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百人女博士表观遗传学研究文章受关注

2018-12-03 15:07:28

百人女博士表观遗传学研究文章受关注

生物通综合,中科院生物物理研究所百人计划研究员邓红雨领衔的课题组在PLoS One上发表以:RTA promoter demethylation and histone acetylation regulation of murine gammaherpesvirus 68 reactivation为题的研究性文章,主要解析了鼠疱疹病毒的激活机制。

邓红雨研究员一直从事与人类疾病相关的感染性病毒的研究, 主要研究方向为:病毒之复制机理及与宿主免疫系统之相互作用。本论文的作者是邓红雨研究员指导的博士生杨仉生,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。

研究MHV-68的意义

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。

邓红雨研究员等人的文章发表后受到广泛关注,Trudeau Institute的Marcia Blackman教授推荐在Faculty of 1000 Biology 推荐和点评这篇文章。

点评意见:

论文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。

“Faculty of 1000 Biology”创办于2002年1月,是一种科研评价系统,其推荐原则立足于论文本身的科学意义而非发表在什么杂志上。该系统根据全球4,000多名科学家的意见,提供对近期发表的生物科学论文的快速评论。目的是帮助广大科研人员遴选和发现有价值的论文。

不久前,厦门大学张晓坤教授的一篇癌症细胞凋亡文章也受Faculty of 1000 Biology推荐,具体查看:

生物通推荐原文检索:RTA promoter demethylation and histone acetylation regulation of murine gammaherpesvirus 68 reactivation

【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.

邓红雨

年 博士,美国罗彻斯特大学

年 博士后,爱因斯坦医学院及加州大学洛杉矶分校

年 助理研究员,加州大学洛杉矶分校

2004年- 研究员(“百人计划”),中国科学院生物物理研究所

一直从事与人类疾病相关的感染性病毒的研究, 主要研究方向为:病毒之复制机理及与宿主免疫系统之相互作用。目前正在从事的研究工作包括:肿瘤相关疱疹病毒的基因表达调控,基因组复制及病毒包装的机理;肿瘤相关疱疹病毒与宿主细胞和免疫系统之间的相互作用;全新基因治疗载体之构建与测试;冠状病毒,人丙型肝炎病毒与宿主免疫系统之相互作用。

代表性作品

ng, Y. Liang, and R. Sun. Regulation of KSHV lytic gene expression. CURR TOP Microbiol Immuno, 2007, 312:

F Yu, JN Harada, HJ Brown, H. Deng, MJ Song, TT Wu, J. Kato-Stankiewicz, CG Nelson, J. Vieira, F. Tamanoi, SK Chanda, and R. Sun. Systematic identification of cellular signals reactivating Kaposi?sarcoma-associated herpesvirus. PLoS PathogenS, 2007, 3(3):e44

Wong E., TT Wu, N. Reyes, H. Deng, and R. Sun. Murine gammaherpesvirus 68 open reading frame 24 is required for late gene expression after DNA replication. J Virol, 2007, 81:

Bortz E., L. Wang, Q. Jia, TT Wu, JP Whitelegge, H. Deng, ZH Zhou, R. Sun. Murine Gammaherpesvirus-68 ORF52 Encodes a Tegument Protein Required for Virion Morphogenesis in the Cytoplasm. J Virol, 2007, 81:

J. Benach, L. Wang, Y. Chen, CK Ho, S. Lee, J. Seetharaman, R. Xiao, TB Acton, GT Montelione, H. Deng, R. Sun, and L. Tong. Structural and functional studies of the abundant tegument protein ORF52 from murine gammaherpesvirus-68. J Biol Chem, 2007, 282:

Deng H*, JT Chu, NH Park, and R. Sun. Identification of cis sequences required for lytic DNA replication and packaging of murine gammaherpesvirus 68. J Virol. 78: , 2004. (*Corresponding author.)

Zhu J, P. Trang, K. Kim, T. Zhou, H. Deng, and F. Liu. Effective inhibition of Rta expression and lytic replication of Kaposi’s sarcoma-associated herpesvirus by human RNase P. Proc Natl Acad Sci USA 101: , 2004.

Deng H, JT Chu, MB Rettig, O Martinez-Maza, and R. Sun. Rta of the human herpesvirus 8/Kaposi sarcoma-associated herpesvirus up-regulates human interleukin-6 gene expression. Blood 100: , 2002.

Deng H, MJ Song, JT Chu, and R. Sun. Transcriptional regulation of the interleukin-6 gene of human herpesvirus 8/Kaposi's sarcoma-associated herpesvirus. J Virol. 76: 8252- 8264, 2002.

Deng H, A. Young, and R. Sun. Auto-activation of the rta gene of human herpesvirus-8/Kaposi's sarcoma-associated herpesvirus. J Gen Virol. 81: , 2000.

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