SETD2-dependent H3K36me3 plays a critical role in epigenetic regulation of the HPV31 life cycle.
SETD2-dependent H3K36me3 plays a critical role in epigenetic regulation of the HPV31 life cycle.
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DOI：
10.1371/journal.ppat.1007367
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发表时间：
2018-10
期刊：
影响因子：
6.7
通讯作者：
Moody CA
中科院分区：
文献类型：
--
作者：
Gautam D;Johnson BA;Mac M;Moody CA
HPV的生命周期与其宿主细胞的分化状态有关，其生产性复制、晚期基因表达和病毒粒子的产生仅限于层状上皮的最上层。HPV DNA与组蛋白相关，表现出与宿主染色体相似的染色质结构。尽管HPV染色质受组蛋白翻译后修饰的影响，但病毒生命周期是如何被表观遗传学调控的还不是很清楚。SETD2是一种组蛋白甲基转移酶，它将三甲基标记放置在H3K36 （H3K36me3）上，这是一种活性转录标记。在这里，我们定义了SETD2和H3K36me3在病毒生命周期中的作用。我们发现，HPV阳性细胞表现出SETD2水平的增加，而SETD2的缺失导致了病毒复制和后期病毒rna剪接的缺陷。通过过表达KDM4A（一种H3K36me3去甲基化酶）或H3.3K36M转基因来减少H3K36me3也能阻断病毒的高效复制，这表明这种组蛋白修饰在促进病毒过程中起着重要作用。H3K36me3以依赖SETD2的方式富集在高危HPV31基因组早期区域的3 '端，这表明SETD2可能通过募集H3K36me3读取器到病毒DNA来调节病毒的生命周期。有趣的是，我们发现ATM DNA损伤激酶的激活是病毒增殖所必需的，对于维持病毒染色质上的H3K36me3和后期病毒rna的加工是必要的。此外，我们发现HPV31 E7蛋白通过延长蛋白质半衰期来维持感染细胞中增加的SETD2水平。总的来说，我们的研究结果强调了表观遗传修饰在驱动病毒生命周期中的重要性，并确定了E7以及DNA损伤反应在通过表观遗传修饰调节病毒过程中的新作用。高危人乳头状瘤病毒与多种人类癌症有关，最明显的是宫颈癌。了解HPV选择细胞途径复制的机制可以确定潜在的治疗靶点。HPV基因组以类似于细胞DNA的方式与组蛋白相关，但组蛋白修饰如何影响病毒生命周期尚不清楚。在这里，我们证明高危HPV阳性细胞以e7依赖的方式表现出SETD2水平升高。SETD2将三甲基标记放置在H3K36 （H3K36me3）上，我们发现SETD2和H3K36me3对于在上皮分化过程中高效的病毒复制和晚期病毒rna的剪接是必要的。H3K36me3存在于HPV31基因组上，这表明SETD2通过在病毒DNA上募集H3K36me3的效应蛋白来调节病毒过程。此外，我们发现HPV31维持病毒染色质上的H3K36me3，并通过激活ATM DNA损伤反应来调节病毒rna的剪接，这也是所需的高效病毒复制所必需的。总的来说，这些发现促进了我们对病毒生命周期如何受到表观遗传调控的理解，并确定了DNA损伤反应在促进病毒过程中的新作用。
The life cycle of HPV is tied to the differentiation status of its host cell, with productive replication, late gene expression and virion production restricted to the uppermost layers of the stratified epithelium. HPV DNA is histone-associated, exhibiting a chromatin structure similar to that of the host chromosome. Although HPV chromatin is subject to histone post-translational modifications, how the viral life cycle is epigenetically regulated is not well understood. SETD2 is a histone methyltransferase that places the trimethyl mark on H3K36 (H3K36me3), a mark of active transcription. Here, we define a role for SETD2 and H3K36me3 in the viral life cycle. We have found that HPV positive cells exhibit increased levels of SETD2, with SETD2 depletion leading to defects in productive viral replication and splicing of late viral RNAs. Reducing H3K36me3 by overexpression of KDM4A, an H3K36me3 demethylase, or an H3.3K36M transgene also blocks productive viral replication, indicating a significant role for this histone modification in facilitating viral processes. H3K36me3 is enriched on the 3’ end of the early region of the high-risk HPV31 genome in a SETD2-dependent manner, suggesting that SETD2 may regulate the viral life cycle through the recruitment of H3K36me3 readers to viral DNA. Intriguingly, we have found that activation of the ATM DNA damage kinase, which is required for productive viral replication, is necessary for the maintenance of H3K36me3 on viral chromatin and for processing of late viral RNAs. Additionally, we have found that the HPV31 E7 protein maintains the increased SETD2 levels in infected cells through an extension of protein half-life. Collectively, our findings highlight the importance of epigenetic modifications in driving the viral life cycle and identify a novel role for E7 as well as the DNA damage response in the regulation of viral processes through epigenetic modifications. High-risk HPVs are associated with multiple human cancers, most notably cervical cancer. Understanding mechanisms by which HPV co-opts cellular pathways to replicate could identify potential therapeutic targets. The HPV genome is associated with histones in a manner similar to that of cellular DNA, but how histone modifications influence the viral life cycle is not well understood. Here, we demonstrate that high-risk HPV positive cells exhibit elevated levels of SETD2 in an E7-dependent manner. SETD2 places the trimethyl mark on H3K36 (H3K36me3) and we have found that SETD2 as well as H3K36me3 are necessary for productive viral replication and splicing of late viral RNAs upon epithelial differentiation. H3K36me3 is present on the HPV31 genome suggesting that SETD2 regulates viral processes through the recruitment of effector proteins to H3K36me3 on viral DNA. In addition, we have found that HPV31 maintains H3K36me3 on viral chromatin and regulates splicing of viral RNAs through activation of the ATM DNA damage response, which is also required for required productive viral replication. Overall, these findings advance our understanding of how the viral life cycle is epigenetically regulated and identify a novel role for the DNA damage response in facilitating viral processes.
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