Department of Developmental Biology and Cancer Research, Faculty of Medicine, Hebrew University of Jerusalem, 91120 Jerusalem, Israel.
Department of Medicine, University of California, San Diego, La Jolla, CA 92093.
Proc Natl Acad Sci U S A. 2018 Oct 9;115(41):10387-10391. doi: 10.1073/pnas.1804755115. Epub 2018 Sep 26.
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.
在囊胚期的印迹消除后，整个基因组在着床时会经历从头甲基化，而 CpG 岛则受到这一过程的保护。这种双峰模式随后在整个发育过程和生物的整个生命周期中得到保留。我们使用小鼠胚胎干细胞作为模型系统，证明了在从头甲基化之前，RNA 聚合酶复合物在 DNA 上的结合可预测其免受这种修饰的影响，并且连接实验证明，该复合物的存在实际上足以防止这些位点的甲基化。这种保护很可能是通过募集甲基化组蛋白 H3K4 的酶复合物来介导的，在局部区域，这种酶复合物可以防止从头甲基化复合物的进入。在 DNA 尚未甲基化的情况下形成的 H3K4me3 的拓扑模式为模拟生物全基因组基础甲基化模式提供了一个惊人准确的模板。这些结果对理解 RNA 转录和 DNA 甲基化之间的关系具有深远的影响。
