近日,，中科院生物物理研究所鄧紅雨研究員課題組在PLoS ONE雜志上發(fā)表的題為 “RTA promoter demethylation and histone acetylation regulation of murine gammaherpesvirus 68 reactivation” 研究論文在表觀遺傳學(xué)層面上研究了調(diào)控MHV-68病毒激活的機(jī)制,。
人腫瘤相關(guān)皰疹病毒包括EB病毒（Epstein-Barr virus, EBV）和卡波西肉瘤相關(guān)皰疹病毒（Kaposi’s sarcoma-associated herpesvirus, KSHV）,。EBV感染與淋巴瘤等惡性腫瘤的發(fā)生緊密相關(guān),，也是引起在我國南方及東南亞地區(qū)高發(fā)的鼻咽癌的關(guān)鍵因素,；KSHV感染導(dǎo)致的幾種腫瘤是艾滋病的重要并發(fā)癥,，也是艾滋病患者致死的重要原因,。鼠皰疹病毒68（MHV-68）與EBV和KSHV同屬γ-皰疹病毒, 與EBV和KSHV缺乏有效的動物模型不同,， MHV-68可以感染小鼠，建立小動物模型，進(jìn)行體內(nèi)體外實驗,，因此成為當(dāng)前研究腫瘤相關(guān)皰疹病毒的重要手段,。
論文通過體外實驗研究發(fā)現(xiàn)，組蛋白乙?；荄NA去甲基化是調(diào)控MHV-68激活的主要因素,，病毒從潛伏進(jìn)入裂解感染伴隨MHV-68 RTA啟動子區(qū)被動去甲基化。該發(fā)現(xiàn)有別于已報道的其它γ-皰疹病毒如KSHV的表觀遺傳學(xué)調(diào)控激活的機(jī)制,。重要的是,，論文還通過小鼠感染實驗揭示，MHV-68病毒裂解感染時,，RTA啟動子區(qū)處于去甲基化狀態(tài),；而當(dāng)病毒進(jìn)入潛伏感染時，RTA啟動子開始建立甲基化,，且隨著潛伏感染進(jìn)程,，RTA啟動子區(qū)甲基化程度逐漸增高。文章表明DNA甲基化對維持MHV-68潛伏感染至關(guān)重要,，而組蛋白乙?；鸬娜旧w重塑則是調(diào)控MHV-68病毒激活的重要因素。該發(fā)現(xiàn)為今后更深入地闡明表觀遺傳學(xué)調(diào)控γ-皰疹病毒激活的機(jī)理提供了重要依據(jù),。（生物谷Bioon.com）
生物谷推薦原始出處：
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.
