ZFTA-RELA Dictates Oncogenic Transcriptional Programs to Drive Aggressive Supratentorial Ependymoma
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PROVIDER: PRJNA679065 | ENA |
REPOSITORIES: ENA
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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:Pediatric ependymoma has relatively low frequencies of DNA mutations, which suggest that epigenetics may drive tumors. However, the epigenetic mechanisms for recurrent ependymoma are still poorly understood. Here, we performed longitudinal and comprehensive DNA methylation and gene expression analysis for recurrent pediatric ependymoma tumors from 10 patients, total 46 DNA methylomes (including primary tumors and matched recurrent tumors; normal pediatric brain tissues and PDOX tumors). Both RELA and PFA tumors maintained the subtype DNA methylation signatures during repeated relapses. We further identified the potential DNA methylation predictors, drivers and boosters and their potential regulated genes for recurrent ependymoma tumors. Increased DNA methylation levels within H3K4me1 enriched regions indicates disturbed functions of LSD1 gene in recurrent ependymoma tumors. Combining novel LSD1 inhibitor SYC-836 with radiation (XRT) significantly prolonged animal survival times in PDOX models of recurrent PFA ependymoma. Our PDOX models provide a unique platform for preclinical testing drugs and development of new therapy for pediatric recurrent ependymoma.
2022-07-12 | GSE156619 | GEO
Project description: Not available
| S-EPMC4050669 | biostudies-literature
Project description:Ependymomas exist within distinct genetic subgroups, but the molecular diversity within individual ependymomas is unknown. We performed multiplatform molecular profiling of 6 spatially-distinct samples from an ependymoma with C11orf95-RELA fusion. DNA methylation and RNA sequencing distinguished clusters of samples according to neuronal development gene expression programs that could also be delineated by differences in magnetic resonance blood perfusion. Exome sequencing and phylogenetic analysis revealed epigenomic intratumor heterogeneity, and suggested that chromosomal structural alterations may precede accumulation of single nucleotide variants during ependymoma tumorigenesis. In sum, these findings shed new light on the oncogenesis and intratumor heterogeneity of ependymoma.
2019-12-20 | GSE142320 | GEO
Project description:Ependymoma (EPN) is the third most common central nervous system (CNS) tumor in childhood and, recently, has been classified in nine robust molecular subgroups (Pajtler et al., 2015). However, molecular and clinical features of pediatric EPNs from Brazilian cohorts remain unexplored. Herein, we aimed to analyze the gene expression profile among three different molecular subgroups: ST-EPN-RELA, ST-EPN-YAP1 and PF-EPN-A.
2023-03-03 | GSE181162 | GEO
Project description:Despite extensively growing knowledge on the molecular biology of ependymoma, effective treatments are still lacking for about half patients with high-risk tumors. By applying single cell RNA-sequencing, we comprehensively identify a cellular hierarchy within ependymoma spanning undifferentiated and differentiated tumor cell states across all major molecular groups. This not only refines the concept of these established molecular groups but moreover provides a biological context for the well-known capacity of aggressive ependymomas for late recurrence and treatment resistance. Our newly defined transcriptomic signatures also prove to be of prognostic relevance within established high-risk ependymoma groups. Consequently, the newly characterized cell states could serve as promising future therapeutic targets and biomarkers for clinical trials.
2020-07-13 | GSE141460 | GEO
Project description: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). Here, we report that the inhibitory mechanism of this interaction 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 H3K27M peptide and binds to the SET domain of EZH2. This interaction blocks EZH2 methyltransferase activity and causes H3K27 hypomethylation, an oncogenic mechanism that may be exploited for targeted therapy in PFA ependymoma. Based on its function, we have renamed CXorf67 into EZH2 Inhibitory Protein (EZHIP).
2019-07-08 | PXD012318 | Pride
Project description:We compared molecular characteristics of primary and recurrent pediatric ependymoma to identify sub-group specific differences. Gene expression profiles were used to identify unique immunobiologic sub-types of posterior fossa pediatric ependymoma. Gene expression profiles were generated from surgical tumor (ependymoma) (n=65) using Affymetrix HG-U133plus2 chips (Platform GPL570). Normalization was performed on our entire cohort of ependymoma. Of the 65 samples, a sub-set of 58 were used in the corresponding manuscript. Excluded samples are noted. Gene expression profiles were filtered to obtain gene expression of key immune cell markers. Comparative analyses between tumor samples were used to identifiy unique immunobiology between posterior fossa sub-groups.
2013-08-30 | E-GEOD-50385 | biostudies-arrayexpress
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.
2020-05-26 | PXD018131 | Pride
Project description:We compared molecular characteristics of primary and recurrent pediatric ependymoma to identify sub-group specific differences. Gene expression profiles were used to identify unique immunobiologic sub-types of posterior fossa pediatric ependymoma.
2013-08-30 | GSE50385 | GEO