Shen Li, Inoue Azusa, He Jin, Liu Yuting, Lu Falong, Zhang Yi
Howard Hughes Medical Institute, 200 Longwood Avenue, Boston, MA 02115, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, 200 Longwood Avenue, Boston, MA 02115, USA; Department of Genetics, 200 Longwood Avenue, Boston, MA 02115, USA.
Howard Hughes Medical Institute, 200 Longwood Avenue, Boston, MA 02115, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, 200 Longwood Avenue, Boston, MA 02115, USA; Department of Genetics, 200 Longwood Avenue, Boston, MA 02115, USA; Harvard Stem Cell Institute, Harvard Medical School, WAB-149G, 200 Longwood Avenue, Boston, MA 02115, USA.
Cell Stem Cell. 2014 Oct 2;15(4):459-471. doi: 10.1016/j.stem.2014.09.002.
With the exception of imprinted genes and certain repeats, DNA methylation is globally erased during preimplantation development. Recent studies have suggested that Tet3-mediated oxidation of 5-methylcytosine (5mC) and DNA replication-dependent dilution both contribute to global paternal DNA demethylation, but demethylation of the maternal genome occurs via replication. Here we present genome-scale DNA methylation maps for both the paternal and maternal genomes of Tet3-depleted and/or DNA replication-inhibited zygotes. In both genomes, we found that inhibition of DNA replication blocks DNA demethylation independently from Tet3 function and that Tet3 facilitates DNA demethylation largely by coupling with DNA replication. For both genomes, our data indicate that replication-dependent dilution is the major contributor to demethylation, but Tet3 plays an important role, particularly at certain loci. Our study thus defines the respective functions of Tet3 and DNA replication in paternal DNA demethylation and reveals an unexpected contribution of Tet3 to demethylation of the maternal genome.
除印记基因和某些重复序列外，DNA甲基化在植入前发育过程中会整体消除。最近的研究表明，Tet3介导的5-甲基胞嘧啶（5mC）氧化和DNA复制依赖性稀释都有助于父本DNA的整体去甲基化，但母本基因组的去甲基化是通过复制发生的。在这里，我们展示了Tet3缺失和/或DNA复制受抑制的合子父本和母本基因组的全基因组规模DNA甲基化图谱。在这两个基因组中，我们发现抑制DNA复制会独立于Tet3功能阻断DNA去甲基化，并且Tet3主要通过与DNA复制偶联来促进DNA去甲基化。对于这两个基因组，我们的数据表明复制依赖性稀释是去甲基化的主要贡献因素，但Tet3也发挥着重要作用，特别是在某些位点。因此，我们的研究确定了Tet3和DNA复制在父本DNA去甲基化中的各自功能，并揭示了Tet3对母本基因组去甲基化的意外贡献。
