RNA stability indicates endoplasmic reticulum stress as a novel therapeutic target in endometritis

Endometritis is a persistent inflammatory disorder of the endometrium, associated with infertility, recurrent pregnancy loss and significant economic losses. Despite numerous studies that focused on transcriptome analysis on endometritis, still its molecular pathogenesis is not completely understood. We hypothesized that pathogenesis of endometritis may be associated with stability changes in the expression of genes. RNA stability pattern of genes between healthy and infected samples were investigated using RNA-Seq dataset. Then, a gene co-expression network was constructed by WGCNA approach and a novel propagation-based algorithm was developed to assess identified module consistency. Finally, the results were subjected to functional enrichment and protein-protein interaction (PPI) network analysis. Of the nine identified modules, brown module showed an increase in RNA stability after infection and was mainly associated with endometritis. This module contained 158 genes that were significantly enriched in the pathways related to endoplasmic reticulum (ER) stress and immune response. In this regard, one important finding from recent studies is that ER stress is a key pathway involved in endometritis development. These findings provided further evidence that ER stress and related pathways are important components contributing to modulation of gene regulatory networks involved in endometritis development. Moreover, network propagation and PPI network analysis revealed the functional connectivity of the genes within the module. Hub gene detection analysis resulted in the identification of 28 hub genes that were also significantly related to biological pathways associated with endometritis pathogenesis. Interestingly, several hub genes were found (including CD4 , S100A4 , CSF3 , CCR10 , KLF10 , CD48 , CD19 , CXCL3 , CXCL5 , PDGFRB , PTPRCAP , NR4A2 and HBEGF ) that have been reported previously as biomarkers in endometritis. Notably, most of genes in brown module were of particular interest, because of their known roles in immune response or ER stress. This study achieved the goal of showing that key genes and pathways that modulate cellular response to endometritis development, can be identified by considering stability of genes as a post-transcriptional regulatory mechanism. The investigation of RNA stability in diseases, not only enhances our understanding of the molecular mechanisms behind the infection, but also opens up new avenues for therapeutic intervention.