A distinct epigenetic profile distinguishes stenotic from non-inflamed fibroblasts in the ileal mucosa of Crohn's disease patients.
Andrew Y F Li Yim, Jessica R de Bruyn, Nicolette W Duijvis, Catriona Sharp, Enrico Ferrero, Wouter J de Jonge, Manon E Wildenberg, Marcel M A M Mannens, Christianne J Buskens, Geert R D'Haens, Peter Henneman, Anje A Te Velde
Author Information
Andrew Y F Li Yim: Genome Diagnostics Laboratory, Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands. ORCID
Jessica R de Bruyn: Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
Nicolette W Duijvis: Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands. ORCID
Catriona Sharp: Epigenetics Discovery Performance Unit, GlaxoSmithKline, Stevenage, United Kingdom.
Wouter J de Jonge: Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
Manon E Wildenberg: Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
Marcel M A M Mannens: Genome Diagnostics Laboratory, Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
Christianne J Buskens: Department of Surgery, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
Geert R D'Haens: Department of Gastroenterology, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
Peter Henneman: Genome Diagnostics Laboratory, Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
Anje A Te Velde: Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: Our research provides evidence that the methylome and the transcriptome are systematically dysregulated in stenosis-associated fibroblasts.
