Impaired recruitment of the histone methyltransferase DOT1L contributes to the incomplete reactivation of tumor suppressor genes upon DNA demethylation
Impaired recruitment of the histone methyltransferase DOT1L contributes to the incomplete reactivation of tumor suppressor genes upon DNA demethylation
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DOI：
10.1038/onc.2009.267
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发表时间：
2009-11-26
期刊：
影响因子：
8
通讯作者：
Esteller, M.
中科院分区：
文献类型：
--
作者：
Jacinto, F. V.;Ballestar, E.;Esteller, M.
了解DNA甲基化变化与组蛋白修饰之间的联系机制，对于与启动子CpG岛超甲基化相关的肿瘤抑制基因在癌细胞中发生转录沉默的情况尤其重要。在这项研究中，我们发现，两个组蛋白赖氨酸甲基化标记与活跃的转录，二甲基化的H3 K79（H3 K79 me 2）和三甲基化的H3 K4（H3 K4 me 3），是目前在所有未甲基化的启动子分析，和他们都失去了当这些启动子变得超甲基化。最重要的是，导致DNA去甲基化和基因转录部分恢复的药理学和遗传干预导致H3 K4 me 3的恢复，但不是H3 K79 me 2。我们还表明，DOT 1 L，主要的H3 K79组蛋白甲基转移酶，不再招募到5-氮脱氧胞苷处理或DNA甲基转移酶基因缺失后去甲基化的启动子。DOT 1 L的敲低和转染实验表明，这种酶在保持这些基因的常染色质和活性状态时，未甲基化的直接作用。这些发现表明，单独的DNA去甲基化干预不能恢复完整的常染色质状态和表观遗传沉默的肿瘤抑制基因的完全转录再激活，并加强了针对表观遗传机制的多个元素的必要性，以成功治疗恶性肿瘤。Oncogene（2009）28，4212-4224; doi：10.1038/onc.2009.267; 2009年9月7日在线发表
Understanding the mechanisms that link changes in DNA methylation with histone modifications is particularly relevant in the case of tumor suppressor genes that undergo transcriptional silencing in cancer cells in association with promoter CpG island hypermethylation. In this study, we show that two histone lysine methylation marks associated with active transcription, dimethylation of H3K79 (H3K79me2) and trimethylation of H3K4 (H3K4me3), are present in all the unmethylated promoters analysed, and both of them are lost when these promoters become hypermethylated. Most importantly, pharmacological and genetic interventions that cause DNA demethylation and partial recovery of gene transcription, result in the restoration of H3K4me3, but not of H3K79me2. We also show that DOT1L, the major H3K79 histone methyltransferase, is no longer recruited to the promoters that are demethylated after 5-azadeoxycytidine treatment or genetic deletion of DNA methyltransferases. Knock-down and transfection experiments for DOT1L show that this enzyme has a direct role in maintaining the euchromatic and active status of these genes when unmethylated. These findings suggest that DNA demethylating interventions alone are not able to restore a complete euchromatic status and a full transcriptional reactivation of the epigenetically silenced tumor suppressor genes, and reinforce the necessity of targeting multiple elements of the epigenetics machinery for a successful treatment of malignancies. Oncogene (2009) 28, 4212-4224; doi: 10.1038/onc.2009.267; published online 7 September 2009