Long ncRNA Landscape in the Ileum of Treatment Naïve Early Onset Crohn Disease

Objective: Long non-coding RNAs (lncRNA) regulate gene transcription and diverse cellular functions. We previously defined a novel core inflammatory and metabolic ileal gene signature in treatment naïve pediatric Crohn Disease (CD), however, genome-wide characterization of lncRNA expression was lacking. We now extend our analyses to define a more comprehensive view that includes lncRNA. Design: Using RNAseq, we performed a systematic profiling of lncRNAs and protein-coding genes expression in 177 ileal biopsies. Co-expression analysis was used to identify functions and tissue-specific expression. RT-PCR was used to test lncRNAs regulation by IL-1ß in Caco-2 enterocytes model. Results: We characterize a widespread dysregulation of 459 lncRNA in the ileum of treatment naïve pediatric CD patients. Unsupervised and supervised classifications using the 459 lncRNA showed comparable patients' grouping as the 2160 dysregulated protein-coding genes, linking lncRNA to CD pathogenesis. Co-expression and functional annotation enrichment analyses across several tissues and cell types showed that the up-regulated LINC01272 is associated with a myeloid pro-inflammatory signature while the down-regulated HNF4A-AS1 exhibits association with an epithelial metabolic signature. We further validated expression and regulation of prioritized lncRNA upon IL-1ß exposure in differentiated Caco-2 cells. Finally, we identified significant correlations between LINC01272 and HNF4A-AS1 expression and more severe mucosal injury. Conclusion: We define differentially expressed lncRNA in the ileum of treatment naive pediatric CD. We show lncRNA utility to correctly classify disease or healthy states and demonstrate their regulation in response to an inflammatory signal. These lncRNA, after mechanistic exploration, may serve as potential new targets for RNA-based interventions. Overall design: Using RNAseq, we performed a systematic profiling of lncRNAs and protein-coding genes expression in 21 days differentiated caco-2 cells

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Haberman Y, BenShoshan M, Di Segni A, Dexheimer PJ, Braun T, Weiss B, Walters TD, Baldassano RN, Noe JD, Markowitz J, Rosh J, Heyman MB, Griffiths AM, Crandall WV, Mack DR, Baker SS, Kellermayer R, Patel A, Otley A, Steiner SJ, Gulati AS, Guthery SL, LeLeiko N, Moulton D, Kirschner BS, Snapper S, Avivi C, Barshack I, Oliva-Hemker M, Cohen SA, Keljo DJ, Ziring D, Anikster Y, Aronow B, Hyams JS, Kugathasan S, Denson LA