The JAZF1-SUZ12 fusion protein disrupts PRC2 complexes and impairs chromatin repression during human endometrial stromal tumorogenesis.
The JAZF1-SUZ12 fusion protein disrupts PRC2 complexes and impairs chromatin repression during human endometrial stromal tumorogenesis.
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DOI：
10.18632/oncotarget.13270
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发表时间：
2017-01-17
期刊：
影响因子：
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通讯作者：
Sklar JL
中科院分区：
文献类型：
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作者：
Ma X;Wang J;Wang J;Ma CX;Gao X;Patriub V;Sklar JL
Polycomb抑制复合物2（PRC 2）包含三个核心蛋白EZH 2、EED和SUZ 12，通过组蛋白3上赖氨酸27的三甲基化来控制染色质致密化和转录抑制。（7）; 17）（p15; q21）染色体易位存在于大多数子宫内膜间质肉瘤（ESS）病例中，导致JAZF 1和SUZ 12基因的框内融合。我们研究了融合蛋白JAZF 1-SUZ 12是否以及如何在功能上改变PRC 2。我们发现融合蛋白在含有t（7;17）的ESS中以高水平存在。共瞬时转染实验表明JAZF 1-SUZ 12使PRC 2组分EZH 2和EED不稳定，导致组蛋白甲基转移酶（HMT）活性降低，这通过使用重建的PRC 2和核小体阵列底物的体外研究证实。我们还证明了含有融合蛋白的PRC 2降低了与靶染色质基因座的结合亲和力。此外，我们发现，在ESS样品中，H3 K27的三甲基化降低，t（7;17），但在这些组织中，H3 K9没有检测到变化。此外，SUZ 12在Suz 12（-/-）ES细胞中的重新表达挽救了神经元分化，而融合蛋白未能恢复这种功能并增强了细胞增殖。总之，我们的研究表明，JAZF 1-SUZ 12融合蛋白破坏PRC 2复合物，消除HMT活性，随后激活通常被PRC 2抑制的染色质/基因。PRC 2的这种功能异常抑制ES细胞的正常神经分化，并促进细胞增殖。JAZF-SUZ 12蛋白在子宫内膜间质细胞中诱导的相关变化可以解释t（7;17）在ESS中的致癌作用。
The Polycomb repressive complex 2 (PRC2), which contains three core proteins EZH2, EED and SUZ12, controls chromatin compaction and transcription repression through trimethylation of lysine 27 on histone 3. The (7;17)(p15;q21) chromosomal translocation present in most cases of endometrial stromal sarcomas (ESSs) results in the in-frame fusion of the JAZF1 and SUZ12 genes. We have investigated whether and how the fusion protein JAZF1-SUZ12 functionally alters PRC2. We found that the fusion protein exists at high levels in ESS containing the t(7;17). Co-transient transfection assay indicated JAZF1-SUZ12 destabilized PRC2 components EZH2 and EED, resulting in decreased histone methyl transferase (HMT) activity, which was confirmed by in vitro studies using reconstituted PRC2 and nucleosome array substrates. We also demonstrated the PRC2 containing the fusion protein decreased the binding affinity to target chromatin loci. In addition, we found that trimethylation of H3K27 was decreased in ESS samples with the t(7;17), but there was no detectable change in H3K9 in these tissues. Moreover, re-expression of SUZ12 in Suz12 (−/−) ES cells rescued the neuronal differentiation while the fusion protein failed to restore this function and enhanced cell proliferation. In summary, our studies reveal that JAZF1-SUZ12 fusion protein disrupts the PRC2 complex, abolishes HMT activity and subsequently activates chromatin/genes normally repressed by PRC2. Such dyesfunction of PRC2 inhibits normal neural differentiation of ES cell and increases cell proliferation. Related changes induced by the JAZF-SUZ12 protein in endometrial stromal cells may explain the oncogenic effect of the t(7;17) in ESS.