Embryonic stem cells use ZFP809 to silence retroviral DNAs.
Embryonic stem cells use ZFP809 to silence retroviral DNAs.
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DOI：
10.1038/nature07844
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发表时间：
2009-04-30
期刊：
影响因子：
64.8
通讯作者：
Goff, Stephen P.
中科院分区：
文献类型：
--
作者：
Wolf, Daniel;Goff, Stephen P.
胚胎干细胞（ESC）和小鼠的其他原始干细胞已经知道了30多年，可以有效地阻止逆转录病毒的复制。小鼠白血病病毒（MLV）感染ESC导致整合的前病毒DNA的正常建立，但该DNA随后被转录沉默，从而防止病毒进一步传播。这种抑制主要是由反式作用因子介导的，这些因子识别称为引物结合位点的保守序列元件，引物结合位点是与细胞转移RNA的3 ′端互补的18个碱基对序列。特异性tRNA与病毒基因组RNA的引物结合位点序列退火，并用于引发DNA合成。在整合的前病毒DNA的背景下，该相同序列被靶向用于ESC中的沉默。我们最近发现，与胚胎干细胞中引物结合位点结合的大蛋白复合物含有TRIM 28（参考文献，），这是一种特征良好的转录辅阻遏物，，。一个重要的问题仍然是直接识别整合的逆转录病毒DNA并招募TRIM28介导其特异性沉默的因子的身份。在这里，我们确定锌指蛋白ZFP 809作为识别分子，桥梁的整合前病毒DNA和TRIM 28。我们表明，ZFP 809的表达足以使甚至分化的细胞对MLV感染具有高度抗性。此外，我们证明ZFP 809能够有效地阻断人类T细胞嗜淋巴细胞病毒-1（HTLV-1）DNA构建体的转录，该DNA构建体使用相同的引物tRNA。这些结果将ZFP 809鉴定为DNA结合因子，其特异性识别哺乳动物逆转录病毒和逆转录元件的大子集，靶向它们进行转录沉默。我们认为ZFP 809是一种干细胞特异性逆转录病毒限制因子，因此构成了干细胞内在免疫系统的一个新组成部分。
Embryonic stem cells (ESCs) and other primitive stem cells of mice have been known for more than 30 years to potently block retrovirus replication. Infection of ESCs by the murine leukaemia viruses (MLVs) results in the normal establishment of integrated proviral DNA, but this DNA is then transcriptionally silenced, preventing further viral spread. The repression is largely mediated bytrans-acting factors that recognize a conserved sequence element termed the primer binding site, an 18-base pair sequence complementary to the 3′ end of a cellular transfer RNA,,,,. A specific tRNA is annealed to the primer binding site sequence of the viral genomic RNA, and is used to prime DNA synthesis. This same sequence in the context of the integrated proviral DNA is targeted for silencing in ESCs. We have recently shown that a large protein complex binding to the primer binding site in ESCs contains TRIM28 (refs , ), a well-characterized transcriptional co-repressor,,. An important question remains as to the identity of the factor that directly recognizes integrated retroviral DNAs and recruits TRIM28 to mediate their specific silencing. Here we identify the zinc finger protein ZFP809 as the recognition molecule that bridges the integrated proviral DNA and TRIM28. We show that expression of ZFP809 is sufficient to render even differentiated cells highly resistant to MLV infection. Furthermore, we demonstrate that ZFP809 is able to potently block transcription from DNA constructs of human T-cell lymphotropic virus-1 (HTLV-1), which use the same primer tRNA. These results identify ZFP809 as a DNA-binding factor that specifically recognizes a large subset of mammalian retroviruses and retroelements, targeting them for transcriptional silencing. We propose that ZFP809 evolved as a stem-cell-specific retroviral restriction factor, and therefore constitutes a new component of the intrinsic immune system of stem cells.
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