Faculty Collaboration Database

Long ncRNA Landscape in the Ileum of Treatment-Naive Early-Onset Crohn Disease. Inflamm Bowel Dis 2018 Jan 18;24(2):346-360

Date

01/24/2018

Pubmed ID

29361088

Pubmed Central ID

PMC6231367

DOI

10.1093/ibd/izx013

Scopus ID

2-s2.0-85047299770 (requires institutional sign-in at Scopus site)   47 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.

Author List

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

Author

Joshua D. Noe MD Associate Dean, Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adolescent
Caco-2 Cells
Child
Crohn Disease
Down-Regulation
Female
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Gene Regulatory Networks
Hepatocyte Nuclear Factor 4
Humans
Ileum
Male
Oligonucleotide Array Sequence Analysis
RNA, Long Noncoding
RNA, Messenger
Up-Regulation