RTA promoter demethylation and histone acetylation regulation of murine gammaherpesvirus 68 reactivation.
RTA promoter demethylation and histone acetylation regulation of murine gammaherpesvirus 68 reactivation.
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RTA 启动子去甲基化和组蛋白乙酰化调节鼠伽马疱疹病毒 68 重新激活。
DOI：
10.1371/journal.pone.0004556
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发表时间：
2009
期刊：
影响因子：
3.7
通讯作者：
Deng H
中科院分区：
文献类型：
--
作者：
Yang Z;Tang H;Huang H;Deng H
伽玛疱疹病毒具有共同的生物学特征、潜伏期和裂解性复制。鼠伽马疱疹病毒 68 (MHV-68) 中这两个阶段之间的平衡由复制和转录激活因子 (RTA) 基因控制。在本报告中，我们研究了 DNA 去甲基化和组蛋白乙酰化对 MHV-68 复制的影响。我们发现，在潜伏期或裂解复制期间，RTA 启动子处的 MHV-68 具有独特的甲基化模式。用 DNA 甲基转移酶 (DNMT) 抑制剂 5-氮杂胞苷 (5-AzaC) 处理 MHV-68 潜伏感染的 S11E 细胞，尽管导致病毒 RTA 启动子去甲基化，但仅微弱地重新激活 MHV-68。相比之下，用组蛋白脱乙酰酶 (HDAC) 抑制剂曲古抑菌素 A (TSA) 治疗可强烈重新激活潜伏期的 MHV-68，这与 RTA 启动子处组蛋白 H3 和 H4 乙酰化水平的显着变化有关。我们进一步表明，HDAC3 被招募到 RTA 启动子并在病毒潜伏期抑制 RTA 转录。然而，TSA 处理导致 HDAC3 快速去除，并诱导 RTA 启动子被动去甲基化。在体内，我们发现RTA启动子在肺的裂解性感染期间低甲基化，并且甲基化水平随着病毒在脾中的潜伏感染而增加。总的来说，我们的数据表明组蛋白乙酰化足以有效地重新激活 S11E 细胞中潜伏期的 MHV-68，而 DNA 去甲基化则不然。
Gammaherpesviruses have a common biological characteristic, latency and lytic replication. The balance between these two phases in murine gammaherpesvirus 68 (MHV-68) is controlled by the replication and transcription activator (RTA) gene. In this report, we investigated the effect of DNA demethylation and histone acetylation on MHV-68 replication. We showed that distinctive methylation patterns were associated with MHV-68 at the RTA promoter during latency or lytic replication. Treatment of MHV-68 latently-infected S11E cells with a DNA methyltransferases (DNMTs) inhibitor 5-azacytidine (5-AzaC), only weakly reactivated MHV-68, despite resulted in demethylation of the viral RTA promoter. In contrast, treatment with a histone deacetylase (HDAC) inhibitor trichostatin A (TSA) strongly reactivated MHV-68 from latency, and this was associated with significant change in histone H3 and H4 acetylation levels at the RTA promoter. We further showed that HDAC3 was recruited to the RTA promoter and inhibited RTA transcription during viral latency. However, TSA treatment caused rapid removal of HDAC3 and also induced passive demethylation at the RTA promoter. In vivo, we found that the RTA promoter was hypomethylated during lytic infection in the lung and that methylation level increased with virus latent infection in the spleen. Collectively, our data showed that histone acetylation, but not DNA demethylation, is sufficient for effective reactivation of MHV-68 from latency in S11E cells.
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