Abstract
Crohn’s disease (CD) is a debilitating inflammatory bowel disease (IBD) that emerges due to the influence of genetic and environmental factors. microRNAs (miRNAs) have been identified in the tissue and sera of IBD patients and may play an important role in the induction of IBD. Our study aimed to identify differentially expressed miRNAs and miRNAs with the ability to alter transcriptome activity by comparing inflamed tissue samples with their non-inflamed counterparts. We studied changes in miRNA–mRNA interactions associated with CD by examining their differential co-expression relative to normal mucosa from the same patients. Correlation changes between the two conditions were incorporated into scores of predefined gene sets to identify biological processes with altered miRNA-mediated control. Our study identified 28 miRNAs differentially expressed (p-values < 0.01), of which 14 are up-regulated. Notably, our differential co-expression analysis highlights microRNAs (i.e., miR-4284, miR-3194 and miR-21) that have known functional interactions with key mechanisms implicated in IBD. Most of these miRNAs cannot be detected by differential expression analysis that do not take into account miRNA–mRNA interactions. The identification of differential miRNA–mRNA co-expression patterns will facilitate the investigation of the miRNA-mediated molecular mechanisms underlying CD pathogenesis and could suggest novel drug targets for validation.
Highlights
Crohn’s disease (CD) is a debilitating inflammatory bowel disease (IBD) characterized by a multifactorial aetiology, with complex interactions between a multitude of genes, gene products, epigenetic events, and environmental factors
Our study aims to predict the functional implications of microRNAs in CD by considering which pathways are affected by changes of regulatory miRNA activities
To better understand the role of miRNAs in different biological processes, we designed a pathway enrichment analysis method based on the differential co-expression (DC) between miRNAs and messenger RNAs (mRNAs)
Summary
Crohn’s disease (CD) is a debilitating inflammatory bowel disease (IBD) characterized by a multifactorial aetiology, with complex interactions between a multitude of genes, gene products, epigenetic events, and environmental factors. Genetic analyses have successfully classified these genes as core components of several orderly biological mechanisms (e.g., autophagy, defective barrier function, IL-23 signalling, host-microbe interactions, and immune-mediated mechanisms). In IBD, single nucleotide polymorphisms (SNPs) located at miRNA binding sites can affect the expression of target messenger RNAs (mRNAs) involved in the pathogenesis of the disease. MiRNA-mediated dysregulation of IL-23R signaling is correlated with a single nucleotide polymorphism in the IL-23R gene and is strongly associated with IBD susceptibility [17]. The interaction between miR-192 and the nucleotide-binding oligomerization domain-containing protein 2 (NOD2) gene may be relevant in the pathogenesis of IBD; SNP rs3135500 in the 3 -untranslated region (UTR) of NOD2 reduces the ability of miR-192 to inhibit NOD2 expression [18]. Fairfax et al [19] have explored gene expression as a quantitative trait (eQTL mapping) for immunity-related genes and have suggested that specific risk alleles may alter gene expression profiles both locally (cis-acting) and at a distance (trans-acting)
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