Patient-derived organoid biobank identifies epigenetic dysregulation of intestinal epithelial MHC-I as a novel mechanism in severe Crohn's Disease.

Autor:	Dennison TW; Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.; Department of Paediatrics, University of Cambridge, Cambridge, UK.; Milner Therapeutics Institute, University of Cambridge, Cambridge, UK., Edgar RD; European Bioinformatics Institute, Cambridge, Cambridgeshire, UK.; Ajmera Transplant Centre, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada., Payne F; Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.; Department of Paediatrics, University of Cambridge, Cambridge, UK., Nayak KM; Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.; Department of Paediatrics, University of Cambridge, Cambridge, UK., Ross ADB; Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.; Department of Paediatrics, University of Cambridge, Cambridge, UK.; University Department of Medical Genetics, University of Cambridge, Cambridge, UK., Cenier A; Department of Paediatrics, University of Cambridge, Cambridge, UK.; Technische Universität München, ZIEL - Institute for Food & Health, Freising, Germany., Glemas C; Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.; Department of Paediatric Gastroenterology, Hepatology and Nutrition, Cambridge University Hospitals (CUH), Addenbrooke's, Cambridge, UK., Giachero F; Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.; Department of Paediatrics, University of Cambridge, Cambridge, UK.; Department of Paediatric Gastroenterology, Hepatology and Nutrition, Cambridge University Hospitals (CUH), Addenbrooke's, Cambridge, UK., Foster AR; Milner Therapeutics Institute, University of Cambridge, Cambridge, UK.; Wellcome Sanger Institute, Hinxton, Cambridgeshire, UK., Harris R; Milner Therapeutics Institute, University of Cambridge, Cambridge, UK., Kraiczy J; Department of Paediatrics, University of Cambridge, Cambridge, UK., Salvestrini C; Department of Paediatric Gastroenterology, Hepatology and Nutrition, Cambridge University Hospitals (CUH), Addenbrooke's, Cambridge, UK., Stavrou G; Department of Paediatrics, University of Cambridge, Cambridge, UK., Torrente F; Department of Paediatric Gastroenterology, Hepatology and Nutrition, Cambridge University Hospitals (CUH), Addenbrooke's, Cambridge, UK., Brook K; Department of Paediatric Gastroenterology, Hepatology and Nutrition, Cambridge University Hospitals (CUH), Addenbrooke's, Cambridge, UK., Trayers C; Department of Paediatric and Perinatal Pathology, Cambridge University Hospitals (CUH), Addenbrooke's Hospital, Cambridge, UK., Elmentaite R; Wellcome Sanger Institute, Hinxton, Cambridgeshire, UK., Youssef G; Milner Therapeutics Institute, University of Cambridge, Cambridge, UK., Tél B; Pediatric Center, MTA Center of Excellence, Semmelweis University, Budapest, Hungary., Winton DJ; Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.; Cancer Research-UK Cambridge Institute, Li Ka Shing Centre, Robinson Way, Cambridge, UK., Skoufou-Papoutsaki N; Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.; Cancer Research-UK Cambridge Institute, Li Ka Shing Centre, Robinson Way, Cambridge, UK., Adler S; Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.; Cancer Research-UK Cambridge Institute, Li Ka Shing Centre, Robinson Way, Cambridge, UK., Bufler P; Department of Pediatric Gastroenterology, Nephrology and Metabolic Diseases, Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany., Azabdaftari A; Department of Pediatric Gastroenterology, Nephrology and Metabolic Diseases, Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.; Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, Berlin, Germany., Jenke A; Department of Neonatology and General Pediatrics, Children's Hospital Kassel, Kassel, Germany.; Clinical Molecular Genetics and Epigenetics, Centre for Biomedical Education and Research (ZBAF), HELIOS University Hospital Wuppertal, Witten/Herdecke University, Wuppertal, Germany., G N; Department of Paediatric Gastroenterology, Hepatology and Nutrition, Cambridge University Hospitals (CUH), Addenbrooke's, Cambridge, UK., Thomas N; Department of Paediatrics, University of Cambridge, Cambridge, UK., Miele E; Department of Translational Medical Science, Section of Pediatrics, University of Naples 'Federico II', Naples, Italy., Al-Mohammad A; Department of Paediatrics, University of Cambridge, Cambridge, UK., Guarda G; Faculty of Biomedical Sciences, Institute for Research in Biomedicine (IRB), Università della Svizzera italiana, Bellinzona, Switzerland., Kugathasan S; Department of Pediatrics, Emory University, Atlanta, GA, USA.; Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA., Venkateswaran