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首页> 外文期刊>Molecular and Cellular Biology >Transcriptional activation of the Epstein-Barr virus latency C promoter after 5-azacytidine treatment: evidence that demethylation at a single CpG site is crucial.
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Transcriptional activation of the Epstein-Barr virus latency C promoter after 5-azacytidine treatment: evidence that demethylation at a single CpG site is crucial.

机译：5-氮胞苷处理后爱泼斯坦-巴尔病毒潜伏期C启动子的转录激活：证据表明单个CpG位点的去甲基化至关重要。

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摘要

The Epstein-Barr Virus (EBV) latency C promoter (Cp) is the origin of transcripts for six viral proteins. The promoter is active in lymphoblastoid B-cell lines but silent in many EBV-associated tumors and tumor cell lines. In these latter cell lines, the viral episome is hypermethylated in the vicinity of this promoter. We show that in such a cell line (Rael, a Burkitt's lymphoma line), 5-azacytidine inhibits DNA methyltransferase, brings about demethylation of EBV genomes, activates Cp transcription, and induces the expression of EBNA-2. Investigation of the phenomenon demonstrates the importance of the methylation status of a particular CpG site for the regulation of the Cp: (i) genomic sequencing shows that this site is methylated when the Cp is inactive and is not methylated when the promoter is active; (ii) methylation or transition mutation at this site abolishes complex formation with a cellular binding activity (CBF2) as determined by electrophoretic mobility shift analyses, competition binding analyses, and DNase I footprinting; and (iii) a single C --> T transition mutation at this site is associated with a marked reduction (> 50-fold) of transcriptional activity in a reporter plasmid. Thus, the CBF2 binding activity is shown to be methylation sensitive and crucial to EBNA-2-mediated activation of the Cp.
机译：爱泼斯坦巴尔病毒（EBV）潜伏期C启动子（Cp）是六个病毒蛋白转录本的起源。该启动子在淋巴母细胞B细胞系中有活性，但在许多与EBV相关的肿瘤和肿瘤细胞系中却沉默。在这些后面的细胞系中，病毒附加体在该启动子附近被高度甲基化。我们显示，在这样的细胞系（Rael，伯基特氏淋巴瘤系）中，5-氮杂胞苷抑制DNA甲基转移酶，导致EBV基因组脱甲基，激活Cp转录，并诱导EBNA-2的表达。对该现象的研究表明，特定CpG位点的甲基化状态对于调节Cp至关重要：（i）基因组测序表明，当Cp失活时，该位点被甲基化，而启动子活跃时未被甲基化; （ii）通过电泳迁移率迁移分析，竞争结合分析和DNase I足迹测定，该位点的甲基化或转移突变消除了具有细胞结合活性（CBF2）的复合物形成; （iii）在该位点的一个单一的C-> T转换突变与报告质粒中转录活性的显着降低（> 50倍）有关。因此，CBF2结合活性显示出对甲基化敏感，对EBNA-2介导的Cp激活至关重要。

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