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

PLoS One. 2018 Dec 27;13(12):e0209656. doi: 10.1371/journal.pone.0209656. eCollection 2018.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Computational Biology / methods
  • Constriction, Pathologic
  • Crohn Disease / genetics*
  • Crohn Disease / pathology*
  • Crohn Disease / therapy
  • DNA Methylation
  • Epigenesis, Genetic*
  • Gene Expression Profiling
  • Gene Regulatory Networks
  • Genetic Predisposition to Disease
  • Humans
  • Intestinal Mucosa / metabolism*
  • Intestinal Mucosa / pathology*
  • Middle Aged
  • Severity of Illness Index
  • Transcriptome*
  • Young Adult

Grant support

This work was supported by the European Commission, Horizon 2020 Framework Programme (SEP-210163258 to WJJ) and the European Crohn's and Colitis Organisation (project: 'DNA methylation profiles in IBD fibroblasts' to AAV and PH). WJJ was a co-owner of Gut Research BV at the time of writing this manuscript. GlaxoSmithKline provided support in the form of salaries for authors AYFLY and CS and GlaxoSmithKline and Novartis provided support in the form of salaries for author EF. GlaxoSmithKline, Novartis and Gut Research BV had no additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the 'author contributions' section.