title: Modulation of epidermal transcription circuits in psoriasis: new links between inflammation and hyperproliferation.
abstract: BACKGROUND
  Whole-genome expression profiling has been used to characterize molecular-level differences between psoriasis lesions and normal skin. Pathway analysis, however, is complicated by the fact that expression profiles have been derived from bulk skin biopsies with RNA derived from multiple cell types.
  
  
  RESULTS
  We analyzed gene expression across a large sample of psoriatic (PP) and uninvolved/normal (PN) skin biopsies (n = 215 patients). We identified 1975 differentially expressed genes, including 8 associated with psoriasis susceptibility loci. To facilitate pathway analysis, PP versus PN differences in gene expression were analyzed with respect to 235 gene modules, each containing genes with a similar expression pattern in keratinocytes and epidermis. We identified 30 differentially expressed modules (DEMs) biased towards PP-increased or PP-decreased expression. These DEMs were associated with regulatory axes involving cytokines (e.g., IFN-γ, IL-17A, TNF-α), transcription factors (e.g., STAT1, NF-κB, E2F, RUNX1) and chromatin modifiers (SETDB1). We identified an interferon-induced DEM with genes encoding anti-viral proteins (designated "STAT1-57"), which was activated in psoriatic epidermis but repressed following biologic therapy. Genes within this DEM shared a motif near the transcription start site resembling the interferon-stimulated response element (ISRE).
  
  
  CONCLUSIONS
  We analyzed a large patient cohort and developed a new approach for delineating epidermis-specific pathways and regulatory mechanisms that underlie altered gene expression in psoriasis. Our findings highlight previously unrecognized "transcription circuits" that can provide targets for development of non-systemic therapies.
authors.affiliation: Department of Dermatology, University of Michigan School of Medicine, Ann Arbor, Michigan, United States of America.
authors.forename: William R
authors.initials: WR
authors.lastname: Swindell
authors.forename: Andrew
authors.initials: A
authors.lastname: Johnston
authors.forename: Xianying
authors.initials: X
authors.lastname: Xing
authors.forename: John J
authors.initials: JJ
authors.lastname: Voorhees
authors.forename: James T
authors.initials: JT
authors.lastname: Elder
authors.forename: Johann E
authors.initials: JE
authors.lastname: Gudjonsson
mesh_terms: D015331:Cohort Studies; D004817:Epidermis / Q000378:metabolism* / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D011565:Psoriasis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014158:Transcription, Genetic