Inheritance of an epigenetic mark: the CpG DNA methyltransferase 1 is required for de novo establishment of a complex pattern of non-CpG methylation.
Inheritance of an epigenetic mark: the CpG DNA methyltransferase 1 is required for de novo establishment of a complex pattern of non-CpG methylation.
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表观遗传标记的遗传：CpG DNA甲基转移酶1是从头建立非CPG甲基化的复杂模式所必需的。
DOI：
10.1371/journal.pone.0001136
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发表时间：
2007-11-07
期刊：
影响因子：
3.7
通讯作者：
Rassoulzadegan, Minoo
中科院分区：
文献类型：
--
作者：
Grandjean, Valerie;Yaman, Ruken;Cuzin, Francois;Rassoulzadegan, Minoo
胞嘧啶的位点特异性甲基化是脊椎动物DNA的关键表观遗传标记。虽然大多数甲基化残基是对称的（meC）pG:Gp（meC）构型，但在CpA， CpT和CpC不对称（非cpg）二核苷酸中发现了较小但显著的部分。CpG甲基化是通过DNA甲基转移酶1 （Dnmt1）在新复制的半甲基化底物（meC）pG:GpC上的活性来维持的。另一方面，非cpg甲基化模式的建立和遗传维持尚未得到详细分析。我们之前报道过在CpG和非CpG位点发生位点特异性甲基化和等位基因特异性甲基化。在这里，我们描述了一个非CpG甲基化的遗传复合物，与CpG甲基化广泛相关的三种不同的跨代维持比例恒定。这些观察结果提出了导致不对称甲基化模式维持的信号的问题。尽管大多数精子基因组没有或只有一个甲基化的非cpg位点，但每一代都恢复了完整的非cpg模式。这一观察结果使我们提出了一个假设，即稳定的CpG模式可能是维持非CpG DNA甲基化的蓝图。正如预测的那样，在缺乏Dnmt1（负责CpG甲基化的酶）的突变体中，非CpG DNA甲基化谱被取消，但在缺乏Dnmt3a或Dnmt2的突变体中没有。
Site-specific methylation of cytosines is a key epigenetic mark of vertebrate DNA. While a majority of the methylated residues are in the symmetrical (meC)pG:Gp(meC) configuration, a smaller, but significant fraction is found in the CpA, CpT and CpC asymmetric (non-CpG) dinucleotides. CpG methylation is reproducibly maintained by the activity of the DNA methyltransferase 1 (Dnmt1) on the newly replicated hemimethylated substrates (meC)pG:GpC. On the other hand, establishment and hereditary maintenance of non-CpG methylation patterns have not been analyzed in detail. We previously reported the occurrence of site- and allele-specific methylation at both CpG and non-CpG sites. Here we characterize a hereditary complex of non-CpG methylation, with the transgenerational maintenance of three distinct profiles in a constant ratio, associated with extensive CpG methylation. These observations raised the question of the signal leading to the maintenance of the pattern of asymmetric methylation. The complete non-CpG pattern was reinstated at each generation in spite of the fact that the majority of the sperm genomes contained either none or only one methylated non-CpG site. This observation led us to the hypothesis that the stable CpG patterns might act as blueprints for the maintenance of non-CpG DNA methylation. As predicted, non-CpG DNA methylation profiles were abrogated in a mutant lacking Dnmt1, the enzymes responsible for CpG methylation, but not in mutants defective for either Dnmt3a or Dnmt2.
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