CpG-methylation regulates a class of Epstein-Barr virus promoters.
CpG-methylation regulates a class of Epstein-Barr virus promoters.
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DOI：
10.1371/journal.ppat.1001114
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发表时间：
2010-09-23
期刊：
影响因子：
6.7
通讯作者：
Hammerschmidt W
中科院分区：
文献类型：
--
作者：
Bergbauer M;Kalla M;Schmeinck A;Göbel C;Rothbauer U;Eck S;Benet-Pagès A;Strom TM;Hammerschmidt W
DNA甲基化是真核生物基因组的主要修饰，在哺乳动物基因调控中起着重要作用。一般来说，胞嘧啶-磷脂酰-鸟苷（CpG）甲基化启动子转录受到抑制，核蛋白如MECP2、MBD1、MBD2和MBD4结合CpG甲基化的DNA并促进表观遗传沉默。病毒DNA的甲基化也调节eb病毒（EBV）的基因表达，eb病毒是疱疹病毒潜伏期的模型。在潜伏感染的人B细胞中，病毒DNA被cpg甲基化，大多数病毒基因被抑制，因此病毒合成被废除。EBV的BZLF1编码AP-1家族的转录因子（Zta），是克服病毒基因抑制的主基因。在全基因组筛选中，我们现在识别并表征了Zta调节的那些病毒基因。其中包括EBV裂解期所必需的基因，这些基因矛盾地依赖于严格的cpg甲基化启动子来进行zta诱导的表达。我们发现了新的DNA识别基序，称为meZRE（甲基-Zta反应元件），Zta选择性结合以甲基化和序列依赖的方式“读取”DNA，这与任何其他已知蛋白质不同。Zta是一种同型二聚体，但其与meZREs的结合特性表明，它是一种序列的、非回文的、两部分的DNA识别元件，与不含cpg的ZREs相比，它具有更好的DNA结合能力。我们的研究结果表明，Zta已经进化为反激活胞嘧啶甲基化，从而抑制沉默启动子，作为克服表观遗传沉默的规则。eb病毒（EBV）是人类肿瘤病毒和病毒潜伏期的模型。我们之前发现(i) EBV DNA在感染时未甲基化，但随着时间的推移被宿主B细胞甲基化，（ii） bzlf1编码的蛋白Zta （AP-1的表亲）诱导病毒裂解周期，但它更倾向于cpg甲基化的结合位点。因此，裂解期被推迟，直到病毒DNA发生了足够的甲基化。这种机制的分子基础尚未得到解决，但在全基因组筛选中，我们现在确定并表征了Zta调节的那些病毒基因。其中包括EBV裂解期所必需的基因，这些基因矛盾地依赖于严格的cpg甲基化启动子来进行zta诱导的表达。我们的研究结果表明，Zta已经进化为反激活胞嘧啶甲基化，从而抑制沉默启动子，作为克服表观遗传沉默的规则。通过这种方式，EBV病毒创造了自己的时间依赖性表观遗传开关，以控制其双相生命周期。
DNA methylation is the major modification of eukaryotic genomes and plays an essential role in mammalian gene regulation. In general, cytosine-phosphatidyl-guanosine (CpG)-methylated promoters are transcriptionally repressed and nuclear proteins such as MECP2, MBD1, MBD2, and MBD4 bind CpG-methylated DNA and contribute to epigenetic silencing. Methylation of viral DNA also regulates gene expression of Epstein-Barr virus (EBV), which is a model of herpes virus latency. In latently infected human B cells, the viral DNA is CpG-methylated, the majority of viral genes is repressed and virus synthesis is therefore abrogated. EBV's BZLF1 encodes a transcription factor of the AP-1 family (Zta) and is the master gene to overcome viral gene repression. In a genome-wide screen, we now identify and characterize those viral genes, which Zta regulates. Among them are genes essential for EBV's lytic phase, which paradoxically depend on strictly CpG-methylated promoters for their Zta-induced expression. We identified novel DNA recognition motifs, termed meZRE (methyl-Zta-responsive element), which Zta selectively binds in order to ‘read’ DNA in a methylation- and sequence-dependent manner unlike any other known protein. Zta is a homodimer but its binding characteristics to meZREs suggest a sequential, non-palindromic and bipartite DNA recognition element, which confers superior DNA binding compared to CpG-free ZREs. Our findings indicate that Zta has evolved to transactivate cytosine-methylated, hence repressed, silent promoters as a rule to overcome epigenetic silencing. Epstein-Barr virus (EBV) is a model of human tumor viruses and viral latency. We have found previously that (i) EBV DNA is unmethylated upon infection, but becomes methylated over time by the host B cell, and (ii) the BZLF1-encoded protein, Zta (a cousin to AP-1), induces the viral lytic cycle, but it prefers binding sites that are CpG-methylated. As a consequence, the lytic phase gets delayed until enough methylation of viral DNA has occurred. The molecular basis of this mechanism has not been addressed but in a genome-wide screen, we now identify and characterize those viral genes, which Zta regulates. Among them are genes essential for EBV's lytic phase, which paradoxically depend on strictly CpG-methylated promoters for their Zta-induced expression. Our findings indicate that Zta has evolved to transactivate cytosine-methylated, hence repressed, silent promoters as a rule to overcome epigenetic silencing. In this way, the EBV virus has created its own time-dependent, epigenetic switch to control its biphasic life cycle.
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影响因子：
64.5
作者：
Guenther, Matthew G.;Levine, Stuart S.;Young, Richard A.
通讯作者：
Young, Richard A.
影响因子：
3.7
作者：
Granato, M;Farina, A;Angeloni, A
通讯作者：
Angeloni, A
影响因子：
11.4
作者：
CHEVALLIERGRECO, A;MANET, E;SERGEANT, A
通讯作者：
SERGEANT, A
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
模因套件：用于发现和搜索的工具。
影响因子：
14.9
作者：
Bailey TL;Boden M;Buske FA;Frith M;Grant CE;Clementi L;Ren J;Li WW;Noble WS
通讯作者：
Noble WS