The emerging role of miRNAs in inflammatory bowel disease: a review

Abstract

Inflammatory bowel disease (IBD), comprised of ulcerative colitis and Crohn's disease, is believed to develop as a result of a deregulated inflammatory response to environmental factors in genetically susceptible individuals. Despite advances in understanding the genetic risks of IBD, associated single nucleotide polymorphisms have low penetrance, monozygotic twin studies suggest a low concordance rate, and increasing worldwide IBD incidence leave gaps in our understanding of IBD heritability and highlight the importance of environmental influences. Operating at the interface between environment and heritable molecular and cellular phenotypes, microRNAs (miRNAs) are a class of endogenous, small noncoding RNAs that regulate gene expression. Studies to date have identified unique miRNA expression profile signatures in IBD and preliminary functional analyses associate these deregulated miRNAs to canonical pathways associated with IBD pathogenesis. In this review, we summarize and discuss the miRNA expression signatures associated with IBD in tissue and peripheral blood, highlight miRNAs with potential future clinical applications as diagnostic and therapeutic targets, and provide an outlook on how to develop miRNA based therapies.

Keywords: epigenetics; inflammatory bowel disease; microRNA.

Conflict of interest statement

Conflict of interest statement: The authors declare that there is no conflict of interest.

Figures

Figure 1.

Methods of microRNA (miRNA) therapeutics. Endogenous mature miRNAs (center) loaded into the RNA-induced silencing complex (RISC) form a mature miRNA complex capable of silencing mRNA via 3′-UTR binding. The binding results in mRNA translation repression or degradation thereby controlling protein synthesis. (A) Anti-mRNA oligonucleotides are synthetic oligonucleotides with reverse complementary sequences to mature miRNAs that can tightly bind to their miRNA targets with high specificity to block miRNA function. These oligonucleotides utilize chemical modifications including 2′-O-methyl (2′-OMe) and 2′-O-methoxyethyl (2′-MOE) oligoribonucleotides, and 2′,4′-methylene bridge (LNA), and phosphorothioate (PS) modification to confer nuclease stability and/or increase binding affinity. (B) miRNA sponges involve plasmid constructs with strong promoters, containing multiple tandem binding mRNA target sites to the miRNAs of interest allowing simultaneous competitive inhibition of multiple miRNAs. (C) miRNA-masks are inhibitory miRNA antisense oligodeoxyribonucleotides that bind to the 3′-UTR of the target mRNA blocking the access of miRNAs. (D) miRNA mimics are double strand RNA in which one strand is identical to the endogenous mature miRNA of interest and paired with the complete or partially complementary ‘passenger strand’ which is required for loading into the RISC. (E) miRNA expression gene vectors, such as DNA plasmids or viral vectors including adeno-associated viral (AAV) vectors, allow for constitutive expression of miRNA constructs. LNA, locked nucleic acid; ORF, open reading frame; UTR, untranslated region.