Modulation of Epidermal Transcription Circuits in Psoriasis: New Links between Inflammation and Hyperproliferation
Open Access
- 15 November 2013
- journal article
- clinical trial
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 8 (11), e79253
- https://doi.org/10.1371/journal.pone.0079253
Abstract
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. 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). 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.Keywords
This publication has 99 references indexed in Scilit:
- ISG15: leading a double life as a secreted moleculeExperimental & Molecular Medicine, 2013
- A Comprehensive Profile of ChIP-Seq-Based STAT1 Target Genes Suggests the Complexity of STAT1-Mediated Gene Regulatory MechanismsGene Regulation and Systems Biology, 2013
- Genomic Profiling of a Human Organotypic Model of AEC Syndrome Reveals ZNF750 as an Essential Downstream Target of Mutant TP63American Journal of Human Genetics, 2012
- ZNF750 Is a p63 Target Gene that Induces KLF4 to Drive Terminal Epidermal DifferentiationDevelopmental Cell, 2012
- A Subset of Methylated CpG Sites Differentiate Psoriatic from Normal SkinJournal of Investigative Dermatology, 2012
- Human Keratinocytes' Response to Injury Upregulates CCL20 and Other Genes Linking Innate and Adaptive ImmunityJournal of Investigative Dermatology, 2012
- EGFR and IL-1 Signaling Synergistically Promote Keratinocyte Antimicrobial Defenses in a Differentiation-Dependent MannerJournal of Investigative Dermatology, 2011
- Assessment of the Psoriatic Transcriptome in a Large Sample: Additional Regulated Genes and Comparisons with In Vitro ModelsJournal of Investigative Dermatology, 2010
- Global Gene Expression Analysis Reveals Evidence for Decreased Lipid Biosynthesis and Increased Innate Immunity in Uninvolved Psoriatic SkinJournal of Investigative Dermatology, 2009
- Gene module level analysis: identification to networks and dynamicsCurrent Opinion in Biotechnology, 2008