DNA甲基化
生物
表观遗传学
染色质
分子生物学
表观遗传学
重编程
甲基化
癌症研究
CpG站点
染色质免疫沉淀
甲基化DNA免疫沉淀
基因表达
发起人
遗传学
DNA
基因
作者
Chihiro Takeuchi,Satoshi Yamashita,Yuyu Liu,Hideyuki Takeshima,Akira Sasaki,Masahide Fukuda,Taiki Hashimoto,Tomoaki Naka,Kenichi Ishizu,Shigeki Sekine,Takaki Yoshikawa,Akinobu Hamada,Nobutake Yamamichi,Mitsuhiro Fujishiro,Toshikazu Ushijima
出处
期刊:Gut
[BMJ]
日期:2023-09-26
卷期号:73 (2): 255-267
被引量:2
标识
DOI:10.1136/gutjnl-2023-329492
摘要
Objective The presence of intestinal metaplasia (IM) is a risk factor for gastric cancer. However, it is still controversial whether IM itself is precancerous or paracancerous. Here, we aimed to explore the precancerous nature of IM by analysing epigenetic alterations. Design Genome-wide DNA methylation analysis was conducted by EPIC BeadArray using IM crypts isolated by Alcian blue staining. Chromatin immunoprecipitation sequencing for H3K27ac and single-cell assay for transposase-accessible chromatin by sequencing were conducted using IM mucosa. NOS2 was induced using Tet-on gene expression system in normal cells. Results IM crypts had a methylation profile unique from non-IM crypts, showing extensive DNA hypermethylation in promoter CpG islands, including those of tumour-suppressor genes. Also, the IM-specific methylation profile, namely epigenetic footprint, was present in a fraction of gastric cancers with a higher frequency than expected, and suggested to be associated with good overall survival. IM organoids had remarkably high NOS2 expression, and NOS2 induction in normal cells led to accelerated induction of aberrant DNA methylation, namely epigenetic instability, by increasing DNA methyltransferase activity. IM mucosa showed dynamic enhancer reprogramming, including the regions involved in higher NOS2 expression. NOS2 had open chromatin in IM cells but not in gastric cells, and IM cells had frequent closed chromatin of tumour-suppressor genes, indicating their methylation-silencing. NOS2 expression in IM-derived organoids was upregulated by interleukin-17A, a cytokine secreted by extracellular bacterial infection. Conclusions IM cells were considered to have a precancerous nature potentially with an increased chance of converting into cancer cells, and an accelerated DNA methylation induction due to abnormal NOS2 expression.
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