Epigenetic Silencing of HIV-1 by the Histone H3 Lysine 27 Methyltransferase Enhancer of Zeste 2
Epigenetic Silencing of HIV-1 by the Histone H3 Lysine 27 Methyltransferase Enhancer of Zeste 2
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DOI：
10.1128/jvi.00836-11
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发表时间：
2011-09-01
影响因子：
5.4
通讯作者：
Karn, Jonathan
中科院分区：
文献类型：
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作者：
Friedman, Julia;Cho, Won-Kyung;Karn, Jonathan
由于位于病毒长末端重复序列（LTR）的组蛋白去乙酰化和甲基化，潜伏的艾滋病病毒原病毒处于沉默状态。抑制组蛋白去乙酰化酶（HDACs）会导致艾滋病病毒 - 1从潜伏期重新出现，但组蛋白赖氨酸甲基转移酶（HKMTs）对维持艾滋病病毒潜伏期的作用仍不确定。利用潜伏感染的Jurkat T细胞系进行的染色质免疫沉淀实验表明，EZH2（Zeste 2增强子）这种HKMT在沉默的艾滋病病毒原病毒的LTR处大量存在，并且在原病毒重新激活后迅速移位。EZH2是多梳抑制复合物2（PRC2）沉默机制的关键成分，也是三甲基组蛋白赖氨酸27（H3K27me3）合成所需的酶，敲低EZH2可诱导多达40%的潜伏艾滋病病毒原病毒。相比之下，敲低H3K9me3合成所需的SUV39H1后，潜伏原病毒的诱导率不到5%。敲低EZH2还使潜伏原病毒对外部刺激（如T细胞受体刺激）敏感，并减缓重新激活的原病毒恢复到潜伏期的过程。同样，对外部刺激反应不佳的细胞群所携带的艾滋病病毒原病毒富含H3K27me3，而相对缺乏H3K9me3。用针对EZH2的HKMT抑制剂3 - 去氮杂腺苷A处理潜伏感染的细胞，会导致沉默的原病毒重新激活，而毛壳菌素和BIX01294仅显示出极小的重新激活活性。这些发现表明，PRC2介导的沉默是艾滋病病毒潜伏期的一个重要特征，并且组蛋白甲基化抑制剂在旨在根除潜伏艾滋病病毒库的诱导策略中可能发挥有益作用。
Latent HIV proviruses are silenced as the result of deacetylation and methylation of histones located at the viral long terminal repeat (LTR). Inhibition of histone deacetylases (HDACs) leads to the reemergence of HIV-1 from latency, but the contribution of histone lysine methyltransferases (HKMTs) to maintaining HIV latency remains uncertain. Chromatin immunoprecipitation experiments using latently infected Jurkat T-cell lines demonstrated that the HKMT enhancer of Zeste 2 (EZH2) was present at high levels at the LTR of silenced HIV proviruses and was rapidly displaced following proviral reactivation. Knockdown of EZH2, a key component of the Polycomb repressive complex 2 (PRC2) silencing machinery, and the enzyme which is required for trimethyl histone lysine 27 (H3K27me3) synthesis induced up to 40% of the latent HIV proviruses. In contrast, there was less than 5% induction of latent proviruses following knockdown of SUV39H1, which is required for H3K9me3 synthesis. Knockdown of EZH2 also sensitized latent proviruses to external stimuli, such as T-cell receptor stimulation, and slowed the reversion of reactivated proviruses to latency. Similarly, cell populations that responded poorly to external stimuli carried HIV proviruses that were enriched in H3K27me3 and relatively depleted in H3K9me3. Treating latently infected cells with the HKMT inhibitor 3-deazaneplanocin A, which targets EZH2, led to the reactivation of silenced proviruses, whereas chaetocin and BIX01294 showed only minimal reactivation activities. These findings suggest that PRC2-mediated silencing is an important feature of HIV latency and that inhibitors of histone methylation may play a useful role in induction strategies designed to eradicate latent HIV pools.