BACKGROUND High-risk HPV is a causative factor of cervical cancer. HPV DNA fragments integrate into host genome resulting in the constitutive expression of HPV genes E6 and E7 under the regulation of transcription factors, such as p300 and Tip60. Interestingly, Tip60, a factor with HAT (histone acetyl transferase) activity, represses HPV18 E6/E7 genes while another HAT p300 activates the transcription of HPV18 E6/E7. OBJECTIVE To explore the mechanism for the opposite roles of Tip60 and p300 in the virus gene regulation, and the influence of Tip60 and p300 in histone modifications in the regulatory sequence of HPV18 genes. METHODS Tip60 or p300 was either knocked down or overexpressed in HeLa cells. The effects on HPV E6E7 expression were determined with RT-qPCR. The association of RNA polymerase II and the enrichment of acetylated or methylated histones in HPV promoter region were measured by ChIP assays with specific antibodies. RESULTS ChIP results showed that Tip60 and p300 differently affected the modifications of histone H3K9 and the deposition of nucleosomes in HPV18 long control region (LCR). HPV18 LCR in HeLa cells is bivalent chromatin carrying both the active histone H3K9 acetylation mark and the repressive histone H3K9 trimethylation mark, the balance is maintained by Tip60 and p300. CONCLUSION(S) Based on the roles of Tip60 and p300 in HPV gene regulation, chemical compounds targeting Tip60 or p300 are potential anti-cervical cancer drugs.

中文翻译：

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Tip60和p300在子宫颈癌HeLa细胞中HPV18 E6 / E7基因的表观遗传调控中具有拮抗作用。

背景技术高危HPV是宫颈癌的病因。HPV DNA片段整合到宿主基因组中，导致HPV基因E6和E7在转录因子（例如p300和Tip60）的调控下组成型表达。有趣的是，具有HAT（组蛋白乙酰基转移酶）活性的因子Tip60抑制HPV18 E6 / E7基因，而另一个HAT p300激活HPV18 E6 / E7的转录。目的探讨Tip60和p300在病毒基因调控中的相反作用机理，以及Tip60和p300在HPV18基因调控序列中组蛋白修饰中的作用。方法Tip60或p300在HeLa细胞中被敲低或过表达。用RT-qPCR确定对HPV E6E7表达的影响。RNA聚合酶II的结合和HPV启动子区域乙酰化或甲基化组蛋白的富集通过ChIP测定法用特异性抗体进行测定。结果ChIP结果显示Tip60和p300对HPV18长控制区（LCR）中组蛋白H3K9的修饰和核小体沉积的影响不同。HeLa细胞中的HPV18 LCR是带有活性组蛋白H3K9乙酰化标记和抑制性组蛋白H3K9三甲基化标记的二价染色质，Tip60和p300保持平衡。结论基于Tip60和p300在HPV基因调控中的作用，靶向Tip60或p300的化合物是潜在的抗宫颈癌药物。结果ChIP结果显示Tip60和p300对HPV18长控制区（LCR）中组蛋白H3K9的修饰和核小体沉积的影响不同。HeLa细胞中的HPV18 LCR是带有活性组蛋白H3K9乙酰化标记和抑制性组蛋白H3K9三甲基化标记的二价染色质，Tip60和p300保持平衡。结论基于Tip60和p300在HPV基因调控中的作用，靶向Tip60或p300的化合物是潜在的抗宫颈癌药物。结果ChIP结果显示Tip60和p300对HPV18长控制区（LCR）中组蛋白H3K9的修饰和核小体沉积的影响不同。HeLa细胞中的HPV18 LCR是带有活性组蛋白H3K9乙酰化标记和抑制性组蛋白H3K9三甲基化标记的二价染色质，Tip60和p300保持平衡。结论基于Tip60和p300在HPV基因调控中的作用，靶向Tip60或p300的化合物是潜在的抗宫颈癌药物。