Role of transcription complexes in the formation of the basal methylation pattern in early development
Role of transcription complexes in the formation of the basal methylation pattern in early development
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DOI：
10.1073/pnas.1804755115
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发表时间：
2018-10-09
影响因子：
11.1
通讯作者：
Cedar, Howard
中科院分区：
文献类型：
--
作者：
Greenfield, Razi;Tabib, Amalia;Cedar, Howard
在胚泡中擦除后，整个基因组在植入时经历从头甲基化，CpG岛被保护免受该过程的影响。然后，这种双峰模式在生物体的整个发育和生命周期中得以保留。使用小鼠胚胎干细胞作为模型系统，我们证明了在从头甲基化之前DNA上的RNA聚合酶复合物的结合是预测它被保护免受这种修饰的影响，并且拴系实验表明这种复合物的存在实际上足以防止这些位点的甲基化。这种保护最有可能是通过招募酶复合物介导的，该酶复合物在局部区域甲基化组蛋白H3K4，并以这种方式阻止进入从头甲基化复合物。H3K4me3的拓扑模式是在DNA尚未甲基化时形成的，它为生物体的全基因组基础甲基化模式建模提供了惊人准确的模板。这些结果对于理解RNA转录和DNA甲基化之间的关系具有深远的影响。
Following erasure in the blastocyst, the entire genome undergoes de novo methylation at the time of implantation, with CpG islands being protected from this process. This bimodal pattern is then preserved throughout development and the lifetime of the organism. Using mouse embryonic stem cells as a model system, we demonstrate that the binding of an RNA polymerase complex on DNA before de novo methylation is predictive of it being protected from this modification, and tethering experiments demonstrate that the presence of this complex is, in fact, sufficient to prevent methylation at these sites. This protection is most likely mediated by the recruitment of enzyme complexes that methylate histone H3K4 over a local region and, in this way, prevent access to the de novo methylation complex. The topological pattern of H3K4me3 that is formed while the DNA is as yet unmethylated provides a strikingly accurate template for modeling the genome-wide basal methylation pattern of the organism. These results have far-reaching consequences for understanding the relationship between RNA transcription and DNA methylation.