G-tract RNA removes Polycomb repressive complex 2 from genes
G-tract RNA removes Polycomb repressive complex 2 from genes
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DOI：
10.1038/s41594-019-0293-z
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发表时间：
2019-10-01
影响因子：
16.8
通讯作者：
Jenner, Richard G.
中科院分区：
文献类型：
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作者：
Beltran, Manuel;Tavares, Manuel;Jenner, Richard G.
多梳抑制复合体2(PRC2)维持对特定细胞类型基因的抑制，但也与癌症中的异位基因相关。虽然目前还不清楚PrC2是如何从基因中移除的，但这种知识将有助于有针对性地逆转有害的PrC2招募活动。在这里，我们展示了G-Track RNA特异性地从人类和小鼠细胞的基因中移除PRC2。PRC2优先结合新生的前体mRNA内的G链，特别是在预测的G-四链结构中。G-四链RNA将PRC2催化核心从底物核小体中逐出。在细胞中，当基因激活时，PRC2从染色质转移到前mRNA，染色质相关的G-Track RNA去除PRC2，导致H3K27me3从基因中耗尽。在恶性横纹肌样瘤细胞中，针对肿瘤抑制基因CDKN2A的G-TRAIL RNA重新激活该基因并诱导衰老。这些数据支持一种模型，在该模型中，前mRNA在基因激活期间驱逐PRC2，并提供了选择性地从特定基因中移除PRC2的方法。
Polycomb repressive complex 2 (PRC2) maintains repression of cell-type-specific genes but also associates with genes ectopically in cancer. While it is currently unknown how PRC2 is removed from genes, such knowledge would be useful for the targeted reversal of deleterious PRC2 recruitment events. Here, we show that G-tract RNA specifically removes PRC2 from genes in human and mouse cells. PRC2 preferentially binds G tracts within nascent precursor mRNA (pre-mRNA), especially within predicted G-quadruplex structures. G-quadruplex RNA evicts the PRC2 catalytic core from the substrate nucleosome. In cells, PRC2 transfers from chromatin to pre-mRNA upon gene activation, and chromatin-associated G-tract RNA removes PRC2, leading to H3K27me3 depletion from genes. Targeting G-tract RNA to the tumor suppressor gene CDKN2A in malignant rhabdoid tumor cells reactivates the gene and induces senescence. These data support a model in which pre-mRNA evicts PRC2 during gene activation and provides the means to selectively remove PRC2 from specific genes.