Transcriptomic network interactions in the human skin treated with topical glucocorticoid clobetasol propionate.

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. Our validated bioinformatics analysis of human skin transcriptome (RNASeq) induced by topical glucocorticoid clobetasol propionate (CBP) in healthy volunteers identified numerous unreported 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 feed-forward loop in GR signaling, not previously reported. 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 showing 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.