Long noncoding RNA MALAT1 releases epigenetic silencing of HIV-1 replication by displacing the polycomb repressive complex 2 from binding to the LTR promoter
Long noncoding RNA MALAT1 releases epigenetic silencing of HIV-1 replication by displacing the polycomb repressive complex 2 from binding to the LTR promoter
复制标题
长非编码RNA MALAT1通过取代多梳抑制复合物2与LTR启动子的结合来释放HIV-1复制的表观遗传沉默
DOI：
10.1093/nar/gkz117
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发表时间：
2019-04-08
影响因子：
14.9
通讯作者：
Wang, Jian-Hua
中科院分区：
文献类型：
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作者：
Qu, Di;Sun, Wei-Wei;Wang, Jian-Hua
摘要长链非编码RNA（lncRNA）可以抑制或激活HIV-1的复制和潜伏期，然而，其作用的具体机制并不总是清楚的。在HIV-1感染的CD 4 + T细胞中，我们进行了RNA测序（RNA-Seq）分析，发现了MALAT 1（转移相关肺腺癌转录本1）的上调，这是一种先前在癌细胞中描述的与癌症发病机制相关的lncRNA。此外，我们发现MALAT 1促进了HIV-1的转录和感染，因为CRISPR/Cas9对它的敲低显著降低了HIV-1长末端重复序列（LTR）驱动的基因转录和病毒复制。在机制上，通过与染色质调节剂多梳抑制复合物2（PRC 2）的结合，MALAT 1使zeste同源物2的核心组分增强子（EZH 2）脱离与HIV-1 LTR启动子的结合，从而去除PRC 2复合物介导的组蛋白H3在赖氨酸27（H3 K27 me 3）上的甲基化，并减轻HIV-1转录的表观遗传沉默。此外，潜伏逆转剂（LRA）刺激的HIV-1的再激活诱导MALAT 1在潜伏感染细胞中的表达。成功的联合抗逆转录病毒治疗（cART）伴随着显着减少MALAT 1表达的患者，表明MALAT 1表达与HIV-1复制呈正相关。我们的数据已经确定MALAT 1作为HIV-1转录的启动子，并表明MALAT 1可能成为开发新疗法的靶点。
Abstract Long noncoding RNAs (lncRNAs) may either repress or activate HIV-1 replication and latency; however, specific mechanisms for their action are not always clear. In HIV-1 infected CD4+ T cells, we performed RNA-Sequencing (RNA-Seq) analysis and discovered an up-regulation of MALAT1 (metastasis-associated lung adenocarcinoma transcript 1), an lncRNA previously described in cancer cells that associate with cancer pathogenesis. Moreover, we found that MALAT1 promoted HIV-1 transcription and infection, as its knockdown by CRISPR/Cas9 markedly reduced the HIV-1 long terminal repeat (LTR)-driven gene transcription and viral replication. Mechanistically, through an association with chromatin modulator polycomb repressive complex 2 (PRC2), MALAT1 detached the core component enhancer of zeste homolog 2 (EZH2) from binding with HIV-1 LTR promoter, and thus removed PRC2 complex-mediated methylation of histone H3 on lysine 27 (H3K27me3) and relieved epigenetic silencing of HIV-1 transcription. Moreover, the reactivation of HIV-1 stimulated with latency reversal agents (LRAs) induced MALAT1 expression in latently infected cells. Successful combination antiretroviral therapy (cART) was accompanied by significantly diminished MALAT1 expression in patients, suggesting a positive correlation of MALAT1 expression with HIV-1 replication. Our data have identified MALAT1 as a promoter of HIV-1 transcription, and suggested that MALAT1 may be targeted for the development of new therapeutics.