Longitudinal DNA methylation profiling of the rectal mucosa identifies cell-specific signatures of disease status, severity and clinical outcomes in ulcerative colitis cell-specific DNA methylation signatures of UC

• Type of Material: Article
• Authors: Suresh Venkateswaran, Emory University; Hari KK Somineni, Emory University; Jason Matthews, Emory University; Varun Kilaru, Emory University; Jeffrey S Hyams, Connecticut Children’s Medical Center; Lee A Denson, Cincinnati Children’s Hospital Medical Center; Richard Kellamayer, Texas Childrens Hosp; Gregory Gibson, Emory University; David Cutler, Emory University; Karen Conneely, Emory University; Alicia Smith, Emory University; Subramaniam Kugathasan, Emory University
• Language: English
• Date: 2023-03-24
• Publisher: BMC
• Publication Version: Final Published Version
• Copyright Statement: © Crown 2023
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1186/s13148-023-01462-4
• Title of Journal or Parent Work: CLINICAL EPIGENETICS
• Volume: 15
• Issue: 1
• Start Page: 50
• End Page: 50
• Grant/Funding Information: This research was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH), under grant numbers R21DK119997 (SK) and 5U01DK095745 (LAD and JH).; This work was also supported by a research initiative grant (RISK) from the Crohn’s and Colitis Foundation, New York, NY.
• Keywords: Children; DIFFERENTIATE; EXPRESSION; CROHNS-DISEASE; Oncology; INFLAMMATORY-BOWEL-DISEASE; Inflammatory bowel disease; Genetics & Heredity; Life Sciences & Biomedicine; GENOME-WIDE ASSOCIATION; Epigenetic changes; VALIDATION; Risk Stratification and Identification of Immunogenetic and Microbial Markers of Rapid Disease Progression in Children with Crohn's Disease (RISK) study; MICROARRAY; Predicting Response to Standardized Pediatric Colitis Therapy (PROTECT) study; Science & Technology; CHILDREN; INSIGHTS; FIBROBLASTS
• Research Categories: Health Sciences, Obstetrics and Gynecology; Health Sciences, Nutrition

Abstract

Background: In peripheral blood, DNA methylation (DNAm) patterns in inflammatory bowel disease patients reflect inflammatory status rather than disease status. Here, we examined DNAm in diseased rectal mucosa from ulcerative colitis (UC) patients, focusing on constituent cell types with the goal of identifying therapeutic targets for UC other than the immune system. We profiled DNAm of rectal mucosal biopsies of pediatric UC at diagnosis (n = 211) and non-IBD control (n = 85) patients and performed epigenome-wide association studies (EWAS) of specific cell types to understand DNAm changes in epithelial, immune and fibroblast cells across disease states, course, and clinical outcomes. We also examined longitudinal analysis on follow-up samples (n = 73), and comparisons were made among patients with clinical outcomes including those undergoing colectomy versus those who did not. Additionally, we included RNA-seq from the same subjects to assess the impact of CpG sites on the transcription of nearby genes during the disease course. Results: At diagnosis, UC rectal mucosa exhibited a lower proportion of epithelial cells and fibroblasts, and higher proportion of immune cells, in conjunction with variation in the DNAm pattern. While treatment had significant effects on the methylation signature of immune cells, its effects on fibroblasts and epithelial cells were attenuated. Individuals who required colectomy exhibited cell composition and DNAm patterns at follow-up more similar to disease onset than patients who did not require colectomy. Combining these results with gene expression profiles, we identify CpG sites whose methylation patterns are most consistent with a contribution to poor disease outcomes and could thus be potential therapeutic targets. Conclusions: Cell-specific epigenetic changes in the rectal mucosa in UC are associated with disease severity and outcome. Current therapeutics may more effectively target the immune than the epithelial and fibroblast compartments. Graphical abstract: [Figure not available: see fulltext.]