The epigenetic landscape of latent Kaposi sarcoma-associated herpesvirus genomes.
The epigenetic landscape of latent Kaposi sarcoma-associated herpesvirus genomes.
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DOI：
10.1371/journal.ppat.1000935
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发表时间：
2010-06-03
期刊：
影响因子：
6.7
通讯作者：
Grundhoff A
中科院分区：
文献类型：
--
作者：
Günther T;Grundhoff A
疱疹病毒潜伏期通常被认为是由表观遗传修饰，但在潜伏感染的早期时间点的病毒染色质的动力学知之甚少。在这里，我们报告了一个全面的空间和时间分析的DNA甲基化和组蛋白修饰潜伏感染与卡波西肉瘤相关疱疹病毒（KSHV），病原体卡波西肉瘤和原发性渗出性淋巴瘤（PEL）。通过使用高分辨率平铺微阵列结合免疫沉淀的甲基化DNA（MeDIP）或修饰的组蛋白（染色质IP，ChIP），我们的研究揭示了高度不同的景观表观遗传修饰与潜伏KSHV感染在几个肿瘤衍生的细胞系，以及从头感染的内皮细胞。我们发现，KSHV基因组受到深刻的甲基化在CpG二核苷酸，导致建立特征性的全球DNA甲基化模式。然而，这种模式发展缓慢，因此不太可能控制早期延迟。相反，我们观察到潜伏特异性组蛋白修饰模式在从头感染后迅速建立。我们的分析进一步表明，这种模式的特点是没有激活组蛋白修饰，H3K9/K14-ac和H3K4-me3标记显着检测在几个位点，包括启动子的裂解周期反式激活因子Rta。虽然这些区域在很大程度上缺乏组成型异染色质标记H3K9-me3，但我们观察到H3K27-me3在潜伏KSHV基因组中快速且广泛的沉积，这是一种二价修饰，尽管同时存在激活标记，但仍能够抑制转录。我们的研究结果表明，这里确定的修饰模式诱导在病毒潜伏期的镇压，这可以迅速逆转，一旦裂解周期诱导的平衡状态。疱疹病毒的一个特征是它们能够建立潜伏感染，在此期间大多数病毒基因被沉默。因此，不产生病毒后代，宿主细胞保持活力。虽然病毒基因组可以无限期地存在于这些细胞的细胞核中，但如果细胞中的条件变得不利，则其保留重新进入裂解周期并产生新病毒体的能力。建立潜伏期的分子要求知之甚少，但被认为取决于病毒附加体的表观遗传修饰。在这里，我们报告了一个全基因组筛选，以调查与卡波西肉瘤相关疱疹病毒（KSHV）潜伏感染相关的DNA甲基化和组蛋白修饰模式，KSHV是一种与几种癌症发展相关的肿瘤病毒。我们发现，潜伏期很可能是由通常与转录“平衡”的基因相关的修饰决定的。这些基因的启动子具有激活以及抑制性组蛋白标记，使得它们被沉默，但是它们可以在去除抑制性标记后被快速激活。因此，我们的研究结果可以解释KSHV如何在潜伏期实现有效的静止，但保留了在诱导溶解周期后快速恢复到完全活跃状态的潜力。
Herpesvirus latency is generally thought to be governed by epigenetic modifications, but the dynamics of viral chromatin at early timepoints of latent infection are poorly understood. Here, we report a comprehensive spatial and temporal analysis of DNA methylation and histone modifications during latent infection with Kaposi Sarcoma-associated herpesvirus (KSHV), the etiologic agent of Kaposi Sarcoma and primary effusion lymphoma (PEL). By use of high resolution tiling microarrays in conjunction with immunoprecipitation of methylated DNA (MeDIP) or modified histones (chromatin IP, ChIP), our study revealed highly distinct landscapes of epigenetic modifications associated with latent KSHV infection in several tumor-derived cell lines as well as de novo infected endothelial cells. We find that KSHV genomes are subject to profound methylation at CpG dinucleotides, leading to the establishment of characteristic global DNA methylation patterns. However, such patterns evolve slowly and thus are unlikely to control early latency. In contrast, we observed that latency-specific histone modification patterns were rapidly established upon a de novo infection. Our analysis furthermore demonstrates that such patterns are not characterized by the absence of activating histone modifications, as H3K9/K14-ac and H3K4-me3 marks were prominently detected at several loci, including the promoter of the lytic cycle transactivator Rta. While these regions were furthermore largely devoid of the constitutive heterochromatin marker H3K9-me3, we observed rapid and widespread deposition of H3K27-me3 across latent KSHV genomes, a bivalent modification which is able to repress transcription in spite of the simultaneous presence of activating marks. Our findings suggest that the modification patterns identified here induce a poised state of repression during viral latency, which can be rapidly reversed once the lytic cycle is induced. A characteristic feature of herpesviruses is their ability to establish a latent infection during which most of the viral genes are silenced. As a consequence, no viral progeny is produced and the host cell remains viable. While the viral genome may persist in the nucleus of such cells indefinitely, it retains the ability to re-enter the lytic cycle and produce new virions if conditions in the cell become unfavorable. The molecular requirements for the establishment of latency are poorly understood, but are thought to depend on epigenetic modifications of the viral episome. Here, we report a genome-wide screen to investigate DNA methylation and histone modification patterns associated with latent infection by Kaposi Sarcoma-associated herpesvirus (KSHV), a tumor virus linked to the development of several cancers. We find that latency is likely to be determined by modifications commonly associated with genes that are transcriptionally “poised”. The promoters of such genes harbor activating as well as repressive histone marks such that they are silenced, but they can be rapidly activated upon removal of the repressive marks. Our findings thus may explain how KSHV achieves efficient quiescence during latency, yet retains the potential to quickly revert to a fully active state upon induction of the lytic cycle.
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