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Transcriptomic Network Interactions in Human Skin Treated with Topical Glucocorticoid Clobetasol Propionate
- Source :
- J Invest Dermatol
- Publication Year :
- 2019
- Publisher :
- Elsevier BV, 2019.
-
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.
- Subjects :
- Adult
Male
STAT3 Transcription Factor
0301 basic medicine
Administration, Topical
Kruppel-Like Transcription Factors
Human skin
Dermatology
Biology
Biochemistry
White People
Article
Transcriptome
03 medical and health sciences
Transactivation
Sex Factors
0302 clinical medicine
Glucocorticoid receptor
Skin Physiological Phenomena
medicine
Humans
Gene Regulatory Networks
Glucocorticoids
Molecular Biology
Transcription factor
Skin
Transrepression
Clobetasol
integumentary system
Computational Biology
Cell Biology
Middle Aged
Cell biology
Black or African American
KLF9
030104 developmental biology
Gene Knockdown Techniques
030220 oncology & carcinogenesis
Female
Interferons
Glucocorticoid
medicine.drug
Subjects
Details
- ISSN :
- 0022202X
- Volume :
- 139
- Database :
- OpenAIRE
- Journal :
- Journal of Investigative Dermatology
- Accession number :
- edsair.doi.dedup.....6cbb45904c56e4cf137277d817288be3