Towards the human cancer epigenome - A first draft of histone modifications
Towards the human cancer epigenome - A first draft of histone modifications
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DOI：
10.4161/cc.4.10.2113
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发表时间：
2005-10-01
期刊：
影响因子：
4.3
通讯作者：
Esteller, M
中科院分区：
文献类型：
--
作者：
Fraga, MF;Esteller, M
基因组DNA甲基化模式的破坏是人类癌症中描述的第一个表观遗传异常。这种不平衡涉及肿瘤抑制基因的启动子CpG岛超甲基化，引起转录抑制，以及全局基因组低甲基化，导致染色体不稳定和内寄生序列的再激活。DNA甲基化和组蛋白修饰之间的关系最初是在女性X染色体失活和DNA甲基化机制与染色质修饰剂之间强相互作用的证明的背景下描述的。肿瘤抑制基因的启动子超甲基化的抑制也被发现与一个特定的组蛋白修饰指数。然而，这个拼图缺少了一块：关于组蛋白修饰景观如何在癌细胞中被扭曲的全局视图。我们最近发现了这一难题，表明癌症中DNA甲基化和组蛋白修饰畸变之间的关联也发生在全球水平。在人类和小鼠肿瘤中，组蛋白H4分别经历单乙酰化和三甲基化赖氨酸16和20的损失。最重要的是，这些改变发生在重复DNA序列的背景下，这些重复DNA序列在转化细胞中也变得低甲基化。组蛋白乙酰化状态的整体变化提示了组蛋白乙酰转移酶（HAT）、组蛋白甲基转移酶（HMT）和组蛋白去乙酰化酶（HDAC）可能作为肿瘤抑制基因或癌基因发挥作用的新途径。在这方面，我们已经表明，在白血病中涉及HAT的特定融合蛋白的产生如何与单乙酰化赖氨酸16-H4标记的擦除相关，而赖氨酸20-H4的三甲基化的丧失破坏异染色质结构域，并可能降低对癌细胞DNA损伤的反应。
The disruption of genomic DNA methylation patterns was the first epigenetic abnormality to be described in human cancer. This imbalance involves the promoter CpG island hypermethylation of tumor-suppressor genes, causing transcriptional repression, and global genomic hypomethylation, leading to chromosomal instability and reactivation of endoparasitic sequences. The relationship between DNA methylation and histone modifications was initially described in the context of the inactivation of female X chromosomes and of the demonstration of strong interactions between the DNA methylation machinery and chromatin modifiers. The repression of tumor-suppressor genes by promoter hypermethylation was also found to be associated with a specific histone modification index. However, this jigsaw was missing a piece: a global view of how the histone modification landscape was distorted in cancer cells. We have recently discovered this piece of the puzzle, demonstrating that the association between DNA methylation and histone modification aberrations in cancer also occurs at the global level. In human and mouse tumors, histone H4 undergoes a loss of monoacetylated and trimethylated lysines 16 and 20, respectively. Most importantly, these alterations occur within the context of the repetitive DNA sequences that also become hypomethylated in transformed cells. The global alterations of histone acetylation status suggest novel pathways by which histone acetyltransferases (HATs), histone methyltransferases (HMTs), and histone deacetylases (HDACs) may play roles as tumor-suppressor genes or oncogenes. In this regard, we have shown how the generation of particular fusion proteins involving HATs in leukemias is associated with an erasure of the monoacetylated lysine 16-H4 marker, whilst the loss of trimethylation at lysine 20-H4 disrupts heterochromatic domains and may reduce the response to DNA damage of cancer cells.