Hypoxic stress induces dimethylated histone H3 lysine 9 through histone methyltransferase G9a in mammalian cells
Hypoxic stress induces dimethylated histone H3 lysine 9 through histone methyltransferase G9a in mammalian cells
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DOI：
10.1158/0008-5472.can-06-0101
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发表时间：
2006-09-15
期刊：
影响因子：
11.2
通讯作者：
Costa, Max
中科院分区：
文献类型：
--
作者：
Chen, Haobin;Yan, Yan;Costa, Max
二甲基化组蛋白H3赖氨酸9（H3 K9 me 2）是基因抑制和沉默的关键表观遗传标记，在胚胎发生和癌症发生中起着重要作用。在这里，我们研究了缺氧应激对H3 K9 me 2在全球和基因特异性水平的影响。我们发现，缺氧增加全球H3 K9 me 2在几个哺乳动物细胞系。这种缺氧诱导的H3 K9 me 2与组蛋白甲基转移酶G9 a蛋白和酶活性的增加在时间上相关。低氧刺激后，G9 a（-/-）小鼠胚胎干细胞中H3 K9 me 2的增加显著减轻，表明G9 a参与了低氧诱导的H3 K9 me 2。除了G9 a的激活外，我们的结果还表明缺氧通过抑制H3 K9去甲基化过程来增加H3 K9 me 2。还发现降血压模拟物，如去铁胺和二甲基草酰甘氨酸，增加H3 K9 me 2以及G9 a蛋白和活性。最后，缺氧增加了H3 K9 me 2在Mlh 1和Dhfr基因的启动子区，这些增加时间与这些基因的抑制。总的来说，这些结果表明G9 a在缺氧诱导的H3 K9 me 2中起重要作用，其将抑制可能导致实体瘤进展的几个基因的表达。
Dimethylated histone H3 lysine 9 (H3K9me2) is a critical epigenetic mark for gene repression and silencing and plays an essential role in embryogenesis and carcinogenesis. Here, we investigated the effects of hypoxic stress on H3K9me2 at both global and gene-specific level. We found that hypoxia increased global H3K9me2 in several mammalian cell lines. This hypoxia-induced H3K9me2 was temporally correlated with an increase in histone methyltransferase G9a protein and enzyme activity. The increase in H3K9me2 was significantly mitigated in G9a(-/-) mouse embryonic stem cells following hypoxia challenge, indicating that G9a was involved in the hypoxia-induced H3K9me2. In addition to the activation of G9a, our results also indicated that hypoxia increased H3K9me2 by inhibiting H3K9 demethylation processes. Hypoxic mimetics, such as deferoxamine and dimethyloxalylglycine, were also found to increase H3K9me2 as well as G9a protein and activity. Finally, hypoxia increased H3K9me2 in the promoter regions of the Mlh1 and Dhfr genes, and these increases temporally correlated with the repression of these genes. Collectively, these results indicate that G9a plays an important role in the hypoxia-induced H3K9me2, which would inhibit the expression of several genes that would likely lead to solid tumor progression.