Arsenite alters global histone H3 methylation
Arsenite alters global histone H3 methylation
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DOI：
10.1093/carcin/bgn063
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发表时间：
2008-09-01
期刊：
影响因子：
4.7
通讯作者：
Costa, Max
中科院分区：
文献类型：
--
作者：
Zhou, Xue;Sun, Hong;Costa, Max
砷(As)是一种具有良好特性的人类致癌物，但通常不会致突变。有证据表明，AS可导致DNA整体甲基化缺失和基因启动子DNA高甲基化，表观遗传机制可能在AS的致癌过程中起重要作用。在本研究中，我们检测了AS暴露下组蛋白甲基化的变化。在人肺癌A549细胞中，接触无机三价砷(亚砷酸盐)增加了H3K9二甲基化(H3K9me2)和减少了H3K27三甲基化(H3K27me3)，这两个都代表基因沉默标志，同时增加了基因激活标志H3K4三甲基化(H3K4me3)的全球水平。H3K9me2的增加是通过组蛋白甲基转移酶G9a蛋白和信使RNA水平的增加而介导的。我们还观察到极低剂量(0.1微米)亚砷酸盐引起显著的组蛋白修饰改变。综上所述，这些结果提示了一种潜在的机制，即AS通过改变代表基因沉默和激活标记的特定组蛋白甲基化来诱导癌症发生。此外，这些标记已知会影响DNA甲基化，砷的影响很可能不仅限于组蛋白修饰，而且可能通过它们延伸到DNA甲基化。我们实验室的未来研究将利用芯片技术解决这些沉默和激活标记的基因组位置。
Arsenic (As) is a well-characterized human carcinogen but is generally not mutagenic. The evidence that As induces both loss of global DNA methylation and gene promoter DNA hypermethylation has suggested that epigenetic mechanisms may play an important role in As-induced carcinogenesis. In the present study, we examined the change in histone methylation by As exposure. In human lung carcinoma A549 cells, exposure to inorganic trivalent As (arsenite) increased H3K9 dimethylation (H3K9me2) and decreased H3K27 trimethylation (H3K27me3), both of which represent gene silencing marks, while increasing the global levels of the H3K4 trimethylation (H3K4me3), a gene-activating mark. The increase in H3K9me2 was mediated by an increase in the histone methyltransferase G9a protein and messenger RNA levels. We also observed strikingly significant altered histone modifications induced by very low-dose (0.1 mu M) arsenite. Taken together, these results suggest a potential mechanism by which As induces carcinogenesis through the alteration of specific histone methylations that represent both gene silencing and activating marks. Furthermore, these marks are known to affect DNA methylation, and it is likely that arsenic's effect is not limited to histone modifications alone, but extends, perhaps by them, to DNA methylations as well. Future studies in our laboratory will address the genomic location of these silencing and activating marks using ChIP-on-chip technology.