Retroviral DNA Methylation and Epigenetic Repression Are Mediated by the Antiviral Host Protein Daxx
Retroviral DNA Methylation and Epigenetic Repression Are Mediated by the Antiviral Host Protein Daxx
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DOI：
10.1128/jvi.02026-12
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发表时间：
2012-12
影响因子：
5.4
通讯作者：
N. Shalginskikh;A. Poleshko;A. Skalka;R. Katz
中科院分区：
文献类型：
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作者：
N. Shalginskikh;A. Poleshko;A. Skalka;R. Katz
摘要整合的逆转录病毒DNA以不同的频率受到表观遗传转录沉默的影响。这一过程是由抑制性DNA甲基化和病毒染色质上的组蛋白修饰介导的。然而，启动和维持逆转录病毒沉默的详细机制还不清楚。使用一个模型系统，其中禽肉瘤病毒（ASV）DNA在哺乳动物细胞中被表观遗传抑制，我们以前发现，细胞支架蛋白，Daxx，作为一种抗逆转录病毒因子，促进通过招募组蛋白脱乙酰酶（HDAC）的表观遗传抑制。在这里，我们表明，人类Daxx蛋白水平增加，在响应逆转录病毒感染，Daxx的行为在感染时启动表观遗传抑制。与快速和积极的抗病毒表观遗传反应相一致，我们发现抑制性组蛋白标记和长末端重复序列（LTR）DNA甲基化可以在感染后12小时至3天内分别检测到。还发现Daxx是长期ASV沉默维持和完全病毒DNA甲基化所必需的，并且它与病毒DNA和DNA甲基转移酶（DNMT）物理相关。这些发现支持了一种模型，其中进入的逆转录病毒蛋白-DNA复合物被Daxx检测到，并且整合的前病毒被DNA甲基化和组蛋白修饰作为抗病毒反应的一部分快速染色质化和抑制。这些结果揭示了一种可能的直接和积极的抗病毒机制，DNMT可以招募到逆转录病毒DNA。
ABSTRACT Integrated retroviral DNA is subject to epigenetic transcriptional silencing at different frequencies. This process is mediated by repressive DNA methylation and histone modifications on viral chromatin. However, the detailed mechanisms by which retroviral silencing is initiated and maintained are not well understood. Using a model system in which avian sarcoma virus (ASV) DNA is epigenetically repressed in mammalian cells, we previously found that a cellular scaffolding protein, Daxx, acts as an antiretroviral factor that promotes epigenetic repression through recruitment of histone deacetylases (HDACs). Here we show that human Daxx protein levels are increased in response to retroviral infection and that Daxx acts at the time of infection to initiate epigenetic repression. Consistent with a rapid and active antiviral epigenetic response, we found that repressive histone marks and long terminal repeat (LTR) DNA methylation could be detected within 12 h to 3 days postinfection, respectively. Daxx was also found to be required for long-term ASV silencing maintenance and full viral DNA methylation, and it was physically associated with both viral DNA and DNA methyltransferases (DNMTs). These findings support a model in which incoming retroviral protein-DNA complexes are detected by Daxx, and the integrated provirus is rapidly chromatinized and repressed by DNA methylation and histone modification as part of an antiviral response. These results uncover a possible direct and active antiviral mechanism by which DNMTs can be recruited to retroviral DNA.