School of Life Sciences and Frontiers in Genetics Program, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
Development. 2013 Feb 1;140(3):519-29. doi: 10.1242/dev.087585.
Endogenous retroviruses (ERVs) undergo de novo DNA methylation during the first few days of mammalian embryogenesis, although the factors that control the targeting of this process are largely unknown. We asked whether KAP1 (KRAB-associated protein 1) is involved in this mechanism because of its previously defined role in maintaining the silencing of ERVs through the histone methyltransferase ESET and histone H3 lysine 9 trimethylation. Here, we demonstrate that introduced ERV sequences are sufficient to direct rapid de novo methylation of a flanked promoter in embryonic stem (ES) cells. This mechanism requires the presence of an ERV sequence-recognizing KRAB zinc-finger protein (ZFP) and both KAP1 and ESET. Furthermore, this process can also take place on a strong cellular promoter and leads to methylation signatures that are subsequently maintained in vivo throughout embryogenesis. Finally, we show that methylation of ERVs residing in the genome is affected by knockout of KAP1 in early embryos. KRAB-ZFPs, KAP1 and ESET are thus likely to be responsible for the early embryonic instatement of stable epigenetic marks at ERV-containing loci.
内源性逆转录病毒（ERVs）在哺乳动物胚胎发生的头几天经历从头 DNA 甲基化，尽管控制该过程靶向的因素在很大程度上是未知的。我们询问 KAP1（KRAB 相关蛋白 1）是否参与该机制，因为其先前在通过组蛋白甲基转移酶 ESET 和组蛋白 H3 赖氨酸 9 三甲基化来维持 ERV 沉默方面的定义作用。在这里，我们证明引入的 ERV 序列足以指导胚胎干细胞（ES 细胞）中侧翼启动子的快速从头甲基化。该机制需要存在识别 ERV 序列的 KRAB 锌指蛋白（ZFP）以及 KAP1 和 ESET。此外，该过程也可以发生在强大的细胞启动子上，并导致随后在体内整个胚胎发生过程中保持的甲基化特征。最后，我们表明，基因组中 ERV 的甲基化受早期胚胎中 KAP1 敲除的影响。因此，KRAB-ZFPs、KAP1 和 ESET 可能负责在含有 ERV 的基因座上建立稳定的表观遗传标记。
