近日，中科院生物物理研究所邓红雨研究员课题组在PLoS ONE杂志上发表的题为 “RTA promoter demethylation and histone acetylation regulation of murine gammaherpesvirus 68 reactivation” 研究论文在表观遗传学层面上研究了调控MHV-68病毒激活的机制。
人肿瘤相关疱疹病毒包括EB病毒（Epstein-Barr virus, EBV）和卡波西肉瘤相关疱疹病毒（Kaposi’s sarcoma-associated herpesvirus, KSHV）。EBV感染与淋巴瘤等恶性肿瘤的发生紧密相关，也是引起在我国南方及东南亚地区高发的鼻咽癌的关键因素；KSHV感染导致的几种肿瘤是艾滋病的重要并发症，也是艾滋病患者致死的重要原因。鼠疱疹病毒68（MHV-68）与EBV和KSHV同属γ-疱疹病毒, 与EBV和KSHV缺乏有效的动物模型不同， MHV-68可以感染小鼠，建立小动物模型，进行体内体外实验，因此成为当前研究肿瘤相关疱疹病毒的重要手段。
论文通过体外实验研究发现，组蛋白乙酰化而非DNA去甲基化是调控MHV-68激活的主要因素，病毒从潜伏进入裂解感染伴随MHV-68 RTA启动子区被动去甲基化。该发现有别于已报道的其它γ-疱疹病毒如KSHV的表观遗传学调控激活的机制。重要的是，论文还通过小鼠感染实验揭示，MHV-68病毒裂解感染时，RTA启动子区处于去甲基化状态；而当病毒进入潜伏感染时，RTA启动子开始建立甲基化，且随着潜伏感染进程，RTA启动子区甲基化程度逐渐增高。文章表明DNA甲基化对维持MHV-68潜伏感染至关重要，而组蛋白乙酰化引起的染色体重塑则是调控MHV-68病毒激活的重要因素。该发现为今后更深入地阐明表观遗传学调控γ-疱疹病毒激活的机理提供了重要依据。（生物谷Bioon.com）
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PLoS ONE 4(2): e4556. doi:10.1371/journal.pone.0004556
RTA Promoter Demethylation and Histone Acetylation Regulation of Murine Gammaherpesvirus 68 Reactivation
Zhangsheng Yang1,2, Haidong Tang1,2, Hai Huang1,2, Hongyu Deng1,3*
1 Center for Infection and Immunity and National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China, 2 Graduate School of the Chinese Academy of Sciences, Beijing, China, 3 School of Dentistry, University of California Los Angeles, Los Angeles, California, United States of America
Abstract
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.
