Unintegrated HIV-1 DNAs are loaded with core and linker histones and transcriptionally silenced
Unintegrated HIV-1 DNAs are loaded with core and linker histones and transcriptionally silenced
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DOI：
10.1073/pnas.1912638116
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发表时间：
2019-11-19
影响因子：
11.1
通讯作者：
Goff, Stephen P.
中科院分区：
文献类型：
--
作者：
Geis, Franziska K.;Goff, Stephen P.
在递送到宿主细胞的细胞核中后，线性双链逆转录病毒DNA整合到宿主基因组中以形成前病毒或充当DNA损伤应答的靶标并被环化。关于人类免疫缺陷病毒1型（HIV-1）未整合的逆转录病毒DNA的染色质化状态知之甚少。在这项研究中，我们使用染色质免疫沉淀法来研究未整合的HIV-1 DNA的性质，发现核心组蛋白，组蛋白变体H3.3和H1接头组蛋白都沉积在染色体外HIV-1 DNA上。我们进行了时间过程分析，并确定核心和连接组蛋白的加载发生在病毒应用后的早期。还发现H3.3和H1接头组蛋白装载到莫洛尼鼠白血病病毒的未整合DNA上。未整合的逆转录病毒DNA被有效地沉默，我们提供的证据表明，染色体外HIV-1 DNA的抑制是组蛋白相关的。未整合的DNA标记的转录失活基因的翻译后组蛋白修饰特征：高水平的H3 K9三甲基化和低水平的H3乙酰化。这些发现揭示了未整合的逆转录病毒DNA的性质。
Upon delivery into the nucleus of the host cell, linear double-stranded retroviral DNAs are either integrated into the host genome to form the provirus or act as a target of the DNA damage response and become circularized. Little is known about the chromatinization status of the unintegrated retroviral DNAs of the human immunodeficiency virus type 1 (HIV-1). In this study, we used chromatin immunoprecipitation to investigate the nature of unintegrated HIV-1 DNAs and discovered that core histones, the histone variant H3.3, and H1 linker histones are all deposited onto extrachromosomal HIV-1 DNA. We performed a time-course analysis and determined that the loading of core and linker histones occurred early after virus application. H3.3 and H1 linker histones were also found to be loaded onto unintegrated DNAs of the Moloney murine leukemia virus. The unintegrated retroviral DNAs are potently silenced, and we provide evidence that the suppression of extrachromosomal HIV-1 DNA is histone-related. Unintegrated DNAs were marked by posttranslational histone modifications characteristic of transcriptionally inactive genes: high levels of H3K9 trimethylation and low levels of H3 acetylation. These findings reveal insights into the nature of unintegrated retroviral DNAs.