原病毒在胚胎干细胞中的沉默需要组蛋白甲基转移酶 ESET。
Proviral silencing in embryonic stem cells requires the histone methyltransferase ESET.
机构信息
Experimental Research Center for Infectious Diseases, Institute for Virus Research, Kyoto University, 53 Shogoin, Kawara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
出版信息
Nature. 2010 Apr 8;464(7290):927-31. doi: 10.1038/nature08858. Epub 2010 Feb 17.
Endogenous retroviruses (ERVs), retrovirus-like elements with long terminal repeats, are widely dispersed in the euchromatic compartment in mammalian cells, comprising approximately 10% of the mouse genome. These parasitic elements are responsible for >10% of spontaneous mutations. Whereas DNA methylation has an important role in proviral silencing in somatic and germ-lineage cells, 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). 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. 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 Krüppel-associated box (KRAB)-associated protein 1 (KAP1, also called TRIM28) 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.
内源性逆转录病毒(ERVs)是带有长末端重复序列的逆转录病毒样元件,广泛分布在哺乳动物细胞的常染色质区,约占小鼠基因组的 10%。这些寄生元件导致了超过 10%的自发突变。虽然 DNA 甲基化在体细胞核和生殖系细胞中对前病毒的沉默起着重要作用,但在胚胎癌细胞和胚胎干细胞(ES 细胞)中,一种额外的非 DNA 甲基化依赖途径也能抑制外源性γ逆转录病毒鼠白血病病毒(MLV)的转录。值得注意的是,最近的全基因组研究表明,ERVs 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则没有。然而,这些标记在原病毒沉默中的作用仍未被探索。在这里,我们表明 H3K9 甲基转移酶 ESET(也称为 SETDB1 或 KMT1E)和 KRAB 相关盒(KRAB)相关蛋白 1(KAP1,也称为 TRIM28)对于 ES 细胞中内源性和引入的逆转录病毒的 H3K9me3 和沉默是必需的。此外,尽管 ESET 的酶活性对于 HP1 结合和有效的前病毒沉默至关重要,但 H4K20 甲基转移酶 Suv420h1 和 Suv420h2 对于沉默则是可有可无的。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,ERVs 仅被轻微去抑制。我们提出,一种涉及 KAP1 和 ESET/ESET 介导的 H3K9me3 的非 DNA 甲基化依赖途径,在 DNA 甲基化动态重编程的早期胚胎发生阶段,对于前病毒沉默是必需的。