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 7

HNF1A-AS1 reduction is linked with UC severity.

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HNF1A-AS1 reduction is linked with UC severity. (A and B) HNF1A-AS1 exp...
(A and B) HNF1A-AS1 expression is reduced in CD ileum (A and B) — SOURCE (18 CD, 25 control [Ctl]) and RISK (213 CD, 47 Ctl) bulk biopsies and isolated epithelia (38) (25 CD, 27 Ctl) — and in UC rectum (C and D) —PROTECT (206 UC, 20 Ctl) and RISK (43 UC, 55 Ctl) bulk biopsies and isolated epithelia (16 UC and 16 Ctl). (E and F) HNF1A-AS1 at baseline is further reduced in UC cases with more severe clinical and endoscopic phenotype (E) and in those with less favorable outcome — week4 and week52 nonresponders (noR), or required colectomy within 3 years (F). Mice experiments included HNF1A-AS1intestine–/– (intestine-specific deletion of the HNF1A-AS1 promotor), HNF1A-AS1+/+, and HNF1A-AS1intestine+/–. (G) HNF1A-AS1 was significantly reduced in rectal tissue of HNF1A-AS1intestine–/– in comparison HNF1A-AS1+/+, Kruskal-Wallis test with Dunn’s correction, n = 4. Mice were treated with DSS (2.5%) for 5 days, followed by 6 days of water washout. (H) Kaplan-Meier survival curve during the experiment and differences between groups were calculated using the Mantel-Cox test. (I) Rectal bleeding was recorded (Left: bleeding duration more than one day. Right, bleeding duration more than 2 days). Differences were calculated using 2-sided Fisher exact test. (J) Colon weight to length (colon mass) at the end of the experiment. Histopathological evaluation using a predefined histologic scoring focusing on Inflammation score & percent of the involved region. (K) Differences between groups were tested using a 2-tailed t test. (L and M) PCoA Plot of fecal microbiome prior to the DSS treatment (Day 1) colored by mice group (L) or cage (M) n = 52. α Divesity (Faith’s phylogenetic) between HNF1A-AS1+/+ (n = 20), HNF1A-AS1intestine+/– (n = 8), and HNF1A-AS1intestine –/– (n = 24), prior to the DSS treatment (Day1). The q values were calculated using Mann-Whitney U test with FDR correction (N). *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001, ****P ≤ 0.0001 Mann-Whitney test. Graphs central line indicates median and lateral lines represent upper and lower quartiles.