Global Gene Expression Analysis Reveals Evidence for Decreased Lipid Biosynthesis and Increased Innate Immunity in Uninvolved Psoriatic Skin

Abstract

Psoriasis is a genetically determined inflammatory skin disease. Although the transition from uninvolved into lesional skin is accompanied by changes in the expression of multiple genes, much less is known about the difference between uninvolved skin from psoriatic patients as opposed to skin from normal individuals. Multiple biochemical and morphological changes were reported decades ago in uninvolved psoriatic skin but remain poorly understood. Here we demonstrate dysregulation of 223 transcripts representing 179 unique genes in uninvolved psoriatic skin, 178 of which were not previously known to be altered in their expression. The proteins encoded by these transcripts are involved in lipid metabolism, antimicrobial defenses, epidermal differentiation and control of cutaneous vasculature. Cluster analysis of transcripts with significantly altered expression identified a group of genes involved in lipid metabolism with highly correlated gene expression. Promoter analysis demonstrated enrichment for binding sites of three transcription factors; peroxisome proliferator-activator receptor alpha (PPARA), sterol regulatory element-binding protein (SREBF) and estrogen receptor 2 (ESR2), suggesting that coordinate regulation of lipid metabolic genes may be related to the action of these factors. Taken together, our results identify a “pre-psoriatic” gene expression signature, suggesting decreased lipid biosynthesis and increased innate immunity in uninvolved psoriatic skin.

Epidermal ablation of Dlx3 is linked to IL-17–associated skin inflammation

“…Characterization of altered gene expression patterns has provided insights into the pathophysiology of each disorder (9). In this study, we demonstrated up-regulation of Sprr2d, Defb3, Cdsn, and S100a9 expression in K14cre;Dlx3 Kin/f skin, indicating overlap in gene expression between this mouse model and the PS gene expression signature (9,22). Moreover, marked down-regulation of Dlx3 expression was detected in human psoriatic lesions, suggesting that the lack of Dlx3 transcriptional function is potentially involved in the pathophysiology of human inflammatory diseases.…”

Computational Systems Biology of Psoriasis: Are We Ready for the Age of Omics and Systems Biomarkers?

“…Computational analysis is essential in analyzing the extensive data retrieved from these studies by incorporating the integration of various 'omics' platforms to fully represent the underlying mechanism of psoriasis. Gudjonsson et al (2009) characterized and compared gene expression in skin from psoriatic patients to identify patterns that are involved in lipid metabolism, innate immunity, and keratinocyte differentiation. Coda et al (2012) investigated differential gene expression in samples of lesional and nonlesional skin to identify psoriatic disease-associated pathways at the tissue level.…”

Investigations on molecular mechanisms of epithelial cell stress responses

“…Previous studies have shown that the gene expression pattern of lesional psoriatic skin is significantly different from normal skin of unaffected individuals [117,134,140]. Additionally, the transition from non-involved into involved psoriatic skin is accompanied by changes in the expression of multiple genes [139]. Some of the earliest identified genes as having significant over-expression in involved psoriatic skin include transforming growth factor-α (TGF-α) [141], tumor necrosis factor-α (TNF-α) [142], vascular endothelial growth factor (VEGF) and its receptors [143] and proteinase inhibitors such as peptidase inhibitor 3 (SKALP) [144].…”

“…Some of the earliest identified genes as having significant over-expression in involved psoriatic skin include transforming growth factor-α (TGF-α) [141], tumor necrosis factor-α (TNF-α) [142], vascular endothelial growth factor (VEGF) and its receptors [143] and proteinase inhibitors such as peptidase inhibitor 3 (SKALP) [144]. Whereas previous investigations have focused only on the expression of small number of genes [145], recently more comprehensive analyses such as have identified a wide range of dysregulated genes in lesional and non-lesional psoriatic skin samples compared with normal skin samples using microarray analyses [136,139,140].…”

“…A number of gene expression profiling methods like serial analysis of gene expression (SAGE) and microarray analyses have been used in studies to characterize transcriptional changes in psoriasis and identificate large number of novel disease markers [134][135][136][137][138][139]. These studies were performed on skin biopsies of involved and non-involved, normal appearing psoriatic skin and normal skin from patients with active psorasis and from healthy individuals, respectively.…”