Distribution, silencing potential and evolutionary impact of promoter DNA methylation in the human genome
Distribution, silencing potential and evolutionary impact of promoter DNA methylation in the human genome
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DOI：
10.1038/ng1990
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发表时间：
2007-04-01
期刊：
影响因子：
30.8
通讯作者：
Schubeler, Dirk
中科院分区：
文献类型：
--
作者：
Weber, Michael;Hellmann, Ines;Schubeler, Dirk
为了深入了解顺式调控区DNA甲基化的功能及其对基因表达的影响，我们测量了原代人类体细胞和生殖细胞中16，000个启动子的甲基化，RNA聚合酶占用率和组蛋白修饰。我们发现CpG-穷人启动子在体细胞中高甲基化，这并不妨碍他们的活动。这种甲基化存在于雄性配子中，并导致CpG二核苷酸的进化丢失，如通过人类和灵长类动物之间的差异所测量的。相比之下，强CpG岛启动子即使在失活时也大多未甲基化。弱CpG岛启动子是独特的，因为它们是体细胞中从头甲基化的优先靶点。值得注意的是，大多数生殖系特异性基因在体细胞中被甲基化，这表明了额外的功能选择。这些结果表明，启动子序列和基因功能是启动子甲基化状态的主要预测因子。此外，我们观察到非活性的未甲基化的CpG岛启动子显示组蛋白H3的Lys 4二甲基化水平升高，这表明该染色质标记可以保护DNA免受甲基化。
To gain insight into the function of DNA methylation at cis-regulatory regions and its impact on gene expression, we measured methylation, RNA polymerase occupancy and histone modifications at 16,000 promoters in primary human somatic and germline cells. We find CpG-poor promoters hypermethylated in somatic cells, which does not preclude their activity. This methylation is present in male gametes and results in evolutionary loss of CpG dinucleotides, as measured by divergence between humans and primates. In contrast, strong CpG island promoters are mostly unmethylated, even when inactive. Weak CpG island promoters are distinct, as they are preferential targets for de novo methylation in somatic cells. Notably, most germline-specific genes are methylated in somatic cells, suggesting additional functional selection. These results show that promoter sequence and gene function are major predictors of promoter methylation states. Moreover, we observe that inactive unmethylated CpG island promoters show elevated levels of dimethylation of Lys4 of histone H3, suggesting that this chromatin mark may protect DNA from methylation.