Similar Datasets
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.
2022-10-27 | GSE181867 | GEO
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.
2022-10-27 | GSE206926 | GEO
Project description:Phase separation of YAP fusion proteins drives supratentorial ependymoma
| PRJNA854642 | ENA
Project description:Phase separation of YAP fusion proteins drives supratentorial ependymoma I
| PRJNA753777 | ENA
Project description:Phase separation of YAP fusion proteins drives supratentorial ependymoma (methyl-seq)
| PRJNA852700 | ENA
Project description:Two distinct genetically defined entities of ependymoma arising in the supratentorial compartment are characterized by the presence of either a C11orf95-RELA or a YAP-MAMLD1 fusion, respectively. There is growing evidence that supratentorial ependymomas without these genetic features exist. In this study, we report on 18 pediatric non-RELA/non-YAP supratentorial ependymomas that were systematically characterized by means of their histology, immunophenotype, genetics, and epigenomics. Comprehensive molecular analyses included high-resolution copy number analysis, methylation profiling, analysis of fusion transcripts by Nanostring technology, and RNA sequencing. Based upon histological and immunohistochemical features two main patterns were identified-RELA-like (n = 9) and tanycytic ependymomas (n = 6). In the RELA-like group histologically assigned to WHO grade III and resembling RELA-fused ependymomas, tumors lacked nuclear expression of p65-RelA as a surrogate marker for a pathological activation of the NF-κB pathway. Three tumors showed alternative C11orf95 fusions to MAML2 or NCOA1. A methylation-based brain tumor classifier assigned two RELA-like tumors to the methylation class "EP, RELA-fusion"; the others demonstrated no significant similarity score. Of the tanycytic group, 5/6 tumors were assigned a WHO grade II. No gene fusions were detected. Methylation profiling did not show any association with an established methylation class. We additionally identified two astroblastoma-like tumors that both presented with chromothripsis of chromosome 22 but lacked MN1 breaks according to FISH analysis. They revealed novel fusion events involving genes in chromosome 22. One further tumor with polyploid cytogenetics was interpreted as PFB ependymoma by the brain tumor methylation classifier but had no relation to the posterior fossa. Clinical follow-up was available for 16/18 patients. Patients with tanycytic and astroblastoma-like tumors had no relapse, while 2 patients with RELA-like ependymomas died. Our data indicate that in addition to ependymomas discovered so far, at least two more supratentorial ependymoma types (RELA-like and tanycytic) exist.
| S-EPMC7882569 | biostudies-literature
Project description:To further determine chromatin conformation and long-range enhancer/promoter interactions altered by YAP-M, we performed a whole-genome chromatin capture assay using Hi-ChIP.
2022-10-27 | GSE207801 | GEO
Project description:BACKGROUND:A desperate need for novel therapies in pediatric ependymoma (EPN) exists, as chemotherapy remains ineffective and radiotherapy often fails. EPN have significant infiltration of immune cells, which correlates with outcome. Immune checkpoint inhibitors provide an avenue for new treatments. This study characterizes tumor-infiltrating immune cells in EPN and aims at predicting candidates for clinical trials using checkpoint inhibitors targeting PD-L1/PD-1 (programmed death ligand 1/programmed death 1). METHODS:The transcriptomic profiles of the primary study cohort of EPN and other pediatric brain tumors were interrogated to identify PD-L1 expression levels. Transcriptomic findings were validated using the western blotting, immunohistochemistry and flow cytometry. RESULTS:We evaluated PD-L1 mRNA expression across four intracranial subtypes of EPN in two independent cohorts and found supratentorial RELA fusion (ST-RELA) tumors to have significantly higher levels. There was a correlation between high gene expression and protein PD-L1 levels in ST-RELA tumors by both the western blot and immunohistochemisty. The investigation of EPN cell populations revealed PD-L1 was expressed on both tumor and myeloid cells in ST-RELA. Other subtypes had little PD-L1 in either tumor or myeloid cell compartments. Lastly, we measured PD-1 levels on tumor-infiltrating T cells and found ST-RELA tumors express PD-1 in both CD4 and CD8 T cells. A functional T-cell exhaustion assay found ST-RELA T cells to be exhausted and unable to secrete IFN? on stimulation. CONCLUSIONS:These findings in ST-RELA suggest tumor evasion and immunsuppression due to PD-L1/PD-1-mediated T-cell exhaustion. Trials of checkpoint inhibitors in EPN should be enriched for ST-RELA tumors.
| S-EPMC5867234 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2024-05-24 | GSE211456 | GEO
Project description:Supratentorial ependymoma (ST-EPN) is a type of malignant brain tumor mainly seen in children. Since 2014, it has been known that an intrachromosomal fusion C11orf95-RELA is an oncogenic driver in ST-EPN [Parker et al. Nature 506:451-455 (2014); Pietsch et al. Acta Neuropathol 127:609-611 (2014)] but the molecular mechanisms of oncogenesis are unclear. Here we show that the C11orf95 component of the fusion protein dictates DNA binding activity while the RELA component is required for driving the expression of ependymoma-associated genes. Epigenomic characterizations using ChIP-seq and HiChIP approaches reveal that C11orf95-RELA modulates chromatin states and mediates chromatin interactions, leading to transcriptional reprogramming in ependymoma cells. Our findings provide important characterization of the molecular underpinning of C11orf95-RELA fusion and shed light on potential therapeutic targets for C11orf95-RELA subtype ependymoma.
| S-EPMC7666583 | biostudies-literature