TY - JOUR
KW - CROHN'S DISEASE
KW - inflammatory bowel disease
KW - INTESTINAL EPITHELIUM
KW - METHYLATION
AU - Thomas W. Dennison
AU - Rachel D. Edgar
AU - Felicity Payne
AU - Komal M. Nayak
AU - Alexander D. B. Ross
AU - Aurelie Cenier
AU - Claire Glemas
AU - Federica Giachero
AU - April R. Foster
AU - Rebecca Harris
AU - Judith Kraiczy
AU - Camilla Salvestrini
AU - Georgia Stavrou
AU - Franco Torrente
AU - Kimberley Brook
AU - Claire Trayers
AU - Rasa Elmentaite
AU - Gehad Youssef
AU - Bálint Tél
AU - Douglas James Winton
AU - Nefeli Skoufou-Papoutsaki
AU - Sam Adler
AU - Philip Bufler
AU - Aline Azabdaftari
AU - Andreas Jenke
AU - Natasha G
AU - Natasha Thomas
AU - Erasmo Miele
AU - Abdulrahman Al-Mohammad
AU - Greta Guarda
AU - Subra Kugathasan
AU - Suresh Venkateswaran
AU - Menna R. Clatworthy
AU - Tomas Castro-Dopico
AU - Ondrej Suchanek
AU - Caterina Strisciuglio
AU - Marco Gasparetto
AU - Seokjun Lee
AU - Xingze Xu
AU - Erica Bello
AU - Namshik Han
AU - Daniel R. Zerbino
AU - Sarah A. Teichmann
AU - Josquin Nys
AU - Robert Heuschkel
AU - Francesca Perrone
AU - Matthias Zilbauer
AB - 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.
BT - Gut
DA - 2024/09/01
DO - 10.1136/gutjnl-2024-332043
LA - en
N2 - 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.
PY - 2024
SP - 1464
EP - 1477
T2 - Gut
TI - Patient-derived organoid biobank identifies epigenetic dysregulation of intestinal epithelial MHC-I as a novel mechanism in severe Crohn’s Disease
UR - https://gut.bmj.com/content/73/9/1464
VL - 73
Y2 - 2024-08-13
SN - 0017-5749, 1468-3288
ER -