TULIPs decorate the three-dimensional genome of PFA ependymoma
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE186599 | GEO | 2024/07/05
REPOSITORIES: GEO
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Project description:RNA-seq (n=52) data from a variety of pediatric brain tumors including ependymoma (PFA, PFB, Ste, spinal), medulloblastoma (G3, G4, SHH), high grade glioma (H3K27 and H3-WT), pilocytic astrocytoma, and more. Raw data provided as FASTQ. Data generated on Illumina HiSeq2500.
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Project description:Hi-C (n=72) data from a variety of pediatric brain tumors including ependymoma (PFA, PFB, Ste, spinal), medulloblastoma (G3, G4, SHH), high grade glioma (H3K27 and H3-WT), pilocytic astrocytoma, and more. Raw data provided as FASTQ. Data generated on Illumina HiSeq2500.
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Project description:Childhood brain tumor ependymoma remains incurable in approximately 50 percent of cases. No oncogenic mechanism has been firmly established for the commonest ependymoma variant posterior fossa subgroup A (PFA), impeding clinical advances. Uncovering how heterogeneous cell types within the tumor microenvironment interact is crucial to a complete understanding of PFA disease progression. The underlying cellular components of the PFA tumor microenvironment have been revealed by single cell transcriptomics, identifying divergent epithelial differentiation and EMT lineages. Here we utilize spatial transcriptomics (Visium) of 14 PFA samples to chart neoplastic and immune cell architecture and identify novel biological processes.
2022-10-13 | GSE195661 | GEO
Project description:Expression of CXorf67 is an oncogenic mechanism that drives H3K27 hypomethylation in PFA ependymomas by mimicking K27M mutated oncohistones. Background: Posterior fossa A (PFA) ependymomas comprise one out of nine molecular groups of ependymoma. PFA tumors are mainly diagnosed in infants and young children, show a poor prognosis and are characterized by a lack of the repressive histone H3 lysine 27 trimethylation (H3K27me3) mark. Recently, we reported CXorf67 overexpression as hallmark of PFA ependymoma and showed that CXorf67 can interact with EZH2 thereby inhibiting polycomb repressive complex 2 (PRC2), but the mechanism of action remained unclear. Methods: We performed mass spectrometry (MS) and peptide modelling analyses to identify the functional domain of CXorf67 responsible for binding and inhibition of EZH2. Our findings were validated by immunocytochemistry, western blot and methyltransferase assays. Results: We find that the inhibitory mechanism of CXorf67 is similar as in diffuse midline gliomas harboring H3K27M mutations. A small, highly conserved peptide sequence located in the C-terminal region of CXorf67 mimics the sequence of K27M mutated histones and binds to the SET domain of EZH2. This interaction blocks EZH2 methyltransferase activity and inhibits PRC2 function causing de-repression of PRC2 target genes including genes involved in neurodevelopment. Conclusions: Expression of CXorf67 is an oncogenic mechanism that drives H3K27 hypomethylation in PFA tumors by mimicking K27M mutated histones. Disrupting the interaction between CXorf67 and EZH2 may serve as a novel targeted therapy for PFA tumors but also for other tumors that overexpress CXorf67. Based on its function, we have renamed CXorf67 into EZH Inhibitory Protein (EZHIP).
2022-03-06 | GSE127941 | GEO
Project description:DNA methylation analysis was perfomed using Infinium EPIC Methylation BeadChip platform on 65 PFA ependymoma patient samples. Resulting .idat files were then uploaded to the molecularneuropathology.org classifier to obtain molecular subgroup and copy number variance. Idat files were batch normalized and background corrected using default settings of the R package ChAMP to obtain GpG methylation beta values for analysis of differentially methylated GpG regions.
