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

被引:14
作者
Yim, Andrew Y. F. Li [1 ,2 ]
de Bruyn, Jessica R. [3 ,4 ]
Duijvis, Nicolette W. [3 ]
Sharp, Catriona [2 ]
Ferrero, Enrico [6 ,7 ]
de Jonge, Wouter J. [3 ]
Wildenberg, Manon E. [3 ]
Mannens, Marcel M. A. M. [1 ]
Buskens, Christianne J. [5 ]
D'Haens, Geert R. [4 ]
Henneman, Peter [1 ]
te Velde, Anje A. [3 ]
机构
[1] Univ Amsterdam, Amsterdam UMC, Dept Clin Genet, Genome Diagnost Lab, Amsterdam, Netherlands
[2] GlaxoSmithKline, Epigenet Discovery Performance Unit, Stevenage, Herts, England
[3] Univ Amsterdam, Amsterdam UMC, Tytgat Inst Liver & Intestinal Res, Amsterdam, Netherlands
[4] Univ Amsterdam, Amsterdam UMC, Dept Gastroenterol, Amsterdam, Netherlands
[5] Univ Amsterdam, Amsterdam UMC, Dept Surg, Amsterdam, Netherlands
[6] GlaxoSmithKline, Target Sci, Computat Biol, Stevenage, Herts, England
[7] Novartis Inst Biomed Res, Autoimmun Transplantat & Inflammat Bioinformat, Basel, Switzerland
关键词
INFLAMMATORY-BOWEL-DISEASE; EPITHELIUM-DERIVED FACTOR; PROTEIN-KINASE-A; TRANSCRIPTIONAL REGULATION; MOLECULAR-MECHANISMS; METHYLATION CHANGES; GENE-EXPRESSION; MEIOTIC ARREST; FACTOR-I; FIBROSIS;
D O I
10.1371/journal.pone.0209656
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
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页数:23
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