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CircRNA expression profiling of colon tissue from mesalazine-treated mouse of inflammatory bowel disease reveals an important circRNA-miRNA-mRNA pathway.

ABSTRACT: Mesalazine (5-aminosalicylic acid, 5-ASA) has been widely used to treat inflammatory bowel disease (IBD). However, it remains unclear about the underlying biological mechanisms of IBD pathogenesis and mesalazine treatment, which could be partially clarified by exploring the profiling of circular RNAs (circRNAs) using RNA-seq. A total of 15 mice (C57BL/6) were randomly assigned to three equally sized groups: control, dextran sulfate sodium (DSS, using DSS to induce IBD), and DSS+5-ASA (using mesalazine to treat IBD). We randomly selected three mice of each group to collect colon tissues for RNA-seq and then performed bioinformatic analysis for two comparisons: DSS vs. control and DSS+5-ASA vs. DSS. Comparisons of a series of indicators (e.g., body weight) verified the establishment of DSS-induced IBD mouse model and the effectiveness of mesalazine in treating IBD. We identified 182 differentially expressed circRNAs, including 55 up-regulated and 47 down-regulated circRNAs when comparing the DSS+5-ASA with the DSS group. These 102 circRNA-associated genes were significantly involved in the N-Glycan biosynthesis and lysine degradation. The network analysis of circRNA-miRNA-mRNAs identified an important pathway, i.e., chr10:115386962-115390436+/mmu-miR-6914-5p/Atg7, which is related to autophagy. The findings provide new insights into the biological mechanisms of IBD pathogenesis and mesalazine treatment, particularly highlighting the circRNA-miRNA-mRNA pathway.

SUBMITTER: Zhou W

PROVIDER: S-EPMC8064189 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundUlcerative colitis (UC) is associated with differential colonic expression of genes involved in immune response (e.g. IL8) and barrier integrity (e.g. cadherins). MicroRNAs (miRNAs) are regulators of gene expression and are involved in various immune-related diseases. In this study, we investigated (1) if miRNA expression in UC mucosa is altered and (2) if any of these changes correlate with mucosal mRNA expression. Integration of mRNA and miRNA expression profiling may allow the identification of functional links between dysregulated miRNAs and their target mRNA.MethodologyColonic mucosal biopsies were obtained from 17 UC (10 active and 7 inactive) patients and 10 normal controls. Total RNA was used to analyze miRNA and mRNA expression via Affymetrix miRNA 2.0 and Affymetrix Human Gene 1.0ST arrays, respectively. Both miRNA and gene expression profiles were integrated by correlation analysis to identify dysregulated miRNAs with their corresponding predicted target mRNA. Microarray data were validated with qRT-PCR. Regulation of IL8 and CDH11 expression by hsa-miR-200c-3p was determined by luciferase reporter assays.ResultsWhen comparing active UC patients vs. controls, 51 miRNAs and 1543 gene probe sets gave significantly different signals. In contrast, in inactive UC vs. controls, no significant miRNA expression differences were found while 155 gene probe sets had significantly different signals. We then identified potential target genes of the significantly dysregulated miRNAs and genes in active UC vs. controls and found a highly significant inverse correlation between hsa-miR-200c-3p and IL8, an inflammatory marker, and between hsa-miR-200c-3p and CDH11, a gene related to intestinal epithelial barrier function. We could demonstrate that hsa-miR-200c-3p directly regulates IL8 and CDH11 expression.ConclusionDifferential expression of immune- and barrier-related genes in inflamed UC mucosa may be influenced by altered expression of miRNAs. Integrated analysis of miRNA and mRNA expression profiles revealed hsa-miR-200c-3p for use of miRNA mimics as therapeutics.

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CircRNA expression profiling of colon tissue from mesalazine-treated mouse of inflammatory bowel disease reveals an important circRNA-miRNA-mRNA pathway.

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