Abstract
INTRODUCTION: Primary Sjögren's syndrome (pSS) is a common autoimmune disease, with the minor salivary gland (MSG) being the main affected tissue; however, its pathogenesis remains unclear. Although changes in long noncoding RNA (lncRNA) expression have been reported in pSS, their biological functions are uncertain, despite the regulatory roles suggested. Therefore, it would be meaningful to systematically investigate the gene expression of lncRNAs in pSS for their regulatory roles and possible contribution to the disease development. METHODS: Deep stranded total transcriptome sequencing was performed on MSG samples from 92 patients with pSS and 34 non-Sjögren's syndrome (non-SS) controls. Differentially expressed genes between pSS and non-SS were identified, and a genome-wide competing endogenous RNA (ceRNA) network was constructed based on shared miRNA binding sites and gene-expression correlations. The regulatory roles of lncRNAs in dysregulated pathways in pSS were assessed by examining expression changes of interacting lncRNAs and coding genes. In vitro overexpression experiments in a salivary gland cell line were performed to evaluate the regulatory roles of three selected lncRNAs as ceRNAs. RESULTS: Genome-wide coding and noncoding gene expression correlation analysis suggests the regulatory function of lncRNAs in pSS. LncRNA could regulate coding gene expression via ceRNA mechanisms. The genome-wide ceRNA network comprising 3,035 lncRNAs and 10,838 coding genes was constructed. Eight lncRNAs were predicted to play essential roles on coding gene expression changes in pSS. The regulatory effect for three of the eight key lncRNAs-BISPR, LINC00926, and HCP5-were validated by in vitro experiment and their expression was correlated with clinical features of pSS. DISCUSSION: Systematic analysis of coding and lncRNA expression in MSG samples suggests a genome-wide regulatory role for lncRNAs in pSS. We constructed, for the first time, a genome-wide ceRNA network. This ceRNA network can be used to infer lncRNA functions based on their interacting coding genes. The gene regulatory roles of three lncRNAs were validated. Our study suggests that lncRNAs contribute significantly to coding gene expression changes in pSS via ceRNA mechanisms, and the identified regulatory lncRNA candidates could be useful for diagnosis, sub-classification, and treatment.