Modulation of Epidermal Transcription Circuits in Psoriasis: New Links between Inflammation and Hyperproliferation

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.背景：全基因组表达谱（Whole-genome expression profiling）已被用于表征银屑病皮损与正常皮肤之间的分子水平差异。然而，由于表达谱源自包含多种细胞类型RNA的批量皮肤活检标本，通路分析的开展面临阻碍。 结果：本研究对215例患者的银屑病皮损（PP）和未受累/正常皮肤（PN）活检标本进行了大规模基因表达分析。共鉴定出1975个差异表达基因，其中8个与银屑病易感基因座（psoriasis susceptibility loci）相关。为便于通路分析，本研究针对235个基因模块（gene modules）分析了PP与PN皮肤的基因表达差异；每个基因模块均包含在角质形成细胞（keratinocytes）和表皮（epidermis）中表达模式相似的基因。最终鉴定出30个差异表达模块（DEMs），其表达偏向于PP上调或PP下调。这些差异表达模块与涉及细胞因子（IFN-γ、IL-17A、TNF-α等）、转录因子（STAT1、NF-κB、E2F、RUNX1等）以及染色质修饰因子（SETDB1）的调控轴相关。本研究还鉴定出一个由干扰素诱导的差异表达模块（命名为“STAT1-57”），其包含编码抗病毒蛋白的基因；该模块在银屑病表皮中被激活，但在接受生物治疗后被抑制。该模块内的基因在转录起始位点附近共享一个与干扰素刺激应答元件（interferon-stimulated response element, ISRE）相似的基序。 结论：本研究对大型患者队列进行了分析，并开发了一种新方法，用于解析银屑病中基因表达改变背后的表皮特异性通路及调控机制。本研究结果揭示了此前未被发现的“转录回路”，可为非系统性治疗药物的开发提供靶点。