S; Department of Pediatrics, Emory University, Atlanta, GA, USA., Clatworthy MR; Molecular Immunity Unit, Department of Medicine, University of Cambridge, Cambridge, UK.; Cellular Genetics, Wellcome Sanger Institute, Hinxton, UK.; Cambridge Institute of Therapeutic Immunology and Infectious Diseases, University of Cambridge, Cambridge, UK., Castro-Dopico T; Molecular Immunity Unit, Department of Medicine, University of Cambridge, Cambridge, UK., Suchanek O; Molecular Immunity Unit, Department of Medicine, University of Cambridge, Cambridge, UK.; Cambridge Institute of Therapeutic Immunology and Infectious Diseases, University of Cambridge, Cambridge, UK., Strisciuglio C; Department of Woman, Child ad General and Specialistic Surgery, University of Campania ' Vanvitelli', Naples, Italy., Gasparetto M; Norfolk and Norwich University Hospital, Jenny Lind Children's Hospital, Norwich, UK., Lee S; Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.; Milner Therapeutics Institute, University of Cambridge, Cambridge, UK., Xu X; Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.; Milner Therapeutics Institute, University of Cambridge, Cambridge, UK., Bello E; Milner Therapeutics Institute, University of Cambridge, Cambridge, UK., Han N; Milner Therapeutics Institute, University of Cambridge, Cambridge, UK.; Cambridge Centre for AI in Medicine, Department of Applied Mathematics and Theoretical Physics, University of Cambridge, Cambridge, UK., Zerbino DR; European Bioinformatics Institute, Cambridge, Cambridgeshire, UK., Teichmann SA; Wellcome Sanger Institute, Hinxton, Cambridgeshire, UK.; Cambridge Centre for AI in Medicine, Department of Applied Mathematics and Theoretical Physics, University of Cambridge, Cambridge, UK.; Dept Physics/Cavendish Laboratory, Theory of Condensed Matter, JJ Thomson Ave, Cambridge, UK., Nys J; Bioscience Asthma and Skin Immunity, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK., Heuschkel R; Department of Paediatric Gastroenterology, Hepatology and Nutrition, Cambridge University Hospitals (CUH), Addenbrooke's, Cambridge, UK., Perrone F; Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK mz304@cam.ac.uk fp385@cam.ac.uk.; Department of Paediatrics, University of Cambridge, Cambridge, UK., Zilbauer M; Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK mz304@cam.ac.uk fp385@cam.ac.uk.; Department of Paediatrics, University of Cambridge, Cambridge, UK.; Department of Paediatric Gastroenterology, Hepatology and Nutrition, Cambridge University Hospitals (CUH), Addenbrooke's, Cambridge, UK.
Jazyk:	angličtina
Zdroj:	Gut [Gut] 2024 Aug 08; Vol. 73 (9), pp. 1464-1477. Date of Electronic Publication: 2024 Aug 08.
DOI:	10.1136/gutjnl-2024-332043
Abstrakt:	Objective: Epigenetic mechanisms, including DNA methylation (DNAm), have been proposed to play a key role in Crohn's disease (CD) pathogenesis. However, the specific cell types and pathways affected as well as their potential impact on disease phenotype and outcome remain unknown. We set out to investigate the role of intestinal epithelial DNAm in CD pathogenesis. Design: We generated 312 intestinal epithelial organoids (IEOs) from mucosal biopsies of 168 patients with CD (n=72), UC (n=23) and healthy controls (n=73). We performed genome-wide molecular profiling including DNAm, bulk as well as single-cell RNA sequencing. Organoids were subjected to gene editing and the functional consequences of DNAm changes evaluated using an organoid-lymphocyte coculture and a nucleotide-binding oligomerisation domain, leucine-rich repeat and CARD domain containing 5 (NLRC5) dextran sulphate sodium (DSS) colitis knock-out mouse model. Results: We identified highly stable, CD-associated loss of DNAm at major histocompatibility complex (MHC) class 1 loci including NLRC5 and cognate gene upregulation. Single-cell RNA sequencing of primary mucosal tissue and IEOs confirmed the role of NLRC5 as transcriptional transactivator in the intestinal epithelium. Increased mucosal MHC-I and NLRC5 expression in adult and paediatric patients with CD was validated in additional cohorts and the functional role of MHC-I highlighted by demonstrating a relative protection from DSS-mediated mucosal inflammation in NLRC5-deficient mice. MHC-I DNAm in IEOs showed a significant correlation with CD disease phenotype and outcomes. Application of machine learning approaches enabled the development of a disease prognostic epigenetic molecular signature. Conclusions: Our study has identified epigenetically regulated intestinal epithelial MHC-I as a novel mechanism in CD pathogenesis. Competing Interests: Competing interests: None declared. (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu