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

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• dc.contributor.author Braun, Tzipi
• dc.contributor.author Ferrer, Jorge
• dc.contributor.author Haberman, Yael
• dc.date.accessioned 2023-10-30T07:08:02Z
• dc.date.available 2023-10-30T07:08:02Z
• dc.date.issued 2023
• dc.description.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.
• dc.description.sponsorship This study was supported by the ERC starting grant (YH, grant No 758313), the Israel Science Foundation (YH, grant No 908/15), the I-CORE program (YH, grants No. 41/11), the Helmsley Charitable Trust, and NIDDK P30 DK078392 (Integrative Morphology and Gene Expression Cores). PROTECT was supported by the NIDDK 5U01DK095745, RISK was supported by Crohn’s & Colitis Foundation, SEEM by the Bill and Melinda Gates Foundation (OPP1144149 and OPP1138727), and SOURCE is supported by the Helmsley Charitable Trust. The funding sources did not play a role in the writing of the manuscript or the decision to submit it for publication and did not play a role in data collection, analysis, interpretation, trial design, patient recruitment, or any aspect pertaining to the study.
• dc.format.mimetype application/pdf
• dc.identifier.citation Braun T, Sosnovski KE, Amir A, BenShoshan M, VanDussen KL, Karns R, et al. Mucosal transcriptomics highlight lncRNAs implicated in ulcerative colitis, Crohn's disease, and celiac disease. JCI Insight. 2023 Jul 24;8(14):e170181. DOI: 10.1172/jci.insight.170181
• dc.identifier.doi http://dx.doi.org/10.1172/jci.insight.170181
• dc.identifier.issn 2379-3708
• dc.identifier.uri http://hdl.handle.net/10230/58181
• dc.language.iso eng
• dc.publisher American Society for Clinical Investigation
• dc.relation.ispartof JCI Insight. 2023 Jul 24;8(14):e170181
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/758313
• dc.rights © 2023, Braun et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Gastroenterology
• dc.subject.keyword Inflammatory bowel disease
• dc.title Mucosal transcriptomics highlight lncRNAs implicated in ulcerative colitis, Crohn's disease, and celiac disease
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion