-deficient from AD patients. Aspartic acid and 3-hydroxyanthranillic acid (3HAA, a tryptophan degradation pathway intermediate) were up-regulated in DOCK8 deficiency, whereas hypotaurine, leucyl-phenylalanine, glycyl-phenylalanine, and guanosine were down-regulated. Hypotaurine, 3-hydroxyanthranillic acid, and glycyl-phenyalanine were identified as potential biomarkers specific to DOCK8 deficiency. Aspartate availability has been recently implicated as a limiting metabolite for tumour growth and 3HAA; furthermore, other tryptophan metabolism pathway-related molecules have been considered as potential novel targets for cancer therapy. Taken together, perturbations in tryptophan degradation and increased availability of aspartate suggest a link of DOCK8 deficiency to oncogenesis. Additionally, perturbations in taurine and dipeptides metabolism suggest altered antixidation and cell signaling states in DOCK8 deficiency. Further studies examining the mechanisms underlying these observations are necessary.

Dataset Information

Promoter DNA methylation contributes to human ?-defensin-1 deficiency in atopic dermatitis.

Publications

Promoter DNA methylation contributes to human <i>β</i>-defensin-1 deficiency in atopic dermatitis.

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