De novo DNA methylation of endogenous retroviruses is shaped by KRAB-ZFPs/KAP1 and ESET.
De novo DNA methylation of endogenous retroviruses is shaped by KRAB-ZFPs/KAP1 and ESET.
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DOI：
10.1242/dev.087585
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发表时间：
2013-02-01
期刊：
影响因子：
--
通讯作者：
Trono D
中科院分区：
文献类型：
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作者：
Rowe HM;Friedli M;Offner S;Verp S;Mesnard D;Marquis J;Aktas T;Trono D
内源性逆转录病毒（erv）在哺乳动物胚胎发生的最初几天经历从头DNA甲基化，尽管控制这一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）是否参与这一机制，因为其先前定义的作用是通过组蛋白甲基转移酶ESET和组蛋白H3赖氨酸9三甲基化维持erv沉默。在这里，我们证明了引入的ERV序列足以指导胚胎干细胞（ES）中侧翼启动子的快速从头甲基化。这一机制需要ERV序列识别的蟹状锌指蛋白（ZFP）以及KAP1和ESET的存在。此外，这一过程也可以发生在一个强大的细胞启动子上，并导致甲基化特征，随后在整个胚胎发生过程中在体内维持。最后，我们发现在早期胚胎中，基因组中erv的甲基化受到KAP1敲除的影响。因此，KRAB-ZFPs、KAP1和ESET可能是在胚胎早期在含有erv的位点上建立稳定表观遗传标记的原因。
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 if KAP1 (KRAB-associated protein 1) is involved in this mechanism because of its previously defined role in maintaining ERVs silent 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 responsible for the early embryonic instatement of stable epigenetic marks at ERV-containing loci.