整合表观基因组和转录组分析以阐明表观遗传抑制剂对 GIST 的影响。

An Integrated Epigenome and Transcriptome Analysis to Clarify the Effect of Epigenetic Inhibitors on GIST.

机构信息

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.

出版信息

Anticancer Res. 2021 Jun;41(6):2817-2828. doi: 10.21873/anticanres.15062.

DOI:10.21873/anticanres.15062

PMID:34083271

Abstract

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.

MATERIALS AND METHODS

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.

RESULTS

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.

CONCLUSION

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.

摘要

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。

材料和方法

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。

结果

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。