Mucosal transcriptomics highlight lncRNAs implicated in ulcerative colitis, Crohn’s disease, and celiac disease
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
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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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 4

Ulcerative colitis mucosal transcriptomes reveal lncRNA landscape linked with personalized disease severity and treatment response.

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Ulcerative colitis mucosal transcriptomes reveal lncRNA landscape linked...
(A) Scheme for the PROTECT transcriptomics (206 UC and 20 controls). The scheme was created with biorender.com. (B andC) PCA using 2,378 lncRNAs that passed expression filtering in PROTECT, colored by diagnosis (B) and disease severity (C). Pediatric Ulcerative Colitis Activity Index (PUCAI): mild, 10−30; moderate, 35−60; and severe, 65 or higher. (D) Spearman’s correlation between clinical metadata and lncRNAs PCA’s PC1 (22.8% variation) and PC2 values (13.2% variation) showing significant correlations with PC1 or PC2 values (P ≤ 0.05); PC1 and PC2 r values mark the arrowhead x axis and y axis coordinates, respectively. (E) Box plots of PC2 values stratified by clinical (left, PUCAI; 53 mild, 85 moderate, 68 severe UC cases) and endoscopic severity (right, endoscopic Mayo score: 27 Mayo 1, 108 Mayo 2, 71 Mayo 3 UC cases stratified by endoscopic severity). (F) Box plots of PC2 values stratified by UC course (left, week 4 remissions after 5-ASA/steroids: 105 W4R and 101 no W4R; right, colectomy within 3 years: 189 no colectomy and 17 had colectomy). *q < 0.05, **q < 0.01 ***q < 0.001, calculated using Mann-Whitney U test with Benjamini-Hochberg FDR correction. (G) WGCNA lncRNAs coexpression modules heatmap (represented by module eigengenes and numbered M1–M5), which were correlated with UC diagnosis (P < 0.001, Supplemental Data 1 includes all modules) and the indicative clinical features. Data are shown as the correlation coefficient and P value for each comparison. All clinical data besides the outcome data are from the time of diagnosis. Graphs’ central lines indicates median and lateral lines represent upper and lower quartiles.