A role for EZH2 in silencing of IFN-γ inducible MHC2TA transcription in uveal melanoma
A role for EZH2 in silencing of IFN-γ inducible MHC2TA transcription in uveal melanoma
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DOI：
10.4049/jimmunol.179.8.5317
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发表时间：
2007-10-15
影响因子：
4.4
通讯作者：
Van den Elsen, Peter J.
中科院分区：
文献类型：
--
作者：
Holling, Tjadine M.;Bergevoet, Marloes W. T.;Van den Elsen, Peter J.
我们研究了表观遗传机制在葡萄膜黑色素瘤中MHC2TA转录沉默中的作用。虽然没有观察到ifn - γ诱导后CIITA转录物水平受损与MHC2TA启动子IV (CIITA- piv) DNA甲基化之间的相关性，但发现CIITA- piv染色质中高水平的三甲基化组蛋白h3 -赖氨酸27 （3Me-K27-H3）存在关联。3Me-K27-H3修饰与RNA聚合酶ii招募到CIITA-PIV的强烈减少相关。有趣的是，我们观察到这些表观遗传修饰都没有影响激活转录因子对该启动子的募集。随后，我们证明了CIITA-PIV染色质中存在组蛋白甲基转移酶EZH2，该酶已知是Polycomb抑制复合体2的一个组成部分，并且能够三甲基化组蛋白h3 -赖氨酸27。RNA干扰介导的EZH2表达下调导致ifn - γ诱导后CIITA转录物水平升高。因此，我们的数据表明EZH2有助于抑制葡萄膜黑色素瘤细胞中ifn - γ诱导的MHC2TA转录。
We investigated the contribution of epigenetic mechanisms in MHC2TA transcriptional silencing in uveal melanoma. Although no correlation was observed between impaired CIITA transcript levels after IFN-gamma induction and DNA methylation of MHC2TA promoter IV (CIITA-PIV), an association was found with high levels of trimethylated histone H3-lysine 27 (3Me-K27-H3) in CIITA-PIV chromatin. The 3Me-K27-H3 modification correlated with a strong reduction in RNA polymerase II-recruitment to CIITA-PIV. Interestingly, we observed that none of these epigenetic modifications affected recruitment of activating transcription factors to this promoter. Subsequently, we demonstrated the presence of the histone methyltransferase EZH2 in CIITA-PIV chromatin, which is known to be a component of the Polycomb repressive complex 2 and able to triple methylate histone H3-lysine 27. RNA interference-mediated down-regulation of EZH2 expression resulted in an increase in CIITA transcript levels after IFN-gamma induction. Our data therefore reveal that EZH2 contributes to silencing of IFN-gamma-inducible transcription of MHC2TA in uveal melanoma cells.