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Phase separation of YAP fusion proteins drives supratentorial ependymoma

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE207293 | GEO | 2022/10/27

REPOSITORIES: GEO

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Phase separation of YAP fusion proteins drives supratentorial ependymoma I

Project description:HIPPO-YAP/TAZ signaling has been implicated in supratentorial ependymoma formation from neural progenitor cells (NPC) in the brain, however, the underlying mechanisms to trigger the neural progenitor cell transformation remains elusive. Here, we uncover that patient-derived tumorigenic YAP-fusion proteins (YAP-MAMLD1 and C11ORF95-YAP) promote ependymoma tumorigenesis through forming liquid-liquid phase-separated condensates. Intrinsically disordered regions (IDR) in the fusion proteins promote oligomerization of YAP-transcriptional co-activators and self-assembly of nuclear puncta-like membrane-less organelles. Phase separation of YAP-fusion proteins further facilitates the compartmentalization of transcriptional coactivators, BRD4 and MED1, resulting in pervasive enhancer landscape changes and exclusion of transcriptional repressors such as PRC2 complexes. YAP-fusion proteins-induced nuclear puncta recruit RNA polymerase II to promote transcriptional bursting of multiple oncogenic pathways. Moreover, we show that IDR-mediated phase separation is necessary for YAP-fusion protein-induced tumor formation. Distinct YAP fusion-proteins identified in other human tumors also encompass IDR features. Together, our data suggest that IDR-mediated phase separation is an integral component of YAP-fusion protein-induced tumorigenesis and might serve as a therapeutic target in supratentorial ependymoma.

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Project description:YAP1 gene fusions have been observed in a subset of paediatric ependymomas. Here we show that, ectopic expression of active nuclear YAP1 (nlsYAP5SA) in ventricular zone neural progenitor cells using conditionally-induced NEX/NeuroD6-Cre is sufficient to drive brain tumour formation in mice. Neuronal differentiation is inhibited in the hippocampus. Deletion of YAP1’s negative regulators LATS1 and LATS2 kinases in NEX-Cre lineage in double conditional knockout mice also generates similar tumours, which are rescued by deletion of YAP1 and its paralog TAZ. YAP1/TAZ-induced mouse tumours display molecular and ultrastructural characteristics of human ependymoma. RNA sequencing and quantitative proteomics of mouse tumours demonstrate similarities to YAP1-fusion induced supratentorial ependymoma. Finally, we find that transcriptional cofactor HOPX is upregulated in mouse models and in human YAP1-fusion induced ependymoma, supporting their similarity. Our results show that uncontrolled YAP1/TAZ activity in neuronal precursor cells leads to ependymoma-like tumours in mice.

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