ZFTA fusion oncoproteins drive tumorigenesis through transcriptional condensates
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PROVIDER: PRJNA1106842 | ENA |
REPOSITORIES: ENA
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Project description:Over 95% of ependymomas (EPNs) that arise in the cortex are driven by a gene fusion involving the zinc finger translocation associated (ZFTA) protein. Using super-resolution and lattice light sheet microscopy, we demonstrate that the most frequent fusion variant, ZFTA-RELA (ZR), forms dynamic nuclear condensates that are required for oncogene expression and tumorigenesis. Mutagenesis of ZR reveals a key intrinsically disordered region (IDR) that governs condensate formation. Condensate-modulating ZR IDR mutations impaired genomic occupancy at oncogenic loci, and inhibited the recruitment of transcriptional effector proteins, such as MED1, BRD4 and RNA polymerase II. Using nuclear magnetic resonance spectroscopy, we examined the protein structure of the critical zinc finger found in ZR, and characterized its significance for condensate formation, genomic binding, and oncogene activation. Our data leverages microscopy, genomics, cell biology, animal modeling, structural biology, and machine learning approaches to provide mechanistic insights into the processes that govern oncogene expression in ZFTA FO-driven tumors.
2025-07-21 | GSE266375 | GEO
Project description:ZFTA-RELA ependymomas are malignant brain tumors that are frequently lethal. They are defined by fusions formed between the putative chromatin remodeler ZFTA and the NFkB-mediator-RELA. We identified that ZFTA-RELA cells produced itaconate, a key macrophage-associated immunomodulator metabolite. However, itaconate production by tumor cells and its tumor-intrinsic role are not well-established. Itaconate is synthesized by the enzyme Aconitate Decarboxylase-1 (ACOD1) and the ZFTA-RELA fusion upregulated ACOD1 in an NFkB-dependent manner. Additionally, itaconate production enabled a feed-forward system that maintained pathogenic ZFTA-RELA fusion expression through epigenetic activation. To supply the metabolic fuel needed to generate itaconate, these tumors epigenetically activated PI3K/mTOR signaling to enhance glutaminolysis, which provided the carbons necessary for itaconate synthesis. Consequently, antagonizing glutamine metabolism lowered pathogenic ZFTA-RELA levels and was potently therapeutic in multiple in vivo models. Finally, combining glutamine antagonism with PI3K/mTOR inhibition abrogated spinal metastasis. Our data demonstrate that ZFTA-RELA ependymomas subvert a macrophage-like itaconate metabolic pathway to maintain expression of the ZFTA-RELA fusion driver, implicating itaconate as an oncometabolite. Taken together, our results position itaconate upregulation as a previously unappreciated driver of ZFTA-RELA ependymomas. This study therefore has implications for future drug development for children with this devastating brain tumor and will further our understanding of oncometabolites as a novel class of therapeutic dependencies in cancers.
2025-11-17 | GSE294955 | GEO
Project description:ZFTA-RELA ependymomas are malignant brain tumors that are frequently lethal. They are defined by fusions formed between the putative chromatin remodeler ZFTA and the NFkB-mediator-RELA. We identified that ZFTA-RELA cells produced itaconate, a key macrophage-associated immunomodulator metabolite. However, itaconate production by tumor cells and its tumor-intrinsic role are not well-established. Itaconate is synthesized by the enzyme Aconitate Decarboxylase-1 (ACOD1) and the ZFTA-RELA fusion upregulated ACOD1 in an NFkB-dependent manner. Additionally, itaconate production enabled a feed-forward system that maintained pathogenic ZFTA-RELA fusion expression through epigenetic activation. To supply the metabolic fuel needed to generate itaconate, these tumors epigenetically activated PI3K/mTOR signaling to enhance glutaminolysis, which provided the carbons necessary for itaconate synthesis. Consequently, antagonizing glutamine metabolism lowered pathogenic ZFTA-RELA levels and was potently therapeutic in multiple in vivo models. Finally, combining glutamine antagonism with PI3K/mTOR inhibition abrogated spinal metastasis. Our data demonstrate that ZFTA-RELA ependymomas subvert a macrophage-like itaconate metabolic pathway to maintain expression of the ZFTA-RELA fusion driver, implicating itaconate as an oncometabolite. Taken together, our results position itaconate upregulation as a previously unappreciated driver of ZFTA-RELA ependymomas. This study therefore has implications for future drug development for children with this devastating brain tumor and will further our understanding of oncometabolites as a novel class of therapeutic dependencies in cancers.
