Recruitment of chromatin-modifying enzymes by CTIP2 promotes HIV-1 transcriptional silencing
Recruitment of chromatin-modifying enzymes by CTIP2 promotes HIV-1 transcriptional silencing
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DOI：
10.1038/sj.emboj.7601516
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发表时间：
2007-01-24
期刊：
影响因子：
11.4
通讯作者：
Rohr, Olivier
中科院分区：
文献类型：
--
作者：
Marban, Celine;Suzanne, Stella;Rohr, Olivier
在进入和逆转录之后，HIV-1基因组整合到宿主基因组中。与生产性感染的细胞相反，潜伏性感染的细胞通常含有整合在异染色质结构中的HIV-1基因组，从而使转录沉默的前病毒持续存在。小胶质细胞是中枢神经系统中主要的HIV-1靶细胞，并且构成病毒致病的重要储库。在目前的工作中，我们表明，在小胶质细胞中，共阻遏COUP-TF相互作用蛋白2（CTIP 2）招聘一个多酶染色质修饰复合物，并在HIV-1启动子建立异染色质环境。我们报告CTIP 2招募组蛋白去乙酰化酶（HDAC）1和HDAC 2，以促进HIV-1启动子区域的局部组蛋白H3去乙酰化。此外，DNA结合的CTIP 2还与组蛋白甲基转移酶SUV 39 H1结合，其增加局部组蛋白H3赖氨酸9甲基化。这允许同时募集HP 1蛋白到病毒启动子和形成局部异染色质，导致HIV-1沉默。总而言之，我们的发现揭示了从细胞库中清除潜伏的HIV-1病毒的新治疗机会。
Following entry and reverse transcription, the HIV-1 genome is integrated into the host genome. In contrast to productively infected cells, latently infected cells frequently harbor HIV-1 genomes integrated in heterochromatic structures, allowing persistence of transcriptionally silent proviruses. Microglial cells are the main HIV-1 target cells in the central nervous system and constitute an important reservoir for viral pathogenesis. In the present work, we show that, in microglial cells, the co-repressor COUP-TF interacting protein 2 (CTIP2) recruits a multienzymatic chromatin-modifying complex and establishes a heterochromatic environment at the HIV-1 promoter. We report that CTIP2 recruits histone deacetylase (HDAC) 1 and HDAC2 to promote local histone H3 deacetylation at the HIV-1 promoter region. In addition, DNA-bound CTIP2 also associates with the histone methyltransferase SUV39H1, which increases local histone H3 lysine 9 methylation. This allows concomitant recruitment of HP1 proteins to the viral promoter and formation of local heterochromatin, leading to HIV-1 silencing. Altogether, our findings uncover new therapeutic opportunities for purging latent HIV-1 viruses from their cellular reservoirs.