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

Dennison, Thomas, Edgar, Rachel, Payne, Felicity, Nayak, Komal, Ross, Alexander, Cenier, Aurelie, Glemas, Claire, Giachero, Federica, Foster, April, Harris, Rebecca, Kraiczy, Judith, Salvestrini, Camilla, Stavrou, Georgia, Torrente, Franco, Brook, Kimberley, Trayers, Claire, Elmentaite, Rasa, Youssef, Gehad, Tel, Balint, Winton, Douglas, Skoufou-Papoutsaki, Nafeli, Adler, Sam, Bufler, Philip, Azabdaftari, Aline, Jenke, Andreas, G, Natasha, Thomas, Natasha, Miele, Erasmo, Al-Mohammad, Abdulrahman, Guarda, Greta, Kugathasan, Subra, Venkateswaran, Suresh, Clatworthy, Menna, Castro-Dopico, Tomas, Suchanek, Ondrej, Strisciuglio, Caterina, Gasparetto, Marco ORCID: https://orcid.org/0000-0002-3882-3606, Lee, Seokjun, Xu, Xingze, Bello, Erica, Han, Namshik, Zerbino, Daniel, Teichmann, Sarah, Nys, Josquin, Heuschkel, Robert, Perrone, Francesca and Zilbauer, Matthias (2024) Patient-derived organoid biobank identifies epigenetic dysregulation of intestinal epithelial MHC-I as a novel mechanism in severe Crohn's Disease. Gut, 73 (9). pp. 1464-1477. ISSN 0017-5749

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Abstract

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.

Item Type:	Article
Uncontrolled Keywords:	crohn's disease,inflammatory bowel disease,methylation,intestinal epithelium
Faculty \ School:	Faculty of Medicine and Health Sciences > Norwich Medical School
Related URLs:	https://www.scopus.com/pages/publication...
Depositing User:	LivePure Connector
Date Deposited:	14 Aug 2026 14:49
Last Modified:	16 Aug 2026 05:33
URI:	https://ueaeprints.uea.ac.uk/id/eprint/104151
DOI:	10.1136/gutjnl-2024-332043

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