m6A modified lncRNA WAKMAR2 induces intestinal inflammation through an allele-specific RNA methylation dependent splicing mechanism

Abstract

Abstract Inflammatory bowel disease is a chronic inflammatory disorder of the intestine that develops in genetically susceptible individuals and which etiology remains unknown. Long non-coding RNAs (lncRNAs) have emerged as tissue-specific regulators of inflammation. In addition, m6A methylation modulates gene expression in an allele-specific manner, particularly in the context of single nucleotide polymorphisms (SNPs). Here, we describe the molecular anti-inflammatory mechanism of the lncRNA WAKMAR2 in intestinal epithelial cells. WAKMAR2 undergoes allele-specific m6A methylation, altering the binding of NOVA1 protein and reducing the expression of WAKMAR2 long isoform which ultimately enables NF-κB activation and downstream CXCL8 induction. The correlation between longWAKMAR2 and CXCL8 levels in intestinal inflammation was confirmed using human biopsy samples from intestinal inflammatory bowel disease patients and controls. Moreover, augmenting longWAKMAR2 ex vivo using an organ culture intestinal system resulted in an amelioration of inflammation. These data point to an involvement of WAKMAR2 in the induction CXCL8 in intestinal epithelial cells and in the development of IBD characteristic intestinal inflammation, explaining genetic susceptibility and providing a novel potential target for therapeutic interventions.