Transcriptomic Network Interactions in Human Skin Treated with Topical Glucocorticoid Clobetasol Propionate

Loukia N. Lili, Anna Klopot, Benjamin Readhead, Gleb Baida, Joel T. Dudley, I. Budunova

Research output: Contribution to journalArticle

Abstract

Glucocorticoids are the most frequently used anti-inflammatory drugs in dermatology. However, the molecular signature of glucocorticoids and their receptor in human skin is largely unknown. Our validated bioinformatics analysis of human skin transcriptome induced by topical glucocorticoid clobetasol propionate (CBP) in healthy volunteers identified numerous unreported glucocorticoid-responsive genes, including over a thousand noncoding RNAs. We observed sexual and racial dimorphism in the CBP response including a shift toward IFN-α/IFN-γ and IL-6/Jak/Signal transducer and activator of transcription (STAT) 3 signaling in female skin; and a larger response to CBP in African-American skin. Weighted gene coexpression network analysis unveiled a dense skin network of 41 transcription factors including circadian Kruppel-like factor 9 (KLF9), and ∼260 of their target genes enriched for functional pathways representative of the entire CBP transcriptome. Using keratinocytes with Kruppel-like factor 9 knockdown, we revealed a feedforward loop in glucocorticoid receptor signaling, previously unreported. Interestingly, many of the CBP-regulated transcription factors were involved in the control of development, metabolism, circadian clock; and 80% of them were associated with skin aging showing similarities between glucocorticoid-treated and aged skin. Overall, these findings indicate that glucocorticoid receptor acts as an important regulator of gene expression in skin—both at the transcriptional and posttranscriptional level—via multiple mechanisms including regulation of noncoding RNAs and multiple core transcription factors.

Original languageEnglish (US)
JournalJournal of Investigative Dermatology
DOIs
StateAccepted/In press - Jan 1 2019

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Clobetasol
Glucocorticoids
Skin
Glucocorticoid Receptors
Kruppel-Like Transcription Factors
Untranslated RNA
Transcription Factors
Transcriptome
Genes
Skin Aging
STAT3 Transcription Factor
Dermatology
Circadian Clocks
Gene Regulatory Networks
Regulator Genes
Computational Biology
Keratinocytes
Sex Characteristics
African Americans
Bioinformatics

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Dermatology
  • Cell Biology

Cite this

Transcriptomic Network Interactions in Human Skin Treated with Topical Glucocorticoid Clobetasol Propionate. / Lili, Loukia N.; Klopot, Anna; Readhead, Benjamin; Baida, Gleb; Dudley, Joel T.; Budunova, I.

In: Journal of Investigative Dermatology, 01.01.2019.

Research output: Contribution to journalArticle

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