Glucocorticoids (GCs) are the most frequently used anti-inflammatory drugs in dermatology. However, the molecular signature of GCs and their receptor (GR) in human skin is largely unknown. We obtained full thickness skin biopsies from healthy volunteers before and after topical treatment with clobetasol propionate (CBP, 0.05% cream applied for 24 hrs to the relatively sun-protected volar aspect of the upper arm skin.  Our validated bioinformatics analysis of CBP-induced human skin transcriptome (RNASeq) identified numerous novel GC-responsive genes, including over a thousand non-coding RNAs. We observed sexual and racial dimorphism in the CBP response including a shift towards IFNα/IFNγ and IL6/JAK/STAT3 signaling in female skin; and a larger response to CBP in African-American skin. Weighted gene co-expression network analysis unveiled a dense skin network of 41 transcription factors (TF) including circadian KLF9, and ~ 260 of their target genes enriched for functional pathways representative of the entire CBP transcriptome. Using keratinocytes with KLF9 knockdown, we revealed a novel feed-forward loop in GR signaling. Interestingly, many of the CBP-regulated TFs were involved in the control of development, metabolism, circadian clock; and 80% of them were associated with skin aging highlighting similarities between GC-treated and aged skin. Overall, these findings indicate that GR acts as an important regulator of gene expression in skin - both at the transcriptional and post-transcriptional level - via multiple mechanisms including regulation of non-coding RNAs and multiple core TFs.

Novel transcriptomic network interactions in the human skin treated with topical glucocorticoid