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

Haberman Y1,2, BenShoshan M2,3, Di Segni A2, Dexheimer PJ1, Braun T2, Weiss B2,3, Walters TD4, Baldassano RN5, Noe JD6, Markowitz J7, Rosh J8, Heyman MB9, Griffiths AM4, Crandall WV10, Mack DR11, Baker SS12, Kellermayer R13, Patel A14, Otley A15, Steiner SJ16, Gulati AS17, Guthery SL18, LeLeiko N19, Moulton D20, Kirschner BS21, Snapper S22, Avivi C2, Barshack I2,3, Oliva-Hemker M23, Cohen SA24, Keljo DJ25, Ziring D26, Anikster Y2,3, Aronow B1, Hyams JS27, Kugathasan S28, Denson LA1. Inflamm Bowel Dis. 2018 Jan 18;24(2):346-360. doi: 10.1093/ibd/izx013.

Author information

1 Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.

2 Sheba Medical Center, Israel.

3 Tel Aviv University, Israel.

4 Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.

5 The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

6 Medical College of Wisconsin, Milwaukee, Wisconsin.

7 North Shore-Long Island Jewish Health System, New York.

8 Goryeb Children's Hospital/Atlantic Health, Morristown, New Jersey.

9 University of California, San Francisco, San Francisco, California.

10 Nationwide Children's Hospital, Columbus, Ohio.

11 Children's Hospital of Eastern Ontario, Ottawa, ON, Canada.

12 University at Buffalo, Buffalo, New York.

13 Baylor College School of Medicine, Houston, Texas.

14 UT Southwestern Medical Center at Dallas, Dallas, Texas.

15 Dalhousie University, Halifax, NS, Canada.

16 Indiana University School of Medicine, Indianapolis, Indiana.

17 University of North Carolina, Chapel Hill, North Carolina.

18 University of Utah, Salt Lake City, Utah.

19 Rhode Island Hospital, Providence, Rhode Island.

20 Vanderbilt Children's Hospital, Nashville, Tennessee.

21 University of Chicago, Chicago, Illinois.

22 Children's Hospital - Boston, Boston, Massachusetts.

23 John Hopkins University, Baltimore, Maryland.

24 Children's Center for Digestive Healthcare, Atlanta, Georgia.

25 Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania.

26 UCLA Medical Center, Los Angeles, California.

27 Connecticut Children's Medical Center, Hartford, Connecticut.

28 Emory University, Atlanta, Georgia.


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.

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