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首页> 外文期刊>Epigenetics: official journal of the DNA Methylation Society >A key role for EZH2 in epigenetic silencing of HOX genes in mantle cell lymphoma
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A key role for EZH2 in epigenetic silencing of HOX genes in mantle cell lymphoma

机译:EZH2在套细胞淋巴瘤HOX基因表观遗传沉默中的关键作用

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摘要

The chromatin modifier EZH2 is overexpressed and associated with inferior outcome in mantle cell lymphoma (MCL). Recently, we demonstrated preferential DNA methylation of HOX genes in MCL compared with chronic lymphocytic leukemia (CLL), despite these genes not being expressed in either entity. Since EZH2 has been shown to regulate HOX gene expression, to gain further insight into its possible role in differential silencing of HOX genes in MCL vs. CLL, we performed detailed epigenetic characterization using representative cell lines and primary samples. We observed significant overexpression of EZH2 in MCL vs. CLL. Chromatin immune precipitation (ChIP) assays revealed that EZH2 catalyzed repressive H3 lysine 27 trimethylation (H3K27me3), which was sufficient to silence HOX genes in CLL, whereas in MCL H3K27me3 is accompanied by DNA methylation for a more stable repression. More importantly, hypermethylation of the HOX genes in MCL resulted from EZH2 overexpression and subsequent recruitment of the DNA methylation machinery onto HOX gene promoters. The importance of EZH2 upregulation in this process was further underscored by siRNA transfection and EZH2 inhibitor experiments. Altogether, these observations implicate EZH2 in the long-term silencing of HOX genes in MCL, and allude to its potential as a therapeutic target with clinical impact.
机译:染色质修饰剂EZH2在套细胞淋巴瘤(MCL)中过表达并且与不良预后相关。最近,我们证明了与慢性淋巴细胞性白血病(CLL)相比,MCL中HOX基因的优先DNA甲基化,尽管这些基因在任何一个实体中均未表达。由于已显示EZH2可以调节HOX基因的表达,以进一步了解其在MCL与CLL中HOX基因差异沉默中的可能作用,因此我们使用代表性细胞系和原代样品进行了详细的表观遗传学表征。我们观察到在MCL与CLL中EZH2明显过表达。染色质免疫沉淀(ChIP)分析表明EZH2催化了H3赖氨酸27抑制性三甲基化(H3K27me3),足以使CLL中的HOX基因沉默,而在MCL中,H3K27me3伴随有DNA甲基化,可实现更稳定的抑制。更重要的是,MCL中HOX基因的超甲基化是由于EZH2的过表达和随后DNA甲基化机制在HOX基因启动子上的募集所致。 siRNA转染和EZH2抑制剂实验进一步强调了EZH2上调在这一过程中的重要性。总而言之,这些观察结果暗示了EZH2与MCL中HOX基因的长期沉默有关,并暗示了其作为具有临床影响的治疗靶标的潜力。

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