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Longitudinal Rectal tissue DNA methylation Profiling Identifies Cell-specific Signatures for Disease severity and Outcome in Ulcerative Colitis

ABSTRACT: Ulcerative colitis is heritable disorder with variable clinical outcome but to date only less than 10% of the disease susceptibility and the disease outcome is explained by IBD (inflammatory bowel disease) associated genetic loci. This missing heritability lay fertile grounds for investigating epigenetics as possible explanation. The aims of the study were to investigate genome-wide DNA methylation of the rectal tissue in an inception cohort of UC at two time points, once at baseline (treatment naïve) and at follow-up to explore how longitudinal DNA methylation influences the disease onset, disease progression and outcome. For this purpose, we profiled DNA methylation within rectal mucosal biopsies of pediatric UC (n=211) and non-IBD control patients (n=85) to perform epigenome-wide association studies (EWAS) of specific cell types (i.e epithelial, immune, and fibroblast), to identify UC specific differences. We have also performed longitudinal analysis on follow-up samples (n =73), and also additional comparisons were made between patients eventually undergoing colectomy versus those who did not.

ORGANISM(S): Homo sapiens

PROVIDER: GSE185061 | GEO | 2022/12/01

REPOSITORIES: GEO

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Project description:Inflammatory bowel disease (IBD) is a complex multi-factorial inflammatory disease with Crohn’s disease (CD) and ulcerative colitis (UC) being the two most common forms. A number of transcriptional profiling studies have provided compelling evidence that describe the role of protein-coding genes and microRNAs in modulating the immune responses in IBD. In the present study, we performed a genome-wide transcriptome profiling of lncRNAs and protein-coding genes in inflamed and non-inflamed colon pinch biopsies from the IBD patients using expression microarrays platform. In this study, we identified widespread dysregulation of lncRNAs and protein-coding genes in both inflamed and non-inflamed CD and UC compared to the healthy controls. In case of inflamed CD and UC (iCD and iUC), we identified 438 and 745 differentially expressed lncRNAs, respectively, while in case of the non-inflamed CD and UC (niCD and niUC), we identified 12 and 19 differentially expressed lncRNAs, respectively. We also observed significant enrichment (p-value < 0.001, Pearson’s Chi-squared test) for 96 differentially expressed lncRNAs and 154 protein-coding genes within the IBD susceptibility loci. Furthermore, we found strong positive expression correlations for the intersecting and cis-neighboring differentially expressed IBD loci-associated lncRNA-protein-coding gene pairs. The functional annotation analysis of differentially expressed genes revealed that they are involved in immune response, pro-inflammatory cytokine activity and MHC protein complex. The lncRNA expression profiling in both inflamed and non-inflamed CD and UC, successfully stratified IBD patients from the healthy controls. Taken together, the identified lncRNA transcriptional signature along with clinically relevant parameters suggests their potential as biomarkers in IBD. A total of 96 biopsy samples (including 6 samples used as technical replicates) extracted from different colonic locations from 45 patients (CD=13, UC=20, Controls=12) were profiled using Agilent Custom 8x60K format lncRNA expression microarray. In Gencode v15 lncRNA microarray design, each lncRNA transcript is targeted by two probes covering 22,001 lncRNA transcripts corresponding to 12,963 lncRNA genes. In addition, each array contains 17,535 randomly-selected protein-coding targets, of which 15,182 (unique 12,787) correspond to protein-coding genes.

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Longitudinal Rectal tissue DNA methylation Profiling Identifies Cell-specific Signatures for Disease severity and Outcome in Ulcerative Colitis

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