Chromosomal translocations frequently promote carcinogenesis by producing gain-of-function fusion proteins. Recent studies have identified highly recurrent chromosomal translocations in patients with endometrial stromal sarcomas (ESSs) and ossifying fibromyxoid tumors (OFMTs), leading to an in-frame fusion of PHF1 (PCL1) to six different subunits of the NuA4/TIP60 complex. While NuA4/TIP60 is a coactivator that acetylates chromatin and loads the H2A.Z histone variant, PHF1 is part of the Polycomb repressive complex 2 (PRC2) linked to transcriptional repression of key developmental genes through methylation of histone H3 on lysine 27. In this study, we characterize the fusion protein produced by the EPC1-PHF1 translocation. The chimeric protein assembles a megacomplex harboring both NuA4/TIP60 and PRC2 activities and leads to mislocalization of chromatin marks in the genome, in particular over an entire topologically associating domain including part of the HOXD cluster. This is linked to aberrant gene expression—most notably increased expression of PRC2 target genes. Furthermore, we show that JAZF1—implicated with a PRC2 component in the most frequent translocation in ESSs, JAZF1-SUZ12—is a potent transcription activator that physically associates with NuA4/TIP60, its fusion creating outcomes similar to those of EPC1-PHF1. Importantly, the specific increased expression of PRC2 targets/HOX genes was also confirmed with ESS patient samples. Altogether, these results indicate that most chromosomal translocations linked to these sarcomas use the same molecular oncogenic mechanism through a physical merge of NuA4/TIP60 and PRC2 complexes, leading to mislocalization of histone marks and aberrant Polycomb target gene expression.

中文翻译：

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肉瘤中反复发生的染色体易位会产生一个巨型复合体，将 NuA4/TIP60 错误定位到 Polycomb 靶位点

染色体易位经常通过产生功能获得性融合蛋白促进癌变。最近的研究已经确定了子宫内膜间质肉瘤 (ESS) 和骨化性纤维粘液样肿瘤 (OFMT) 患者的高度复发性染色体易位，导致 PHF1 (PCL1) 与 NuA4/TIP60 复合体的六个不同亚基框内融合。虽然 NuA4/TIP60 是乙酰化染色质并加载 H2A.Z 组蛋白变体的共激活剂，但 PHF1 是 Polycomb 抑制复合物 2 (PRC2) 的一部分，通过组蛋白 H3 在赖氨酸 27 上的甲基化与关键发育基因的转录抑制相关。研究，我们表征了EPC1 - PHF1产生的融合蛋白易位。嵌合蛋白组装了一个包含 NuA4/TIP60 和 PRC2 活性的巨型复合体，并导致基因组中染色质标记的错误定位，特别是在包括HOXD簇的一部分在内的整个拓扑关联域上。这与异常基因表达有关——最显着的是 PRC2 靶基因表达增加。此外，我们表明 JAZF1（与 ESS 中最频繁的易位JAZF1-SUZ12中的 PRC2 成分有关）是一种有效的转录激活因子，与 NuA4/TIP60 物理结合，其融合产生的结果与EPC1-PHF1的结果相似。重要的是，PRC2 目标/ HOX的特定表达增加基因也通过 ESS 患者样本得到证实。总之，这些结果表明，与这些肉瘤相关的大多数染色体易位通过 NuA4/TIP60 和 PRC2 复合物的物理合并使用相同的分子致癌机制，导致组蛋白标记的错误定位和异常的 Polycomb 靶基因表达。