Long Non-Coding RNAs Modulate Sjögren's Syndrome Associated Gene Expression and Are Involved in the Pathogenesis of the Disease

Abstract

Primary Sjögren's syndrome (pSjS) is a chronic systemic autoimmune disorder, primarily affecting exocrine glands; its pathogenesis is still unclear. Long non-coding RNAs (lncRNAs) are thought to play a role in the pathogenesis of autoimmune diseases and a comprehensive analysis of lncRNAs expression in pSjS is still lacking. To this aim, the expression of more than 540,000 human transcripts, including those ascribed to more than 50,000 lncRNAs is profiled at the same time, in a cohort of 16 peripheral blood mononuclear cells PBMCs samples (eight pSjS and eight healthy subjects). A complex network analysis is carried out on the global set of molecular interactions among modulated genes and lncRNAs, leading to the identification of reliable lncRNA-miRNA-gene functional interactions. Taking this approach, a few lncRNAs are identified as targeting highly connected genes in the pSjS transcriptome, since they have a major impact on gene modulation in the disease. Such genes are involved in biological processes and molecular pathways crucial in the pathogenesis of pSjS, including immune response, B cell development and function, inflammation, apoptosis, type I and gamma interferon, epithelial cell adhesion and polarization. The identification of deregulated lncRNAs that modulate genes involved in the typical features of the disease provides insight in disease pathogenesis and opens avenues for the design of novel therapeutic strategies.

Keywords: gene module; long non-coding RNA; primary Sjögren’s syndrome; protein–protein (PPI) network; signaling pathway.

Figure 1

Network analysis of differentially expressed genes (DEGs) in pSjS patients. (A) Protein–protein interaction (PPI) network of DEGs; (B) Modules originated from the interaction network.

Figure 2

Functional interactions among the three selected lncRNAs and genes modulated in pSjS patients. Degree sorted circle layouts of the protein–protein interaction (PPI) network of differentially expressed genes in pSjS patients are shown. Genes (nodes) are ordered around a circle based on their degree of connectivity (number of edges).

Figure 3

Meaningful pathways enriched in modulated genes targeted by the three selected lncRNAs. Colored squares indicate pathways enriched in genes targeted by the three lncRNAs: CTD-2020K17.1 (green squares); LINC00657 (red squares); LINC00511 (blue squares). The modules with the same enriched pathways are shown.

Figure 4

Pathways enrichment of modulated genes included in the modules. Orange circles represent the seven modules and selected enriched pathways in each module are listed in the orange boxes along with their relative statistical significance (p-value). Colored pie-charts indicate the percentage of genes targeted in each module by CTD-2020K17.1 (green); LINC00657 (red) and LINC00511 (blue). Colored boxes indicate miRNAs that target genes included in the modules and that are targeted by CTD-2020K17.1 (green box), LINC00657 (red box) and LINC00511 (blue box).