Mucosal transcriptomics highlight lncRNAs implicated in ulcerative colitis, Crohn’s disease, and celiac disease
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...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
American Society for Clinical investigation
2023-07-01
|
| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.170181 |
| _version_ | 1797634275438231552 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Tzipi Braun |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T12:05:21Z |
| format | Article |
| id | doaj.art-175d48f8e9c64094a115fe7ffb8e26b5 |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-03-11T12:05:21Z |
| publishDate | 2023-07-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-175d48f8e9c64094a115fe7ffb8e26b52023-11-07T16:25:54ZengAmerican Society for Clinical investigationJCI Insight2379-37082023-07-01814Mucosal transcriptomics highlight lncRNAs implicated in ulcerative colitis, Crohn’s disease, and celiac diseaseTzipi BraunKatya E. SosnovskiAmnon AmirMarina BenShoshanKelli L. VanDussenRebekah KarnsNina LevharHaya Abbas-EgbariyaRotem HadarGilat EfroniDavid CastelCamila AviviMichael J. RosenAnne M. GrifithsThomas D. WaltersDavid R. MackBrendan M. BoyleSyed Asad AliSean R. MooreMelanie SchirmerRamnik J. XavierSubra KugathasanAnil G. JeggaBatya WeissChen MayerIris BarshackShomron Ben-HorinIgor UlitskyAnthony BeucherJorge FerrerJeffrey S. HyamsLee A. DensonYael HabermanUlcerative 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.https://doi.org/10.1172/jci.insight.170181Gastroenterology |
| spellingShingle | 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 Mucosal transcriptomics highlight lncRNAs implicated in ulcerative colitis, Crohn’s disease, and celiac disease JCI Insight Gastroenterology |
| title | Mucosal transcriptomics highlight lncRNAs implicated in ulcerative colitis, Crohn’s disease, and celiac disease |
| title_full | Mucosal transcriptomics highlight lncRNAs implicated in ulcerative colitis, Crohn’s disease, and celiac disease |
| title_fullStr | Mucosal transcriptomics highlight lncRNAs implicated in ulcerative colitis, Crohn’s disease, and celiac disease |
| title_full_unstemmed | Mucosal transcriptomics highlight lncRNAs implicated in ulcerative colitis, Crohn’s disease, and celiac disease |
| title_short | Mucosal transcriptomics highlight lncRNAs implicated in ulcerative colitis, Crohn’s disease, and celiac disease |
| title_sort | mucosal transcriptomics highlight lncrnas implicated in ulcerative colitis crohn s disease and celiac disease |
| topic | Gastroenterology |
| url | https://doi.org/10.1172/jci.insight.170181 |
| work_keys_str_mv | AT tzipibraun mucosaltranscriptomicshighlightlncrnasimplicatedinulcerativecolitiscrohnsdiseaseandceliacdisease AT katyaesosnovski mucosaltranscriptomicshighlightlncrnasimplicatedinulcerativecolitiscrohnsdiseaseandceliacdisease AT amnonamir mucosaltranscriptomicshighlightlncrnasimplicatedinulcerativecolitiscrohnsdiseaseandceliacdisease AT marinabenshoshan mucosaltranscriptomicshighlightlncrnasimplicatedinulcerativecolitiscrohnsdiseaseandceliacdisease AT kellilvandussen mucosaltranscriptomicshighlightlncrnasimplicatedinulcerativecolitiscrohnsdiseaseandceliacdisease AT rebekahkarns mucosaltranscriptomicshighlightlncrnasimplicatedinulcerativecolitiscrohnsdiseaseandceliacdisease AT ninalevhar mucosaltranscriptomicshighlightlncrnasimplicatedinulcerativecolitiscrohnsdiseaseandceliacdisease AT hayaabbasegbariya mucosaltranscriptomicshighlightlncrnasimplicatedinulcerativecolitiscrohnsdiseaseandceliacdisease AT rotemhadar mucosaltranscriptomicshighlightlncrnasimplicatedinulcerativecolitiscrohnsdiseaseandceliacdisease AT gilatefroni mucosaltranscriptomicshighlightlncrnasimplicatedinulcerativecolitiscrohnsdiseaseandceliacdisease AT davidcastel mucosaltranscriptomicshighlightlncrnasimplicatedinulcerativecolitiscrohnsdiseaseandceliacdisease AT camilaavivi mucosaltranscriptomicshighlightlncrnasimplicatedinulcerativecolitiscrohnsdiseaseandceliacdisease AT michaeljrosen mucosaltranscriptomicshighlightlncrnasimplicatedinulcerativecolitiscrohnsdiseaseandceliacdisease AT annemgrifiths mucosaltranscriptomicshighlightlncrnasimplicatedinulcerativecolitiscrohnsdiseaseandceliacdisease AT thomasdwalters mucosaltranscriptomicshighlightlncrnasimplicatedinulcerativecolitiscrohnsdiseaseandceliacdisease AT davidrmack mucosaltranscriptomicshighlightlncrnasimplicatedinulcerativecolitiscrohnsdiseaseandceliacdisease AT brendanmboyle mucosaltranscriptomicshighlightlncrnasimplicatedinulcerativecolitiscrohnsdiseaseandceliacdisease AT syedasadali mucosaltranscriptomicshighlightlncrnasimplicatedinulcerativecolitiscrohnsdiseaseandceliacdisease AT seanrmoore mucosaltranscriptomicshighlightlncrnasimplicatedinulcerativecolitiscrohnsdiseaseandceliacdisease AT melanieschirmer mucosaltranscriptomicshighlightlncrnasimplicatedinulcerativecolitiscrohnsdiseaseandceliacdisease AT ramnikjxavier mucosaltranscriptomicshighlightlncrnasimplicatedinulcerativecolitiscrohnsdiseaseandceliacdisease AT subrakugathasan mucosaltranscriptomicshighlightlncrnasimplicatedinulcerativecolitiscrohnsdiseaseandceliacdisease AT anilgjegga mucosaltranscriptomicshighlightlncrnasimplicatedinulcerativecolitiscrohnsdiseaseandceliacdisease AT batyaweiss mucosaltranscriptomicshighlightlncrnasimplicatedinulcerativecolitiscrohnsdiseaseandceliacdisease AT chenmayer mucosaltranscriptomicshighlightlncrnasimplicatedinulcerativecolitiscrohnsdiseaseandceliacdisease AT irisbarshack mucosaltranscriptomicshighlightlncrnasimplicatedinulcerativecolitiscrohnsdiseaseandceliacdisease AT shomronbenhorin mucosaltranscriptomicshighlightlncrnasimplicatedinulcerativecolitiscrohnsdiseaseandceliacdisease AT igorulitsky mucosaltranscriptomicshighlightlncrnasimplicatedinulcerativecolitiscrohnsdiseaseandceliacdisease AT anthonybeucher mucosaltranscriptomicshighlightlncrnasimplicatedinulcerativecolitiscrohnsdiseaseandceliacdisease AT jorgeferrer mucosaltranscriptomicshighlightlncrnasimplicatedinulcerativecolitiscrohnsdiseaseandceliacdisease AT jeffreyshyams mucosaltranscriptomicshighlightlncrnasimplicatedinulcerativecolitiscrohnsdiseaseandceliacdisease AT leeadenson mucosaltranscriptomicshighlightlncrnasimplicatedinulcerativecolitiscrohnsdiseaseandceliacdisease AT yaelhaberman mucosaltranscriptomicshighlightlncrnasimplicatedinulcerativecolitiscrohnsdiseaseandceliacdisease |