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Influence of ND10 Components on Epigenetic Determinants of Early KSHV Latency Establishment

机译：ND10成分对早期KSHV潜伏期建立的表观遗传决定因素的影响

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We have previously demonstrated that acquisition of intricate patterns of activating (H3K4me3, H3K9/K14ac) and repressive (H3K27me3) histone modifications is a hallmark of KSHV latency establishment. The precise molecular mechanisms that shape the latent histone modification landscape, however, remain unknown. Promyelocytic leukemia nuclear bodies (PML-NB), also called nuclear domain 10 (ND10), have emerged as mediators of innate immune responses that can limit viral gene expression via chromatin based mechanisms. Consequently, although ND10 functions thus far have been almost exclusively investigated in models of productive herpesvirus infection, it has been proposed that they also may contribute to the establishment of viral latency. Here, we report the first systematic study of the role of ND10 during KSHV latency establishment, and link alterations in the subcellular distribution of ND10 components to a temporal analysis of histone modification acquisition and host cell gene expression during the early infection phase. Our study demonstrates that KSHV infection results in a transient interferon response that leads to induction of the ND10 components PML and Sp100, but that repression by ND10 bodies is unlikely to contribute to KSHV latency establishment. Instead, we uncover an unexpected role for soluble Sp100 protein, which is efficiently and permanently relocalized from nucleoplasmic and chromatin-associated fractions into the insoluble matrix. We show that LANA expression is sufficient to induce Sp100 relocalization, likely via mediating SUMOylation of Sp100. Furthermore, we demonstrate that depletion of soluble Sp100 occurs precisely when repressive H3K27me3 marks first accumulate on viral genomes, and that knock-down of Sp100 (but not PML or Daxx) facilitates H3K27me3 acquisition. Collectively, our data support a model in which non-ND10 resident Sp100 acts as a negative regulator of polycomb repressive complex-2 (PRC2) recruitment, and suggest that KSHV may actively escape ND10 silencing mechanisms to promote establishment of latent chromatin.
机译：我们先前已证明，激活（H3K4me3，H3K9 / K14ac）和阻抑性（H3K27me3）组蛋白修饰的复杂模式是KSHV潜伏期建立的标志。然而，形成潜在的组蛋白修饰态的精确分子机制仍然未知。早幼粒细胞白血病核体（PML-NB），也称为核结构域10（ND10），已成为先天免疫反应的介质，可以通过基于染色质的机制限制病毒基因的表达。因此，尽管迄今为止在生产性疱疹病毒感染的模型中几乎仅对ND10功能进行了研究，但有人提出它们也可能有助于建立病毒潜伏期。在这里，我们报告ND10在KSHV潜伏期建立过程中的作用的首次系统研究，并将ND10组分在亚细胞分布中的改变与早期感染阶段组蛋白修饰获得和宿主细胞基因表达的时间分析联系起来。我们的研究表明，KSHV感染会导致短暂的干扰素反应，从而导致ND10组分PML和Sp100的诱导，但是ND10抗体的抑制作用不太可能有助于KSHV潜伏期的建立。取而代之的是，我们发现了可溶性Sp100蛋白的出乎意料的作用，该蛋白可以有效且永久地从核质和染色质相关组分重新定位到不溶性基质中。我们显示LANA表达足以诱导Sp100重新定位，可能通过介导Sp100的SUMOylation。此外，我们证明了当可溶性H3K27me3标记首次在病毒基因组上积累时，可溶性Sp100的消耗就发生了，而Sp100的敲除（但不是PML或Daxx）促进了H3K27me3的获得。总的来说，我们的数据支持一个模型，其中非ND10的居民Sp100充当多梳抑制复合物2（PRC2）募集的负调节剂，并表明KSHV可能会积极逃避ND10沉默机制以促进潜在染色质的建立。

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