2025-11-17 | GSE294954 | GEO
Project description:We report an infantile case of midline ‘supratentorial ependymoma ZFTA fusion-positive’ involving both the infra- and the supra-tentorial compartments (i.e., cerebellar vermis, pons and midbrain). The radiological features, i.e., the upward displacement and compression of the supratentorial anatomical structures and the infiltrative margins of the tumour towards the cerebellar vermis, suggested an infratentorial origin of the lesion with secondary involvement of the supratentorial compartment. This case adds to the limited literature of non-hemispheric ‘supratentorial ependymoma ZFTA fusion-positive’ occurring in midline structures, both supratentorial (pineal region, thalamus) and infratentorial (cervico-medullary region and spinal cord), and in the cerebellum. These cases highlight the need to consider this entity in the differential diagnosis of paediatric non-hemispheric lesions and raise the question of whether the inclusion of the location within the WHO definition of this tumour type may be too restrictive
2023-01-01 | GSE220932 | GEO
Project description:Translocation renal cell carcinoma (tRCC) presents a significant clinical challenge due to its aggressiveness and limited treatment options. This cancer is primarily driven by fusion oncoproteins (FOs) arising from chromosomal rearrangements, yet their role in oncogenesis remains incompletely understood. Here we investigate TFE3 fusion in tRCC, focusing on NONO::TFE3 and SFPQ::TFE3, constituting 30-40% of all TFE3 FOs. We find that TFE3 FOs form liquid-like condensates with heightened transcriptional activity, selectively recruiting active transcription markers to TFE3 target genes and promoting cell proliferation, migration, and drug resistance. The coiled-coil domains (CCD) of NONO and SFPQ are essential for condensate formation, prolonging TFE3 FOs' chromatin binding time and enhancing transcription. We comprehensively investigated the genome-wide recruitment of TFE3 FOs and their CCD-altered variants, uncovering widespread changes in chromatin accessibility and genomic binding specifically at TFE3 and AP-1 regulated loci. We also observe altered H3K27ac deposition at enhancers and super-enhancers notably at pro-growth and stemness markers such as BCL2 and CD44, and identify novel oncogenic target genes of TFE3 FOs. Disruption of condensate formation, resulting from CCD domain alterations in FOs, robustly dysregulates their role in chromatin accessibility, chromatin binding, H3K27ac occupancy, and gene expression. Altogether our integrated analyses underscore the critical functions of TFE3 FO condensates in driving RCC progression, offering pivotal insights for future targeted therapeutic strategies.
2025-04-02 | GSE281477 | GEO
Project description:• Abstract: FET fusion oncoproteins, containing the N-terminal of a FET protein (FUS, EWSR1 and TAF15) together with a DNA-binding transcription factor partner, are characteristic for around 20 different sarcomas and leukemias, including myxoid liposarcoma (MLS) and Ewing sarcoma (EWS). FET oncoproteins interact with all three main subtypes of the SWI/SNF chromatin remodeling complexes cBAF, PBAF and GBAF, resulting in epigenetic changes and oncogenic gene expression patterns. We developed a comprehensive immunoprecipitation (IP) protocol followed by quantitative mass spectrometry (QMS) analysis using a global approach for relative quantification with chemical tandem mass tag (TMT) labels. We employed two immunoprecipitation strategies, by pulling down either all SWI/SNF complexes using BRG1 as a target or FET-FOP-bound SWI/SNF complexes using the fusion oncoproteins FUS-DDIT3 or EWSR1-FLI1 as a target. This approach allowed us to assess differences between SWI/SNF composition and interaction partners in MLS and EWS cells, as well as determine the composition and interactome of FET-FOP-bound SWI/SNF complexes.
2025-09-22 | PXD047503 | Pride
Project description:EWSR1::FLI1 fusion oncoproteins’ regulation of ETS1 (RNA-seq)
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Project description:EWSR1::FLI1 fusion oncoproteins’ regulation of ETS1 (RNA-seq)
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Project description:EWSR1::FLI1 fusion oncoproteins’ regulation of ETS1 (CUT&RUN)
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Project description:EWSR1::FLI1 fusion oncoproteins’ regulation of ETS1 (ChIP-seq)
| PRJNA1016476 | ENA