KAP1 controls endogenous retroviruses in embryonic stem cells
KAP1 controls endogenous retroviruses in embryonic stem cells
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DOI：
10.1038/nature08674
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发表时间：
2010-01-14
期刊：
影响因子：
64.8
通讯作者：
Trono, Didier
中科院分区：
文献类型：
--
作者：
Rowe, Helen M.;Jakobsson, Johan;Trono, Didier
超过 40% 的哺乳动物基因组源自逆转录因子，其中约四分之一是内源逆转录病毒 (ERV)(1)。有些仍然活跃，尤其是在小鼠中高度多态性的早期转座子 (ETn)/MusD 和脑池内 A 型颗粒 (IAP)(2,3)。 ERV 在早期胚胎发生过程中通过组蛋白和 DNA 甲基化 (4-6) 进行转录沉默（参见参考文献 7），尽管这一过程的启动者对于保护基因组完整性至关重要 (8)，但在很大程度上仍然未知。 KAP1（KRAB 相关蛋白 1，也称为含三联基序的蛋白 28、TRIM28）通过招募组蛋白甲基转移酶 SETDB1、异染色质蛋白 1 (HP1) 和 NuRD 组蛋白脱乙酰酶复合物 (9) 来抑制基因，但其生理靶点知之甚少。两条证据表明 KAP1 介导的抑制可能有助于 ERV 的控制：首先，KAP1 可以在早期胚胎发生过程中触发永久性基因沉默 (10)，其次，KAP1 复合物使胚胎细胞中的逆转录病毒鼠白血病病毒沉默 (11-13)。与这一假设一致，我们在此表明，KAP1 缺失会导致小鼠胚胎干 (ES) 细胞和早期胚胎中一系列 ERV，特别是 IAP 元件的显着上调。我们进一步证明，KAP1 与 DNA 甲基化协同作用以沉默 IAP 元件，并且它在 IAP 基因组的 5' 非翻译区 (5'UTR) 处富集，其中 KAP1 缺失导致组蛋白 3 赖氨酸 9 三甲基化 (H3K9me3) 的丧失，这是 KAP1 介导的抑制的标志。相应地，IAP 5'UTR 序列可以对 ES 细胞中的异源启动子施加顺式 KAP1 依赖性抑制。我们的结果证实 KAP1 在早期胚胎发育过程中控制内源性逆转录因子。
More than forty per cent of the mammalian genome is derived from retroelements, of which about one-quarter are endogenous retroviruses (ERVs)(1). Some are still active, notably in mice the highly polymorphic early transposon (ETn)/MusD and intracisternal A-type particles (IAP)(2,3). ERVs are transcriptionally silenced during early embryogenesis by histone and DNA methylation(4-6) (and reviewed in ref. 7), although the initiators of this process, which is essential to protect genome integrity(8), remain largely unknown. KAP1 (KRAB-associated protein 1, also known as tripartite motif-containing protein 28, TRIM28) represses genes by recruiting the histone methyltransferase SETDB1, heterochromatin protein 1 (HP1) and the NuRD histone deacetylase complex(9), but few of its physiological targets are known. Two lines of evidence suggest that KAP1-mediated repression could contribute to the control of ERVs: first, KAP1 can trigger permanent gene silencing during early embryogenesis(10), and second, a KAP1 complex silences the retrovirus murine leukaemia virus in embryonic cells(11-13). Consistent with this hypothesis, here we show that KAP1 deletion leads to a marked upregulation of a range of ERVs, in particular IAP elements, in mouse embryonic stem (ES) cells and in early embryos. We further demonstrate that KAP1 acts synergistically with DNA methylation to silence IAP elements, and that it is enriched at the 5' untranslated region (5'UTR) of IAP genomes, where KAP1 deletion leads to the loss of histone 3 lysine 9 trimethylation (H3K9me3), a hallmark of KAP1-mediated repression. Correspondingly, IAP 5'UTR sequences can impose in cis KAP1-dependent repression on a heterologous promoter in ES cells. Our results establish that KAP1 controls endogenous retroelements during early embryonic development.