A distinct epigenetic profile distinguishes stenotic from non-inflamed fibroblasts in the ileal mucosa of Crohn's disease patients

• Published in: PloS one Vol. 13; no. 12; p. e0209656
• Main Authors: Li Yim, Andrew Y F, de Bruyn, Jessica R, Duijvis, Nicolette W, Sharp, Catriona, Ferrero, Enrico, de Jonge, Wouter J, Wildenberg, Manon E, Mannens, Marcel M A M, Buskens, Christianne J, D'Haens, Geert R, Henneman, Peter, Te Velde, Anje A
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 27.12.2018; Public Library of Science (PLoS)
• Subjects: Adult; Aged; Analysis; Angiogenesis; Apoptosis; Bile; Binding sites; Biology and life sciences; Cell cycle; Computational Biology - methods; Constriction, Pathologic; Crohn Disease - genetics; Crohn Disease - pathology; Crohn Disease - therapy; Crohn's disease; Deoxyribonucleic acid; DNA; DNA Methylation; DNA sequencing; Epigenesis, Genetic; Epigenetic inheritance; Epigenetics; Fibroblasts; Fibrosis; Gastroenterology; Gene expression; Gene Expression Profiling; Gene Regulatory Networks; Gene sequencing; Genes; Genetic aspects; Genetic Predisposition to Disease; Genetics; Genomes; Genotype & phenotype; Growth factors; Humans; Ileum; Inflammation; Inflammatory bowel disease; Intestinal Mucosa - metabolism; Intestinal Mucosa - pathology; Intestine; Laboratories; Liver; Medicine and Health Sciences; Mesenchyme; Metabolism; Middle Aged; Mucosa; Pathogenesis; Pathological physiology; Patients; Physical Sciences; Research and analysis methods; Ribonucleic acid; RNA; Severity of Illness Index; Stenosis; Transcriptome; Wound healing; Young Adult; United States > US; Netherlands
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0209656

The chronic remitting and relapsing intestinal inflammation characteristic of Crohn's disease frequently leads to fibrosis and subsequent stenosis of the inflamed region. Approximately a third of all Crohn's disease patients require resection at some stage in their disease course. As the pathogenesis of Crohn's disease associated fibrosis is largely unknown, a strong necessity exists to better understand the pathophysiology thereof. In this study, we investigated changes of the DNA methylome and transcriptome of ileum-derived fibroblasts associated to the occurrence of Crohn's disease associated fibrosis. Eighteen samples were included in a DNA methylation array and twenty-one samples were used for RNA sequencing. Most differentially methylated regions and differentially expressed genes were observed when comparing stenotic with non-inflamed samples. By contrast, few differences were observed when comparing Crohn's disease with non-Crohn's disease, or inflamed with non-inflamed tissue. Integrative methylation and gene expression analyses revealed dysregulation of genes associated to the PRKACA and E2F1 network, which is involved in cell cycle progression, angiogenesis, epithelial to mesenchymal transition, and bile metabolism. Our research provides evidence that the methylome and the transcriptome are systematically dysregulated in stenosis-associated fibroblasts.