Nuclear condensates of YAP fusion proteins alter transcription to drive ependymoma tumourigenesis
Nuclear condensates of YAP fusion proteins alter transcription to drive ependymoma tumourigenesis
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YAP 融合蛋白的核凝聚物改变转录以驱动室管膜瘤肿瘤发生
DOI：
10.1038/s41556-022-01069-6
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发表时间：
2023-02-02
影响因子：
21.3
通讯作者：
Lu, Q. Richard
中科院分区：
文献类型：
--
作者：
Hu, Xiaohua;Wu, Xiaoping;Lu, Q. Richard
HIPPO-YAP融合蛋白的核定位与幕上室管膜瘤的发生有关。在这里，出乎意料的是，我们发现，液-液相分离，而不是核定位，复发性患者源性雅普融合，YAP-MAMLD 1和C11 ORF 95-雅普，是神经祖细胞室管膜瘤肿瘤发生的基础。突变和嵌合体分析表明，一个内在的无序区域促进低聚化的雅普融合成核，点状，无膜的凝聚物。雅普与转录激活因子GCN 4的卷曲螺旋结构域融合诱导的寡聚化和核凝聚物也促进室管膜瘤形成。YAP-MAMLD 1将转录因子和共激活因子（包括BRD 4、MED 1和TEAD）浓缩在浓缩物中，同时排除转录抑制PRC 2，并诱导促进转录和致癌程序的长距离增强子-启动子相互作用。阻断缩合物介导的转录辅激活因子活性可抑制肿瘤发生，表明液相分离对室管膜瘤中雅普融合致癌活性的关键作用。含有内在无序区域特征的雅普融合体在人类肿瘤中很常见，这表明核浓缩物可以靶向治疗YAP融合体诱导的癌症。Hu等人报道，患者来源的雅普融合蛋白在细胞核中经历液-液相分离以驱动室管膜瘤肿瘤发生，通过转录因子募集和基因组甲基化的改变来改变转录。
Nuclear localization of HIPPO-YAP fusion proteins has been implicated in supratentorial ependymoma development. Here, unexpectedly, we find that liquid-liquid phase separation, rather than nuclear localization, of recurrent patient-derived YAP fusions, YAP-MAMLD1 and C11ORF95-YAP, underlies ependymoma tumourigenesis from neural progenitor cells. Mutagenesis and chimaera assays demonstrate that an intrinsically disordered region promotes oligomerization of the YAP fusions into nuclear, puncta-like, membrane-less condensates. Oligomerization and nuclear condensates induced by YAP fusion with a coiled-coil domain of transcriptional activator GCN4 also promote ependymoma formation. YAP-MAMLD1 concentrates transcription factors and co-activators, including BRD4, MED1 and TEAD, in condensates while excluding transcriptional repressive PRC2, and induces long-range enhancer-promoter interactions that promote transcription and oncogenic programmes. Blocking condensate-mediated transcriptional co-activator activity inhibits tumourigenesis, indicating a critical role of liquid phase separation for YAP fusion oncogenic activity in ependymoma. YAP fusions containing the intrinsically disordered region features are common in human tumours, suggesting that nuclear condensates could be targeted to treat YAP-fusion-induced cancers.Hu et al. report that patient-derived YAP fusion proteins undergo liquid-liquid phase separation in the nucleus to drive ependymoma tumourigenesis, altering transcription through transcription factor recruitment and alteration of genomic methylation.