Glucocorticoid induced gene signature in human skin

ABSTRACT: Glucocorticoids (GCs) are among the most effective and frequently prescribed anti-inflammatory drugs in dermatology. The effects of GCs are mediated by the glucocorticoid receptor (GR), a well-known transcription factor (TF). Despite the well-studied therapeutic and adverse effects of GCs, the molecular signature of GC/GR in human skin is largely unknown. Here, we present a bioinformatics analysis of the human skin transcriptome induced by the glucocorticoid clobetasol propionate (CBP). Full thickness arm skin biopsies were obtained from a cohort of 17 healthy volunteers balanced in sex and race (African-American and Caucasian) 24 hrs after single CBP topical application. Non-treated skin from the same volunteers served as control. Analyses of differentially expressed genes (DEGs) and gene set enrichments (GSE) from RNASeq reflected anti-inflammatory, metabolic and atrophogenic effects of GCs in skin. More than 40% of all DEGs were non-coding RNAs, including long non-coding RNAs (lncRNAs) suggesting that GR effects in skin may extend towards regulation at the post-transcriptional level. Furthermore, we observed sexual and racial dimorphism in the CBP response including a shift towards IFNg/IFNa and IL6/JAK/STAT3 signaling in female skin; and an overall larger response to CBP (increased number of DEGs and increased induction of some GR-target genes) in African-American skin. Weighted gene co-expression network analysis (WGCNA) unveiled a regulatory network comprising 41 TFs, with network hub TFs enriched for direct GR targets and ~ 260 of their target genes that were enriched for the majority of altered functional pathways of the entire CBP transcriptome. Interestingly, ~ 80% of these TFs involved in the regulation of circadian clock, metabolism, and development have been associated with skin aging supporting at the molecular level the known similarities between skin chronically treated with GCs and aged skin. Overall, these findings indicate that GR acts as a master regulator of gene expression in skin via multiple mechanisms including regulation of expression of noncoding RNAs and multiple core TFs

ORGANISM(S): Homo sapiens

PROVIDER: GSE120783 | GEO | 2018/10/04

REPOSITORIES: GEO