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

Yael Haberman, Marina Benshoshan, Ayelet Di Segni, Phillip J. Dexheimer, Tzipi Braun, Batia Weiss, Thomas D. Walters, Robert N. Baldassano, Joshua D. Noe, James Markowitz, Joel Rosh, Melvin B. Heyman, Anne M. Griffiths, Wallace V. Crandall, David R. Mack, Susan S. Baker, Richard Kellermayer, Ashish S Patel, Anthony Otley, Steven J. SteinerAjay S. Gulati, Stephen L. Guthery, Neal Leleiko, Dedrick Moulton, Barbara S. Kirschner, Scott Snapper, Camila Avivi, Iris Barshack, Maria Oliva-Hemker, Stanley A. Cohen, David J. Keljo, David Ziring, Yair Anikster, Bruce Aronow, Jeffrey S. Hyams, Subra Kugathasan, Lee A. Denson

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

Background: Long noncoding RNAs (lncRNA) are key regulators of gene transcription and many show tissue-specific expression. We previously defined a novel inflammatory and metabolic ileal gene signature in treatment-naive pediatric Crohn disease (CD). We now extend our analyses to include potential regulatory lncRNA. Methods: Using RNAseq, we systematically profiled lncRNAs and protein-coding gene expression in 177 ileal biopsies. Co-expression analysis was used to identify functions and tissue-specific expression. RNA in situ hybridization was used to validate expression. Real-time polymerase chain reaction was used to test lncRNA regulation by IL-1β in Caco-2 enterocytes. Results: We characterize widespread dysregulation of 459 lncRNAs in the ileum of CD patients. Using only the lncRNA in discovery and independent validation cohorts showed patient classification as accurate as the protein-coding genes, linking lncRNA to CD pathogenesis. Co-expression and functional annotation enrichment analyses across several tissues and cell types 1showed that the upregulated LINC01272 is associated with a myeloid pro-inflammatory signature, whereas the downregulated HNF4A-AS1 exhibits association with an epithelial metabolic signature. We confirmed tissue-specific expression in biopsies using in situ hybridization, and validated regulation of prioritized lncRNA upon IL-1β exposure in differentiated Caco-2 cells. Finally, we identified significant correlations between LINC01272 and HNF4A-AS1 expression and more severe mucosal injury. Conclusions: We systematically define differentially expressed lncRNA in the ileum of newly diagnosed pediatric CD. We show lncRNA utility to correctly classify disease or healthy states and demonstrate their regulation in response to an inflammatory signal. These lncRNAs, after mechanistic exploration, may serve as potential new tissue-specific targets for RNA-based interventions.

Original languageEnglish (US)
Pages (from-to)346-360
Number of pages15
JournalInflammatory Bowel Diseases
Volume24
Issue number2
DOIs
StatePublished - Jan 18 2018

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Keywords

  • Crohn disease
  • long ncRNA
  • RNA expression
  • RNAseq

ASJC Scopus subject areas

  • Immunology and Allergy
  • Gastroenterology

Cite this

Haberman, Y., Benshoshan, M., Di Segni, A., Dexheimer, P. J., Braun, T., Weiss, B., Walters, T. D., Baldassano, R. N., Noe, J. D., Markowitz, J., Rosh, J., Heyman, M. B., Griffiths, A. M., Crandall, W. V., Mack, D. R., Baker, S. S., Kellermayer, R., Patel, A. S., Otley, A., ... Denson, L. A. (2018). Long ncRNA Landscape in the Ileum of Treatment-Naive Early-Onset Crohn Disease. Inflammatory Bowel Diseases, 24(2), 346-360. https://doi.org/10.1093/ibd/izx013