Proviral silencing in embryonic stem cells requires the histone methyltransferase ESET
Proviral silencing in embryonic stem cells requires the histone methyltransferase ESET
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DOI：
10.1038/nature08858
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发表时间：
2010-04-08
期刊：
影响因子：
64.8
通讯作者：
Shinkai, Yoichi
中科院分区：
文献类型：
--
作者：
Matsui, Toshiyuki;Leung, Danny;Shinkai, Yoichi
内源逆转录病毒 (ERV) 是具有长末端重复序列的逆转录病毒样元件，广泛分散在哺乳动物细胞的常染色质区室中，约占小鼠基因组的 10%(1)。这些寄生元件导致>10% 的自发突变(2)。尽管 DNA 甲基化在体细胞和种系细胞的原病毒沉默中发挥着重要作用 (3-5)，但另一种独立于 DNA 甲基化的途径也在胚胎癌和胚胎干 (ES) 细胞中发挥作用，抑制外源性伽马逆转录病毒鼠白血病病毒 (MLV) 的转录 (6-8)。值得注意的是，最近的一项全基因组研究表明，ERV 在 ES 细胞中也被组蛋白 H3 赖氨酸 9 三甲基化 (H3K9me3) 和 H4K20me3 标记，但在小鼠胚胎成纤维细胞中却没有 (9)。然而，这些标记在原病毒沉默中的作用仍有待探索。在这里，我们表明，H3K9me3 以及小鼠 ES 细胞中内源性和引入的逆转录病毒的沉默需要 H3K9 甲基转移酶 ESET（也称为 SETDB1 或 KMT1E）和 Kruppel 相关盒 (KRAB) 相关蛋白 1 (KAP1，也称为 TRIM28)(10,11)。此外，虽然 ESET 酶活性对于 HP1 结合和有效的原病毒沉默至关重要，但 H4K20 甲基转移酶 Suv420h1 和 Suv420h2 对于沉默来说是可有可无的。值得注意的是，在 DNA 甲基转移酶三重敲除 (Dnmt1(-/-) Dnmt3a(-/-) Dnmt3b(-/-)) 小鼠 ES 细胞中，ESET 和 KAP1 结合以及 ESET 介导的 H3K9me3 得以维持，并且 ERV 的抑制程度最低。我们提出，在胚胎发生早期 DNA 甲基化动态重编程期间，前病毒沉默需要涉及 KAP1 和 ESET/ESET 介导的 H3K9me3 的 DNA 甲基化独立途径。
Endogenous retroviruses (ERVs), retrovirus-like elements with long terminal repeats, are widely dispersed in the euchromatic compartment in mammalian cells, comprising similar to 10% of the mouse genome(1). These parasitic elements are responsible for >10% of spontaneous mutations(2). Whereas DNA methylation has an important role in proviral silencing in somatic and germ-lineage cells(3-5), an additional DNA-methylation-independent pathway also functions in embryonal carcinoma and embryonic stem (ES) cells to inhibit transcription of the exogenous gammaretrovirus murine leukaemia virus (MLV)(6-8). Notably, a recent genome-wide study revealed that ERVs are also marked by histone H3 lysine 9 trimethylation (H3K9me3) and H4K20me3 in ES cells but not in mouse embryonic fibroblasts(9). However, the role that these marks have in proviral silencing remains unexplored. Here we show that the H3K9 methyltransferase ESET (also called SETDB1 or KMT1E) and the Kruppel-associated box (KRAB)associated protein 1 (KAP1, also called TRIM28)(10,11) are required for H3K9me3 and silencing of endogenous and introduced retroviruses specifically in mouse ES cells. Furthermore, whereas ESET enzymatic activity is crucial for HP1 binding and efficient proviral silencing, the H4K20 methyltransferases Suv420h1 and Suv420h2 are dispensable for silencing. Notably, in DNA methyltransferase triple knockout (Dnmt1(-/-) Dnmt3a(-/-) Dnmt3b(-/-)) mouse ES cells, ESET and KAP1 binding and ESET-mediated H3K9me3 are maintained and ERVs are minimally derepressed. We propose that a DNA-methylation-independent pathway involving KAP1 and ESET/ESET-mediated H3K9me3 is required for proviral silencing during the period early in embryogenesis when DNA methylation is dynamically reprogrammed.