Filaggrin-stratified transcriptomic analysis of pediatric skin identifies mechanistic pathways in patients with atopic dermatitis

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:134

Article

Cole, Christian¹  Kroboth, Karin^2,3  Schurch, Nicholas J.¹  Sandilands, Aileen^2,3  Sherstnev, Alexander¹  O'Regan, Grainne M.⁴  Watson, Rosemarie M.⁴  McLean, W. H. Irwin^2,3  Barton, Geoffrey J.¹  Irvine, Alan D.^4,5,6  Brown, Sara J.^2,3,5 

[1] Univ Dundee, Coll Life Sci, Div Computat Biol, Dundee DD1 5EH, Scotland

[2] Univ Dundee, Coll Life Sci, Div Mol Med, Ctr Dermatol & Genet Med, Dundee DD1 5EH, Scotland

[3] Univ Dundee, Coll Med Dent & Nursing, Div Mol Med, Ctr Dermatol & Genet Med, Dundee DD1 5EH, Scotland

[4] Our Ladys Childrens Hosp, Dept Dermatol, Dublin, Ireland

[5] Our Ladys Childrens Hosp, Natl Childrens Res Ctr, Dublin, Ireland

[6] Univ Dublin Trinity Coll, Dublin 2, Ireland

关键词: Atopic dermatitis;    direct RNA sequencing;    eczema;    filaggrin;    gene expression;    single molecule;    skin;    tissue;    transcriptome;   

DOI  :  10.1016/j.jaci.2014.04.021

来源: Elsevier

【 摘 要 】

Background: Atopic dermatitis (AD; eczema) is characterized by a widespread abnormality in cutaneous barrier function and propensity to inflammation. Filaggrin is a multifunctional protein and plays a key role in skin barrier formation. Loss-of-function mutations in the gene encoding filaggrin (FLG) are a highly significant risk factor for atopic disease, but the molecular mechanisms leading to dermatitis remain unclear. Objective: We sought to interrogate tissue-specific variations in the expressed genome in the skin of children with AD and to investigate underlying pathomechanisms in atopic skin. Methods: We applied single-molecule direct RNA sequencing to analyze the whole transcriptome using minimal tissue samples. Uninvolved skin biopsy specimens from 26 pediatric patients with AD were compared with site-matched samples from 10 nonatopic teenage control subjects. Cases and control subjects were screened for FLG genotype to stratify the data set. Results: Two thousand four hundred thirty differentially expressed genes (false discovery rate, P<.05) were identified, of which 211 were significantly upregulated and 490 downregulated by greater than 2-fold. Gene ontology terms for extracellular space'' and defense response'' were enriched, whereas lipid metabolic processes'' were downregulated. The subset of FLG wild-type cases showed dysregulation of genes involved with lipid metabolism, whereas filaggrin haploinsufficiency affected global gene expression and was characterized by a type 1 interferon-mediated stress response. Conclusion: These analyses demonstrate the importance of extracellular space and lipid metabolism in atopic skin pathology independent of FLG genotype, whereas an aberrant defense response is seen in subjects with FLG mutations. Genotype stratification of the large data set has facilitated functional interpretation and might guide future therapy development.

【 授权许可】

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