Cytosine methylation is an important epigenetic mark, but how the distinctive patterns of DNA methylation arise remains elusive. For the first time, we systematically investigated how these patterns can be imparted by the inherent enzymatic preferences of mammalian de novo DNA methyltransferases in vitro and the extent to which this applies in cells. In a biochemical experiment, we subjected a wide variety of DNA sequences to methylation by DNMT3A or DNMT3B and then applied deep bisulfite sequencing to quantitatively determine the sequence preferences for methylation. The data show that DNMT3A prefers CpG and non-CpG sites followed by a 3′-pyrimidine, whereas DNMT3B favors a 3′-purine. Overall, we show that DNMT3A has a sequence preference for a TNC[G/A]CC context, while DNMT3B prefers TAC[G/A]GC. We extended our finding using publicly available data from mouse Dnmt1/3a/3b triple-knockout cells in which reintroduction of either DNMT3A or DNMT3B expression results in the acquisition of the same enzyme specific signature sequences observed in vitro. Furthermore, loss of DNMT3A or DNMT3B in human embryonic stem cells leads to a loss of methylation at the corresponding enzyme specific signatures. Therefore, the global DNA methylation landscape of the mammalian genome can be fundamentally determined by the inherent sequence preference of de novo methyltransferases.

中文翻译：

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全基因组DNA甲基化签名由DNMT3A / B序列首选项确定。

胞嘧啶甲基化是重要的表观遗传标记，但是如何产生DNA甲基化的独特模式仍然难以捉摸。对于第一次，我们系统地研究了如何将这些模式可以通过哺乳动物固有酶促偏好来赋予从头DNA甲基转移酶在体外以及在细胞中的适用程度。在生化实验中，我们通过DNMT3A或DNMT3B对各种DNA序列进行了甲基化，然后应用了亚硫酸氢盐深层测序来定量确定甲基化的序列偏好。数据显示，DNMT3A优选CpG和非CpG位点，其后是3'-嘧啶，而DNMT3B优选3'-嘌呤。总体而言，我们表明DNMT3A具有TNC [G / A] CC上下文的序列优先级，而DNMT3B更喜欢TAC [G / A] GC。我们使用来自小鼠Dnmt1 / 3a / 3b三敲除细胞的公开数据扩展了我们的发现，其中重新引入DNMT3A或DNMT3B表达可导致获得体外观察到的相同酶特异性特征序列。此外，人胚胎干细胞中DNMT3A或DNMT3B的缺失导致相应酶特异性标记处的甲基化缺失。因此，哺乳动物基因组的全球DNA甲基化格局可以从头确定从头甲基转移酶的固有序列偏好。