Network analysis of psoriasis reveals biological pathways and roles for coding and long non-coding RNAs

Abstract

BackgroundPsoriasis is an immune-mediated, inflammatory disorder of the skin characterized by chronic inflammation and hyperproliferation of the epidermis. Differential expression analysis of microarray or RNA-seq data have shown that thousands of coding and non-coding genes are differentially expressed between psoriatic and healthy control skin. However, differential expression analysis may fail to detect perturbations in gene coexpression networks. Sensitive detection of such networks may provide additional insight into important disease-associated pathways. In this study, we applied weighted gene coexpression network analysis (WGCNA) on RNA-seq data from psoriasis patients and healthy controls.ResultsRNA-seq was performed on skin samples from 18 psoriasis patients (pre-treatment and post-treatment with the TNF-α inhibitor adalimumab) and 16 healthy controls, generating an average of 52.3 million 100-bp paired-end reads per sample. Using WGCNA, we identified 3 network modules that were significantly correlated with psoriasis and 6 network modules significantly correlated with biologic treatment, with only 16 % of the psoriasis-associated and 5 % of the treatment-associated coexpressed genes being identified by differential expression analysis. In a majority of these correlated modules, more than 50 % of coexpressed genes were long non-coding RNAs (lncRNA). Enrichment analysis of these correlated modules revealed that short-chain fatty acid metabolism and olfactory signaling are amongst the top pathways enriched for in modules associated with psoriasis, while regulation of leukocyte mediated cytotoxicity and regulation of cell killing are amongst the top pathways enriched for in modules associated with biologic treatment. A putative autoantigen, LL37, was coexpressed in the module most correlated with psoriasis.ConclusionsThis study has identified several networks of coding and non-coding genes associated with psoriasis and biologic drug treatment, including networks enriched for short-chain fatty acid metabolism and olfactory receptor activity, pathways that were not previously identified through differential expression analysis and may be dysregulated in psoriatic skin. As these networks are comprised mostly of non-coding genes, it is likely that non-coding genes play critical roles in the regulation of pathways involved in the pathogenesis of psoriasis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-3188-y) contains supplementary material, which is available to authorized users.

Review—Current Concepts in Inflammatory Skin Diseases Evolved by Transcriptome Analysis: In-Depth Analysis of Atopic Dermatitis and Psoriasis

“…Increased mRNA levels of OR10G7 were recently detected by skin tape stripping in atopic dermatitis patients in the upper epidermal layers. Although this may constitute a potential mechanism of odorant-induced skin inflammation in AD patients [106,107], an earlier study found olfactory receptor genes to be downregulated in AD [40]. This may reflect the above-mentioned difficulties in inter-study comparison or may argue for the high diversity seen in the AD pathophysiology.…”

“…Utilizing weighted gene co-expression network analysis, long non-coding RNA (lncRNA) molecules were shown to be highly abundant in the psoriatic [165] and AD transcriptomes [166]. This high abundance paired with the observed treatment response potentially provides a molecular surrogate marker for successful treatment [107].…”

Genome‐wide association study for insect bite hypersensitivity susceptibility in horses revealed novel associated loci on chromosome 1

“…Alternative splicing is prevalent in the mammalian immune system to control lymphocyte homeostasis (Yabas, Elliott, & Hoyne, 2016). Moreover, lncR-NAs regulate the inflammatory response following activation of innate immunity and have been related to autoimmune diseases such as psoriasis (Ahn et al, 2016;Heward & Lindsay, 2014). Interestingly, 25% of the annotated genes identified among the 30 1-mb non-overlapping windows most associated with IBH susceptibility correspond to lncRNAs.…”

High-throughput RNA sequencing from paired lesional- and non-lesional skin reveals major alterations in the psoriasis circRNAome

“…The analysis of the molecular backdrop of psoriasis has described numerous disease-associated genes and proteins with abnormal expression patterns [3], but little is known about the regulatory pathways responsible for this aberrant expression. Recent findings suggest that non-coding RNAs such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) could be involved in the pathogenesis of psoriasis by influencing protein expression and function in both keratinocytes and inflammatory cells [4][5][6][7][8].…”

“…The analysis of the molecular backdrop of psoriasis has described numerous disease-associated genes and proteins with abnormal expression patterns [3], but little is known about the regulatory pathways responsible for this aberrant expression. Recent findings suggest that non-coding RNAs such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) could be involved in the pathogenesis of psoriasis by influencing protein expression and function in both keratinocytes and inflammatory cells [4][5][6][7][8].Recent discoveries have let to the identification of a subclass of non-coding RNA, the circular RNAs (circRNAs), which are formed by a backsplicing event linking the 3′ end of an exon to the 5′ end of the same or an upstream exon [9][10][11]. Most circRNAs are expressed from known protein coding genes and in human cells more unique circRNAs than genes have been annotated [12].…”