Genome-wide analysis of DNA methylation changes induced by gestational arsenic exposure in liver tumors
Genome-wide analysis of DNA methylation changes induced by gestational arsenic exposure in liver tumors
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DOI：
10.1111/cas.12298
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发表时间：
2013-12-01
期刊：
影响因子：
5.7
通讯作者：
Nohara, Keiko
中科院分区：
文献类型：
--
作者：
Suzuki, Takehiro;Yamashita, Satoshi;Nohara, Keiko
无机砷是已知的人类致癌物。以往的研究表明DNA甲基化改变参与了砷的致癌作用，因此，特异性的DNA甲基化改变将有助于区分砷致肿瘤和其他因素所致肿瘤，并有助于阐明砷的致癌作用。先前的研究表明，妊娠期砷暴露的C3 H小鼠，往往自发发展肝肿瘤，增加肿瘤的发病率在男性后代。在这项研究中，我们使用了相同的实验方案，在这些以前的研究和搜索的DNA区域甲基化状态的砷暴露后代的肝肿瘤特异性改变，通过使用甲基化DNA免疫沉淀-CpG岛微阵列。通过定量甲基化特异性PCR和亚硫酸氢盐测序测量所选DNA区域的甲基化水平。本研究的结果阐明了与正常肝组织相比，C3 H小鼠肝肿瘤中DNA甲基化状态发生改变的许多区域。在这些区域中，我们发现癌基因Fosb的基因体区域通过妊娠期砷暴露发生DNA甲基化改变。我们还发现，Fosb的表达显着增加相应的DNA甲基化水平的基因体在砷暴露组。这些结果表明，DNA甲基化状态可以用来识别妊娠期砷暴露增加的肿瘤。
Inorganic arsenic is known to be a human carcinogen. Previous studies have reported that DNA methylation changes are involved in arsenic-induced carcinogenesis, therefore, DNA methylation changes that are specific to arsenic-induced tumors would be useful to distinguish tumors induced by arsenic from tumors caused by other factors and to dissect arsenic carcinogenesis. Previous studies have shown that gestational arsenic exposure of C3H mice, which tend to spontaneously develop liver tumors, increases the incidence of tumors in male offspring. In this study we used the same experimental protocol as in those previous studies and searched for DNA regions where methylation status was specifically altered in the liver tumors of arsenic-exposed offspring by using methylated DNA immunoprecipitation-CpG island microarrays. The methylation levels of the DNA regions selected were measured by quantitative methylation-specific PCR and bisulfite sequencing. The results of this study clarified a number of regions where DNA methylation status was altered in the liver tumors in the C3H mice compared to normal liver tissues. Among such regions, we showed that a gene body region of the oncogene Fosb underwent alteration in DNA methylation by gestational arsenic exposure. We also showed that Fosb expression significantly increased corresponding to the DNA methylation level of the gene body in the arsenic-exposed group. These findings suggest that the DNA methylation status can be used to identify tumors increased by gestational arsenic exposure.