ZFTA-RELA Dictates Oncogenic Transcriptional Programs to Drive Aggressive Supratentorial Ependymoma
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA679065 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13076449_1.fastq.gz | Fastqsanger.gz | |||
| SRR13076449_2.fastq.gz | Fastqsanger.gz | |||
| SRR13076450_1.fastq.gz | Fastqsanger.gz | |||
| SRR13076450_2.fastq.gz | Fastqsanger.gz | |||
| SRR13076451_1.fastq.gz | Fastqsanger.gz |
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Similar Datasets
Project description:Over 60% of supratentorial (ST) ependymomas harbor a ZFTA-RELA (ZRfus) gene fusion (formerly C11orf95-RELA). To study the biology of ZRfus, we developed an autochthonous mouse tumor model using in utero electroporation (IUE) of the embryonic mouse brain. Integrative epigenomic and transcriptomic mapping was performed on IUE driven ZRfus tumors by CUT&RUN, ChIP, ATAC, and RNA sequencing and compared to human ZRfus driven ependymoma. In addition to direct canonical NF-kB pathway activation, ZRfus dictates a neoplastic transcriptional program and binds to thousands of unique sites across the genome that are enriched with Plagl family transcription factor (TF) motifs. ZRfus activates gene expression programs through recruitment of transcriptional co-activators (Brd4, Ep300, Cbp, Pol2) that are amenable to pharmacologic inhibition. Downstream ZRfus target genes converge on developmental programs marked by Plagl transcription factor proteins, and activate neoplastic programs enriched in Mapk, focal adhesion, and gene imprinting networks.
2021-03-29 | GSE161679 | 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:More than 60% of supratentorial ependymomas harbor a ZFTA-RELA (ZRfus) gene fusion (formerly C11orf95-RELA). To study the biology of ZRfus, we developed an autochthonous mouse tumor model using in utero electroporation (IUE) of the embryonic mouse brain. Integrative epigenomic and transcriptomic mapping was performed on IUE-driven ZRfus tumors by CUT&RUN, chromatin immunoprecipitation sequencing, assay for transposase-accessible chromatin sequencing, and RNA sequencing and compared with human ZRfus-driven ependymoma. In addition to direct canonical NFκB pathway activation, ZRfus dictates a neoplastic transcriptional program and binds to thousands of unique sites across the genome that are enriched with PLAGL family transcription factor (TF) motifs. ZRfus activates gene expression programs through recruitment of transcriptional coactivators (Brd4, Ep300, Cbp, Pol2) that are amenable to pharmacologic inhibition. Downstream ZRfus target genes converge on developmental programs marked by PLAGL TF proteins, and activate neoplastic programs enriched in Mapk, focal adhesion, and gene imprinting networks. SIGNIFICANCE: Ependymomas are aggressive brain tumors. Although drivers of supratentorial ependymoma (ZFTA- and YAP1-associated gene fusions) have been discovered, their functions remain unclear. Our study investigates the biology of ZFTA-RELA-driven ependymoma, specifically mechanisms of transcriptional deregulation and direct downstream gene networks that may be leveraged for potential therapeutic testing.This article is highlighted in the In This Issue feature, p. 2113.
| S-EPMC8418998 | biostudies-literature
Project description:To profile H3K4me3Q5Ser (5HT-H3) distribution in mouse ZFTA-RELA ependymoma tumors Furthermore, we also sought to examine H3K27ac and H3K27me3 distribution in mouse ZFTA-RELA ependymoma versus ETV5 overexpressing tumors
2024-06-03 | GSE246032 | GEO
Project description:To profile gene expression differences between mouse non-tumor cortex versus ZFTA-RELA ependymoma versus ETV5 overexpressing tumors Furthermore, we also sought to profile gene expression differences between ZFTA-RELA ependymoma versus NPY overexpressing tumor
2024-06-03 | GSE246031 | 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: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:Background: A methylation-based classification of ependymoma has recently found broad application. However, the diagnostic advantage and implications for treatment decisions remain unclear. Here, we retrospectively evaluate the impact of surgery and radiotherapy on outcome after molecular reclassification of adult intracranial ependymomas. Methods: Tumors diagnosed as intracranial ependymomas from 170 adult patients collected from eight diagnostic institutions were subjected to DNA methylation profiling. Molecular classes, patient characteristics, and treatment were retrospectively correlated with progression-free survival (PFS). Results: The classifier indicated an ependymal tumor in 73.5%, a different tumor entity in 10.6% and non-classifiable tumors in 15.9% of cases, respectively. The most prevalent molecular classes were posterior fossa ependymoma group B (EPN-PFB, 32.9%), posterior fossa subependymoma (PF-SE, 25.9%), and supratentorial ZFTA fusion-positive ependymoma (EPN-ZFTA, 11.2%). With a median follow-up of 60.0 months, the 5- and 10-year-PFS rates were 64.5% and 41.8% for EPN-PFB, 67.4% and 45.2% for PF-SE and 60.3% and 60.3% for EPN-ZFTA. In EPN-PFB, but not in other molecular classes, gross total resection (p=0.009) and postoperative radiotherapy (p=0.007) were significantly associated with improved PFS in multivariable analysis. Histological tumor grading (WHO 2 vs. 3) was not a predictor of prognosis within molecularly defined ependymoma classes. Conclusions: DNA methylation profiling improves diagnostic accuracy and risk stratification in adult intracranial ependymoma. The molecular class of PF-SE is unexpectedly prevalent among adult tumors with ependymoma histology and relapsed as frequently as EPN-PFB, despite the supposed benign nature. Gross total resection and radiotherapy may represent key factors in determining the outcome of EPN-PFB patients.
2023-02-21 | GSE224218 | GEO
Project description:ZFTA-RELA ependymoma presents a significant clinical challenge due to the lack of effective treatments, driving the need to explore novel immunotherapeutic strategies. Recent studies have identified the skull bone marrow as a source of meningeal immune cells critical for central nervous system (CNS) immunity, yet the role of these cells in childhood CNS tumour surveillance and pathology remains unclear. Here, we demonstrate that intracranial childhood ependymoma tumours harbour a unique myeloid cell population, including hematopoietic stem cells (HSCs) not from the blood, but supplied by adjacent skull bone marrow, ontogenetically distinct from their blood-derived counterparts. Our findings challenge the conventional view of HSCs as passive players in the CNS, revealing that antigen-specific interactions between skull bone marrow-derived HSCs and CD4+ T cells actively promote immunotolerance in childhood brain tumours by enhancing local myelopoiesis and inducing regulatory T cell polarization. This work uncovers a previously unrecognized cellular network linking the skull to brain tumours in children and underscores the therapeutic potential of modulating skull bone marrow haematopoiesis to shift the local immune environment. Targeting this skull-specific immune pathway offers a promising avenue for developing localized immunotherapies to improve treatment outcomes.
2025-12-01 | PXD058239 | Pride
Project description:ZFTA-RELA ependymoma poses a formidable challenge due to limited treatment avenues, prompting exploration into immunotherapeutic approaches. Recent investigations have shed light on the calvaria bone marrow as a source of meningeal immune cells crucial for central nervous system (CNS) immunity. Whether or not cues from the tumour microenvironment can instruct local haematopoiesis within the skull is unknown. We used single cell RNA sequencing (snRNAseq + snATAC) to analyze the dynamic transcriptional regulation of skull, peripheral bone marrow from tumour-bearing and non-tumour bearing ZFTA-RELA fusion driven ependymoma mice.
2025-12-01 | GSE282459 | GEO