Abstract
DNA methylation (DNAm) plays an important role in the pathogenesis of psoriasis through regulating mRNA expressions. This study aimed to identify hub genes regulated by DNAm as biomarkers of psoriasis. Psoriatic skin tissues gene expression and methylation datasets were downloaded from Gene Expression Omnibus (GEO) database. Subsequently, multiple computational approaches, including immune infiltration analysis, enrichment analysis, protein–protein interaction (PPI) network establishment, and machine learning algorithm analysis (lasso, random forest, and SVM-RFE), were performed to analyze the regulatory networks, to recognize hub genes, and to clarify the pathogenesis of psoriasis. Finally, the hypermethylated genes were used to immune cell infiltration analysis, which revealed that psoriasis skin tissues were mainly composed of activated dendritic cells, resting mast cells, T follicular helper cells (cTfh), etc. Differentially expressed-methylated genes (DEMGs) were identified and partitioned into four subgroups and the 97 significantly hypermethylated and downregulated (hyper-down) genes accounted for the highest proportion (47%). Hyper-down genes were mainly enriched in glucose homeostasis, AMP-activated protein kinase (AMPK) signaling pathway, lipid storage disease, partial lipodystrophy, and insulin resistance. Furthermore, insulin receptor substrate 1 (IRS1), Rho guanine nucleotide exchange factor 10 (ARHGEF10) and retinoic acid induced 14 (RAI14) were identified as potential targets. These findings provided new ideas for future studies of psoriasis on the occurrence and the molecular mechanisms.
Highlights
Psoriasis is a chronic skin disease mediated by immune mechanisms that affect 2–3% population of the world, and the WHO considers psoriasis to be chronic, painful, non-infectious, incurable, disabling, and disfiguring [World Health Organization (WHO), 2014]
To identify the differentially expressed genes (DEGs) in the tissues of psoriasis patients compared with matched normal samples, one microarray dataset (GSE30999) had been analyzed and identified 1,589 significant DEGs in psoriasis lesions compared with matched normal skin, in which 634 genes are downregulated and 955 genes are upregulated
A total of 3,265 differentially methylated CpGs (DMCs) were identified by analyzing the DNA methylation (DNAm) microarray of psoriasis skin tissue (GSE115797 and GSE73894)
Summary
Psoriasis is a chronic skin disease mediated by immune mechanisms that affect 2–3% population of the world, and the WHO considers psoriasis to be chronic, painful, non-infectious, incurable, disabling, and disfiguring [World Health Organization (WHO), 2014]. Plaque psoriasis accounts for 80–90% of all cases, characterized by keratinocyte abnormal differentiation and hyperproliferation with a large number of inflammatory cell infiltration, which is the most common psoriasis subtype (Greb et al, 2016). It is a systemic inflammatory disease associated with hypertension, hyperlipidemia, metabolic syndrome, adverse cardiac events, etc., which will increase the Differentially Expressed-Methylated Biomarkers in Psoriasis incidence of malignant tumors, inflammatory arthritis, obesity, and other comorbidities (Lebwohl et al, 2014; Takeshita et al, 2017; Kaushik and Lebwohl, 2019). Previous studies had shown that the DNAm level of skin samples from patients with psoriasis was positively correlated with the Psoriasis Area and Severity Index (PASI) score, and the levels of DNAm in skin lesions and peripheral blood monocytes (PBMCs) were significantly increased in patients with psoriasis (Chen et al, 2008; Zhang et al, 2010). Chen et al (2016) identified the characteristics of human leukocyte antigen (HLA)-C hypermethylation in psoriasis skin lesions, which can be used as an epigenetic marker of psoriasis
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