@article{4011,
  keywords = {CROHN'S DISEASE, inflammatory bowel disease, INTESTINAL EPITHELIUM, METHYLATION},
  author = {Thomas W. Dennison and Rachel D. Edgar and Felicity Payne and Komal M. Nayak and Alexander D. B. Ross and Aurelie Cenier and Claire Glemas and Federica Giachero and April R. Foster and Rebecca Harris and Judith Kraiczy and Camilla Salvestrini and Georgia Stavrou and Franco Torrente and Kimberley Brook and Claire Trayers and Rasa Elmentaite and Gehad Youssef and Bálint Tél and Douglas James Winton and Nefeli Skoufou-Papoutsaki and Sam Adler and Philip Bufler and Aline Azabdaftari and Andreas Jenke and Natasha G and Natasha Thomas and Erasmo Miele and Abdulrahman Al-Mohammad and Greta Guarda and Subra Kugathasan and Suresh Venkateswaran and Menna R. Clatworthy and Tomas Castro-Dopico and Ondrej Suchanek and Caterina Strisciuglio and Marco Gasparetto and Seokjun Lee and Xingze Xu and Erica Bello and Namshik Han and Daniel R. Zerbino and Sarah A. Teichmann and Josquin Nys and Robert Heuschkel and Francesca Perrone and Matthias Zilbauer},
  title = {Patient-derived organoid biobank identifies epigenetic dysregulation of intestinal epithelial MHC-I as a novel mechanism in severe Crohn’s Disease},
  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.},
  year = {2024},
  journal = {Gut},
  volume = {73},
  pages = {1464-1477},
  month = {2024/09/01},
  issn = {0017-5749, 1468-3288},
  url = {https://gut.bmj.com/content/73/9/1464},
  doi = {10.1136/gutjnl-2024-332043},
  language = {en},
}