Genome Diagnostics Laboratory, Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
Epigenetics Discovery Performance Unit, GlaxoSmithKline, Stevenage, United Kingdom.
PLoS One. 2018 Dec 27;13(12):e0209656. doi: 10.1371/journal.pone.0209656. eCollection 2018.
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.
克罗恩病的特征是慢性缓解和复发的肠道炎症，常导致纤维化和随后的炎症区域狭窄。大约三分之一的克罗恩病患者在疾病过程中的某个阶段需要进行切除。由于克罗恩病相关纤维化的发病机制在很大程度上尚不清楚，因此非常有必要更好地了解其病理生理学。
在这项研究中，我们研究了与克罗恩病相关纤维化发生相关的回肠衍生成纤维细胞的 DNA 甲基组和转录组的变化。在 DNA 甲基化阵列中包括了 18 个样本，在 RNA 测序中使用了 21 个样本。
在比较狭窄与非炎症样本时，观察到大多数差异甲基化区域和差异表达基因。相比之下，在比较克罗恩病与非克罗恩病，或炎症与非炎症组织时，观察到的差异较少。整合的甲基化和基因表达分析显示，与 PRKACA 和 E2F1 网络相关的基因失调，该网络涉及细胞周期进展、血管生成、上皮到间充质转化和胆汁代谢。
我们的研究提供了证据表明，狭窄相关成纤维细胞中的甲基组和转录组是系统性失调的。