2023-06-01 | GSE226895 | GEO
Project description:The study of the origin and development of cerebellar tumours has been hampered by the complexity and heterogeneity of cerebellar cells that change over the course of development. We used single-cell transcriptomics to study >60,000 cells from the developing murine cerebellum, and show that different molecular subgroups of childhood cerebellar tumours mirror the transcription of cells from distinct, temporally restricted cerebellar lineages. Sonic Hedgehog medulloblastoma transcriptionally mirrors the granule cell hierarchy as expected, whereas Grp3-MB resemble Nestin+ve stem cells, Group 4 medulloblastomas resemble unipolar brush cells, and PFA/PFB ependymoma and cerebellar pilocytic astrocytoma resemble the pre-natal gliogenic progenitor cells. Furthermore, single-cell transcriptomics of human childhood cerebellar tumours demonstrates that many bulk tumours contain a mixed population of cells with divergent differentiation. Our data highlight cerebellar tumours as a disorder of early brain development, and provide a proximate explanation for the peak incidence of cerebellar tumours in early childhood.
2019-05-01 | GSE118068 | GEO
Project description:Ependymomas are neuroepithelial tumors of the central nervous system (CNS), presenting in both adults and children but accounting for almost 10% of all pediatric CNS tumors and up to 30% of CNS tumors in children under 3 years (Bouffet et al., 2009; McGuire et al., 2009; Rodriguez et al., 2009). In children, most ependymomas arise in the posterior fossa, while most adult ependymomas present around the lower spinal cord and spinal nerve roots. Ependymomas display a wide range of morphological features, and several variants are listed in the World Health Organization (WHO) classification (Ellison et al., 2016). These variants are assigned to three WHO grades (I-III), but the clinical utility of this classification is acknowledged to be limited (Ellison et al., 2011). An increasing understanding of the genomic landscape of ependymoma and the discovery of distinct molecular groups by DNA methylation or gene expression profiling have begun to refine approaches to disease classification and prognostication, but have yet to be translated into clinical routine (Hoffman et al., 2014; Mack et al., 2014; Pajtler et al., 2017; Pajtler et al., 2015; Parker et al., 2014; Wani et al., 2012; Witt et al., 2011). Our comprehensive study of DNA methylation profiling across the entire disease demonstrated three molecular groups for each major anatomic compartment: supratentorial (ST), posterior fossa (PF), and spinal (SP) (Pajtler et al., 2015). In the ST compartment, two molecular groups (ST-EPN-RELA and ST-EPN-YAP1) align with tumors harboring specific genetic alterations, RELA and YAP1 fusion genes, which were initially discovered in a whole genome sequencing study (Parker et al., 2014). Among PF ependymomas, two of three molecular groups, PFA (PF-EPN-A) and PFB (PF-EPN-B), account for nearly all tumors; PF-SE tumors are rare, generally showing the morphology of a subependymoma (Pajtler et al., 2015). PFA tumors are found mainly in infants and young children (median age ≈ 3yrs) and have a relatively poor outcome, while PFB tumors are generally found in young adults (median age ≈ 30yrs) and are associated with a better prognosis (Pajtler et al., 2015; Witt et al., 2011). PFA tumors show few copy number alterations (CNAs), while PFB tumors harbor multiple CNAs that tend to affect entire chromosomes. While recurrent structural variants (SVs) are found in ST ependymomas, recurrent SVs or other mutations, such as single nucleotide variants (SNVs) and insertions or deletions (indels), have not been identified in PF ependymomas to date (Mack et al., 2014; Parker et al., 2014).
2018-06-26 | GSE104210 | GEO
Project description:Sequencing data related the PFA ependymoma study (Michealraj et al., Cell 2020), a lethal glial malignancy of the hindbrain found in babies and toddlers.
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Project description:DNA methylation analysis was perfomed using Infinium 450K Methylation BeadChip platform on 140 PFA ependymoma patient samples. Resulting .idat files were then uploaded to the molecularneuropathology.org classifier to obtain molecular subgroup and copy number variance. Idat files were batch normalized and background corrected using default settings of the R package ChAMP to obtain GpG methylation beta values for analysis of differentially methylated GpG regions.
2023-06-01 | GSE226960 | GEO
Project description:TULIPs decorate the three-dimensional genome of PFA ependymoma
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