Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan.
Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan.
Anticancer Res. 2021 Jun;41(6):2817-2828. doi: 10.21873/anticanres.15062.
BACKGROUND/AIM: Epigenetic alterations play an important role in the pathogenesis of gastrointestinal stromal tumors (GISTs). To obtain further insight into the GIST epigenome, we analyzed genome-wide histone modification and DNA methylation in GIST cells.
To reverse epigenetic silencing, GIST-T1 cells were treated with a DNA methyltransferase inhibitor and a histone deacetylase inhibitor, and subsequently H3K4me3 levels, the DNA methylome, and the transcriptome were analyzed.
Treatment with epigenetic inhibitors not only up-regulated genes with DNA methylation, but also genes related to interferon signaling. ChIP-seq analysis revealed that drug treatment up-regulated H3K4me3 levels in retrotransposons, including endogenous retroviruses (ERV). Finally, utilizing the omics data, we found that hypermethylation of MEG3 is a frequent event and an indicator of poorer prognosis in GIST patients.
Epigenetic inhibitors may activate interferon signaling via viral mimicry in GIST cells. Moreover, epigenome data could be a useful resource to identify novel GIST-related genes.
背景/目的：表观遗传改变在胃肠道间质瘤（GIST）的发病机制中起着重要作用。为了更深入地了解 GIST 的表观基因组，我们分析了 GIST 细胞的全基因组组蛋白修饰和 DNA 甲基化。
为了逆转表观遗传沉默，用 DNA 甲基转移酶抑制剂和组蛋白去乙酰化酶抑制剂处理 GIST-T1 细胞，随后分析 H3K4me3 水平、DNA 甲基组和转录组。
用表观遗传抑制剂处理不仅上调了 DNA 甲基化的基因，还上调了与干扰素信号有关的基因。ChIP-seq 分析显示，药物治疗上调了包括内源性逆转录病毒（ERV）在内的反转录元件中的 H3K4me3 水平。最后，利用组学数据，我们发现 MEG3 的高甲基化是 GIST 患者中一种常见事件，也是预后不良的指标。
表观遗传抑制剂可能通过病毒模拟在 GIST 细胞中激活干扰素信号。此外，表观基因组数据可能是识别新的 GIST 相关基因的有用资源。
