Methylation of multiple genes in gastric glands with intestinal metaplasia - A disorder with polyclonal origins
Methylation of multiple genes in gastric glands with intestinal metaplasia - A disorder with polyclonal origins
复制标题
DOI：
10.2353/ajpath.2006.060552
复制
发表时间：
2006-11-01
影响因子：
6
通讯作者：
Ushijima, Toshikazu
中科院分区：
文献类型：
--
作者：
Mihara, Mami;Yoshida, Yukinari;Ushijima, Toshikazu
启动子CpG岛的甲基化导致的基因沉默与癌症密切相关，但其在多克隆疾病中的作用尚不清楚。在这里，我们分析了胃肠化生(IM)中基因沉默的存在，这是一种多克隆疾病，在这种疾病中，多个胃腺异常分化为具有肠道特征的腺体。通过全基因组筛选，发现4个基因(ZIK1、ZNF141、KAL1和FGF14)启动子区域的CpG岛在IM患者的腺体中特异性甲基化，并且它们的表达显著降低。当5-氮杂-2‘-脱氧胞苷诱导细胞系去甲基化时，ZIK1、KAL1和FGF14的表达恢复，支持甲基化在它们沉默中的因果作用。对单个腺体中ZIK1甲基化的分析表明，从患有IM的腺体中分离出的绝大多数DNA分子是甲基化的，而从没有IM的腺体中分离的DNA分子没有甲基化。ZIK1甲基化存在于分离自胃内物理上较远位置的腺体中，这表明甲基化发生在多个区域。这些数据表明，多个基因的甲基化独立地发生在多个腺体中，每个腺体都有自己的干细胞，这表明异常基因沉默在非遗传性多克隆人类疾病中的参与需要更多的关注。
Gene silencing by methylation of promoter CpG islands is deeply involved in cancers, but its involvement in polyclonal disorders is still unclear. Here, we analyzed the presence of gene silencing in intestinal metaplasia (IM) of the stomach, a polyclonal disorder, in which multiple gastric glands aberrantly differentiate into those with intestinal characteristics. By a genome-wide screening, CpG islands in the putative promoter regions of four genes (ZIK1, ZNF141, KAL1, and FGF14) were found to be specifically methylated in glands with IM, and their expression was markedly decreased. When demethylation was induced in cell lines with their methylation by 5-aza-2'-deoxycytidine, expression of ZIK1, KAL1, and FGF14 was restored, supporting causal roles of methylation in their silencing. Analysis of ZIK1 methylation in a single gland showed that the vast majority of DNA molecules isolated from a gland with IM were methylated and that those from a gland without IM were not. ZIK1 methylation was present in glands isolated from physically distant positions within a stomach, showing that methylation occurred multifocally. These data indicate that methylation of multiple genes occurs independently in multiple glands, each of which has its own stem cell, demonstrating that involvement of aberrant gene silencing in noninherited polyclonal human disorders needs more attention.