Epigenetic Histone Modification of Epstein-Barr Virus BZLF1 Promoter during Latency and Reactivation in Raji Cells
Epigenetic Histone Modification of Epstein-Barr Virus BZLF1 Promoter during Latency and Reactivation in Raji Cells
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DOI：
10.1128/jvi.06768-11
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发表时间：
2012-05-01
影响因子：
5.4
通讯作者：
Tsurumi, Tatsuya
中科院分区：
文献类型：
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作者：
Murata, Takayuki;Kondo, Yutaka;Tsurumi, Tatsuya
EB病毒(Epstein-Barr Virus，EBV)主要在B细胞中建立潜伏感染，病毒从潜伏状态重新激活依赖于病毒BZLF1蛋白的表达。BZLF1启动子(ZP)通常只表现出较低的基础活性，但在化学或生物诱导下被激活，如12-O-十四酰佛波醇-13-乙酸酯(TPA)、钙离子载体或组蛋白脱乙酰酶(HDAC)抑制剂。在一些潜伏感染EBV的细胞系中，单独使用HDAC抑制剂可以诱导BZLF1转录，而在其他细胞系，如B95-8或Raji细胞中，HDAC抑制剂不能增强BZLF1的表达，这表明除了组蛋白去乙酰化之外，这些细胞中的抑制机制尚不清楚。在这里，我们发现组蛋白H3赖氨酸27三甲基化(H3K27me3)、H3K9me2/ME3和H4K20me3在潜伏的Raji细胞中对BZLF1启动子进行了表观遗传修饰。在潜伏细胞中，组蛋白乙酰化和H3K4me3等活性标志物的水平很低，但在重新激活时会增加。H3K27me3和H4K20me3的抑制剂3-去氮杂环素A(DZNep)与HDAC抑制剂曲古抑素A(TSA)联合处理后，显著增强了Raji细胞中BZLF1的转录。H3K27me3或H4K20me3的组蛋白甲基转移酶Ezh2或Suv420h1的敲除进一步证明了甲基化对ZP的抑制。综上所述，这些结果表明，H3K27甲基化和H4K20甲基化至少部分参与了潜伏期的维持，组蛋白乙酰化和H3K4甲基化与Raji细胞中病毒的重新激活有关。
The Epstein-Barr virus (EBV) predominantly establishes latent infection in B cells, and the reactivation of the virus from latency is dependent on the expression of the viral BZLF1 protein. The BZLF1 promoter (Zp) normally exhibits only low basal activity but is activated in response to chemical or biological inducers, such as 12-O-tetradecanoylphorbol-13-acetate (TPA), calcium ionophores, or histone deacetylase (HDAC) inhibitors. In some cell lines latently infected with EBV, an HDAC inhibitor alone can induce BZLF1 transcription, while the treatment does not enhance expression in other cell lines, such as B95-8 or Raji cells, suggesting unknown suppressive mechanisms besides histone deacetylation in those cells. Here, we found the epigenetic modification of the BZLF1 promoter in latent Raji cells by histone H3 lysine 27 trimethylation (H3K27me3), H3K9me2/me3, and H4K20me3. Levels of active markers such as histone acetylation and H3K4me3 were low in latent cells but increased upon reactivation. Treatment with 3-deazaneplanocin A (DZNep), an inhibitor of H3K27me3 and H4K20me3, significantly enhanced the BZLF1 transcription in Raji cells when in combination with an HDAC inhibitor, trichostatin A (TSA). The knockdown of Ezh2 or Suv420h1, histone methyltransferases for H3K27me3 or H4K20me3, respectively, further proved the suppression of Zp by the methylations. Taken together, the results indicate that H3K27 methylation and H4K20 methylation are involved, at least partly, in the maintenance of latency, and histone acetylation and H3K4 methylation correlate with the reactivation of the virus in Raji cells.