Identification of distinct loci for de novo DNA methylation by DNMT3A and DNMT3B during mammalian development
Identification of distinct loci for de novo DNA methylation by DNMT3A and DNMT3B during mammalian development
复制标题
DOI：
10.1038/s41467-020-16989-w
复制
发表时间：
2020-06-24
影响因子：
16.6
通讯作者：
Yamada, Yasuhiro
中科院分区：
文献类型：
--
作者：
Yagi, Masaki;Kabata, Mio;Yamada, Yasuhiro
DNA 甲基化的从头建立是由 DNMT3A 和 DNMT3B 完成的。在这里，我们分析了源自 DNA 低甲基化 2i/L ES 细胞的小鼠胚胎成纤维细胞 (2i-MEF) 中的从头 DNA 甲基化，并去除了 Dnmt3a 或 Dnmt3b。我们在 Dnmt3a 和 Dnmt3b 敲除 (KO) 2i-MEF 中分别鉴定了 355 个和 333 个独特的非甲基化基因。我们发现 Dnmt3a 是 TSS 区域和 Polycomb 群 (PcG) 靶发育基因基因体的从头甲基化所必需的，而 Dnmt3b 在 X 染色体上起主导作用。与此一致的是，Dnmt3a KO 胚胎中 PcG 靶基因的组织特异性 DNA 甲基化显着减少。最后，我们发现具有 DNMT3 突变的人类患者在 Dnmt3 KO 2i-MEF 中低甲基化的区域表现出 DNA 甲基化减少。总之，我们在这里报告了哺乳动物发育过程中两种 DNMT3 酶的一组独特的从头 DNA 甲基化靶位点，这些位点与人类患者的低甲基化位点重叠。
De novo establishment of DNA methylation is accomplished by DNMT3A and DNMT3B. Here, we analyze de novo DNA methylation in mouse embryonic fibroblasts (2i-MEFs) derived from DNA-hypomethylated 2i/L ES cells with genetic ablation of Dnmt3a or Dnmt3b. We identify 355 and 333 uniquely unmethylated genes in Dnmt3a and Dnmt3b knockout (KO) 2i-MEFs, respectively. We find that Dnmt3a is exclusively required for de novo methylation at both TSS regions and gene bodies of Polycomb group (PcG) target developmental genes, while Dnmt3b has a dominant role on the X chromosome. Consistent with this, tissue-specific DNA methylation at PcG target genes is substantially reduced in Dnmt3a KO embryos. Finally, we find that human patients with DNMT3 mutations exhibit reduced DNA methylation at regions that are hypomethylated in Dnmt3 KO 2i-MEFs. In conclusion, here we report a set of unique de novo DNA methylation target sites for both DNMT3 enzymes during mammalian development that overlap with hypomethylated sites in human patients.