Methylation profiling of Epstein-Barr virus immediate-early gene promoters, BZLF1 and BRLF1 in tumors of epithelial, NK- and B-cell origins.
Methylation profiling of Epstein-Barr virus immediate-early gene promoters, BZLF1 and BRLF1 in tumors of epithelial, NK- and B-cell origins.
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上皮细胞、NK 细胞和 B 细胞来源的肿瘤中 Epstein-Barr 病毒立即早期基因启动子、BZLF1 和 BRLF1 的甲基化分析。
DOI：
10.1186/1471-2407-12-125
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发表时间：
2012-03-29
期刊：
影响因子：
3.8
通讯作者：
Tao Q
中科院分区：
文献类型：
--
作者：
Li L;Su X;Choi GC;Cao Y;Ambinder RF;Tao Q
EB病毒（EBV）在EBV相关恶性肿瘤中潜伏，偶尔伴有再活化的裂解周期。EB病毒基因组启动子区CpG甲基化在维持病毒潜伏期中起重要作用。两个立即早期（IE）基因，BZLF 1和BRLF 1，诱导从潜伏性到溶解性感染的转换。关于BZLF 1和BRLF 1与EBV启动子的甲基化依赖性结合的研究已经有了很好的报道，但是关于肿瘤样品中BZLF 1和BRLF 1启动子（Zp和Rp）的甲基化状态知之甚少。我们通过甲基化特异性PCR（MSP）和亚硫酸氢盐基因组测序（BGS）评估了Zp和Rp的甲基化谱，以及通过半定量逆转录（RT）-PCR评估了上皮、NK和B细胞来源肿瘤中BZLF 1和BRLF 1的表达。我们发现，在所有研究的EBV阳性细胞系和淋巴（B-或NK细胞）或上皮来源的肿瘤中，Zp和Rp均高度甲基化，而在表达BZLF 1和BRLF 1的细胞系中检测到未甲基化的Zp和Rp等位基因。在氮杂胞苷治疗或与阿司他丁A（TSA）联合治疗后，BZLF 1和BRLF 1的表达沿着伴随的启动子去甲基化而恢复，随后诱导早期裂解基因BHRF 1和晚期裂解基因BLLF 1的重新激活。Zp和Rp的超甲基化介导了EB病毒相关肿瘤中BZLF 1和BRLF 1的频繁沉默，这些沉默可以被去甲基化剂重新激活，并最终启动EB病毒裂解级联反应。
Epstein-Barr virus (EBV) establishes its latency in EBV-associated malignancies, accompanied by occasionally reactivated lytic cycle. Promoter CpG methylation of EBV genome plays an essential role in maintaining viral latency. Two immediate-early (IE) genes, BZLF1 and BRLF1, induce the switch from latent to lytic infection. Studies of methylation-dependent binding of BZLF1 and BRLF1 to EBV promoters have been well reported, but little is known about the methylation status of BZLF1 and BRLF1 promoters (Zp and Rp) in tumor samples. We evaluated the methylation profiles of Zp and Rp by methylation-specific PCR (MSP) and bisulfite genomic sequencing (BGS), as well as BZLF1 and BRLF1 expression by semiquantitative reverse transcription (RT)-PCR in tumors of epithelial, NK- and B-cell origins. We found that both Zp and Rp were hypermethylated in all studied EBV-positive cell lines and tumors of lymphoid (B- or NK cell) or epithelial origin, while unmethylated Zp and Rp alleles were detected in cell lines expressing BZLF1 and BRLF1. Following azacytidine treatment or combined with trichostatin A (TSA), the expression of BZLF1 and BRLF1 was restored along with concomitant promoter demethylation, which subsequently induced the reactivation of early lytic gene BHRF1 and late lytic gene BLLF1. Hypermethylation of Zp and Rp mediates the frequent silencing of BZLF1 and BRLF1 in EBV-associated tumors, which could be reactivated by demethylation agent and ultimately initiated the EBV lytic cascade.
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影响因子：
3.7
作者：
Flower K;Hellen E;Newport MJ;Jones S;Sinclair AJ
通讯作者：
Sinclair AJ
影响因子：
45.3
作者：
Luebbert, Michael;Suciu, Stefan;Wijermans, Pierre W.
通讯作者：
Wijermans, Pierre W.
影响因子：
12.7
作者：
Oh, Sang Taek;Cha, Jung-Ho;Lee, Suk Kyeong
通讯作者：
Lee, Suk Kyeong
影响因子：
11.2
作者：
Cheng, Yingduan;Geng, Hua;Tao, Qian
通讯作者：
Tao, Qian
DOI：
10.1099/vir.0.007922-0
发表时间：
2009-06
期刊：
The Journal of general virology
影响因子：
--
作者：
Heather J;Flower K;Isaac S;Sinclair AJ
通讯作者：
Sinclair AJ