Mucosal transcriptomics highlight lncRNAs implicated in ulcerative colitis, Crohn’s disease, and celiac disease
Tzipi Braun, … , Lee A. Denson, Yael Haberman
Tzipi Braun, … , Lee A. Denson, Yael Haberman
Published June 1, 2023
Citation Information: JCI Insight. 2023;8(14):e170181. https://doi.org/10.1172/jci.insight.170181.
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Research Article Gastroenterology

Mucosal transcriptomics highlight lncRNAs implicated in ulcerative colitis, Crohn’s disease, and celiac disease

Abstract

Ulcerative colitis (UC), Crohn’s disease (CD), and celiac disease are prevalent intestinal inflammatory disorders with nonsatisfactory therapeutic interventions. Analyzing patient data-driven cohorts can highlight disease pathways and new targets for interventions. Long noncoding RNAs (lncRNAs) are attractive candidates, since they are readily targetable by RNA therapeutics, show relative cell-specific expression, and play key cellular functions. Uniformly analyzing gut mucosal transcriptomics from 696 subjects, we have highlighted lncRNA expression along the gastrointestinal (GI) tract, demonstrating that, in control samples, lncRNAs have a more location-specific expression in comparison with protein-coding genes. We defined dysregulation of lncRNAs in treatment-naive UC, CD, and celiac diseases using independent test and validation cohorts. Using the Predicting Response to Standardized Pediatric Colitis Therapy (PROTECT) inception UC cohort, we defined and prioritized lncRNA linked with UC severity and prospective outcomes, and we highlighted lncRNAs linked with gut microbes previously implicated in mucosal homeostasis. HNF1A-AS1 lncRNA was reduced in all 3 conditions and was further reduced in more severe UC form. Similarly, the reduction of HNF1A-AS1 ortholog in mice gut epithelia showed higher sensitivity to dextran sodium sulfate–induced colitis, which was coupled with alteration in the gut microbial community. These analyses highlight prioritized dysregulated lncRNAs that can guide future preclinical studies for testing them as potential targets.

Authors

Tzipi Braun, Katya E. Sosnovski, Amnon Amir, Marina BenShoshan, Kelli L. VanDussen, Rebekah Karns, Nina Levhar, Haya Abbas-Egbariya, Rotem Hadar, Gilat Efroni, David Castel, Camila Avivi, Michael J. Rosen, Anne M. Grifiths, Thomas D. Walters, David R. Mack, Brendan M. Boyle, Syed Asad Ali, Sean R. Moore, Melanie Schirmer, Ramnik J. Xavier, Subra Kugathasan, Anil G. Jegga, Batya Weiss, Chen Mayer, Iris Barshack, Shomron Ben-Horin, Igor Ulitsky, Anthony Beucher, Jorge Ferrer, Jeffrey S. Hyams, Lee A. Denson, Yael Haberman

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Figure 1

Dysregulated lncRNAs atlas in UC rectum, CD ileum, and celiac duodenum.

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Dysregulated lncRNAs atlas in UC rectum, CD ileum, and celiac duodenum. ...
(A, F, and K) Schemes of test and validation cohorts used for each disease (Supplemental Table 1). (A) UC rectum PROTECT test (206 UC and 20 controls) and RISK validation (43 UC and 55 controls). (F) CD ileum SOURCE test (18 CD and 25 controls) and RISK validation (213 CD and 47 controls). (K) Celiac duodenum SEEM test (17 celiac cases and 25 controls) and PRJNA528755 validation (12 celiac and 15 controls). (B, G, and L) Volcano plots of differentially expressed lncRNAs between disease and control in the test cohorts: PROTECT, SOURCE, SEEM (FC ≥ 1.5, FDR ≤ 0.05). (C, H, and M) Volcano-like plots of the validation cohorts, showing log (FC) and –log10(Q value) values for DE genes obtained in the test cohorts: RISK UC (C), RISK CD (H), PRJNA528755 celiac (M). The direction of change in the test cohort is marked by color. (D, I, and N) PCA of test and validation cohorts: PROTECT and RISK UC (D), SOURCE and RISK CD (I), SEEM and PRJNA528755 celiac (N). lncRNA that passed DE in the test cohorts were used. PC1 and PC2 values box plots for cases and controls within each cohort. (E, J, and O) Receiver operating characteristic (ROC) curves of random forest (RF) analysis trained on the test cohort and tested on both test and validation cohorts showing accurate classification of most cases and controls using either lncRNA or protein-coding gene expression: UC rectum (E), CD ileum (J), celiac duodenum (O). **P < 0.01, ***P < 0.001, Mann-Whitney U test.