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Nuclear condensates of YAP fusion proteins alter transcription to drive ependymoma tumourigenesis
Nature Cell Biology ( IF 17.3 ) Pub Date : 2023-02-02 , DOI: 10.1038/s41556-022-01069-6
Xiaohua Hu 1, 2 , Xiaoping Wu 1, 2 , Kalen Berry 1 , Chuntao Zhao 1 , Dazhuan Xin 1 , Sean Ogurek 1 , Xuezhao Liu 1 , Liguo Zhang 1 , Zaili Luo 1 , Masahide Sakabe 1 , Joanna Trubicka 3 , Maria Łastowska 3 , Frank Szulzewsky 4 , Eric C Holland 4 , Lindsay Lee 5 , Ming Hu 5 , Mei Xin 1 , Q Richard Lu 1
Affiliation  

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.



中文翻译:

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

HIPPO-YAP 融合蛋白的核定位与幕上室管膜瘤的发展有关。在这里,出乎意料的是,我们发现复发性患者来源的 YAP 融合 YAP-MAMLD1 和 C11ORF95-YAP 的液-液相分离,而不是核定位,是神经祖细胞室管膜瘤肿瘤发生的基础。诱变和嵌合体分析表明,本质上无序的区域促进 YAP 融合寡聚化为核、斑点样、无膜凝聚物。YAP 与转录激活因子 GCN4 的卷曲螺旋结构域融合诱导的寡聚化和核凝聚也促进了室管膜瘤的形成。YAP-MAMLD1 将转录因子和共激活因子(包括 BRD4、MED1 和 TEAD)集中在凝聚物中,同时排除转录抑制 PRC2,并诱导促进转录和致癌程序的远程增强子-启动子相互作用。阻断冷凝物介导的转录共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 YAP 融合致癌活性的关键作用。包含本质上无序区域特征的 YAP 融合在人类肿瘤中很常见,这表明核凝聚物可以靶向治疗 YAP 融合诱发的癌症。

更新日期:2023-02-04
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