Metabolic Regulation of the Epigenome Drives Lethal Infantile Ependymoma
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ABSTRACT:
PROVIDER: PRJNA610567 | ENA |
REPOSITORIES: ENA
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Project description:Metabolic regulation of the epigenome drives lethal infantile ependymoma [Cut&Run]
| PRJNA612185 | ENA
Project description:PFA ependymomas are a lethal glial malignancy of the hindbrain found in babies and toddlers. Lacking any highly recurrent somatic mutations, PFAs have been proposed as a largely epigenetically driven tumor type. An almost complete lack of model systems has inhibited discovery of novel PFA therapies. Both in vitro and in vivo, the PFA hypoxic microenvironment controls the availability of specific metabolites to diminish histone methylation, and to increase both histone demethylation and acetylation at H3K27. PFA ependymoma initiates from a cell lineage in the first trimester of human development where there is a known hypoxic microenvironment. Unique to PFA cells, transient exposure to ambient oxygen results in irreversible cellular toxicity. PFA tumors exhibit a low basal level of H3K27me3, and paradoxically inhibition of H3K27 methylation shows significant and specific activity against PFA. Targeting metabolism and/or the epigenome presents a unique opportunity for rational therapy for infants with PFA ependymoma.
2020-08-13 | PXD018191 | Pride
Project description:Posterior fossa type A (PFA) ependymomas are a lethal glial malignancy of the hindbrain found in babies and toddlers. Lacking any highly recurrent somatic mutations, PFAs have been proposed as a largely epigenetically driven tumor type. An almost complete lack of model systems has inhibited discovery of novel PFA therapies. Both in vitro and in vivo, the PFA hypoxic microenvironment controls the availability of specific metabolites to diminish histone methylation, and to increase both histone demethylation and acetylation at H3K27. PFA ependymoma initiates from a cell lineage in the first trimester of human development where there is a known hypoxic microenvironment. Unique to PFA cells, transient exposure to ambient oxygen results in irreversible cellular toxicity. PFA tumors exhibit a low basal level of H3K27me3, and paradoxically inhibition of H3K27 methylation shows significant and specific activity against PFA. Targeting metabolism and/or the epigenome presents a unique opportunity for rational therapy for infants with PFA ependymoma.
2020-07-08 | GSE146426 | GEO
Project description:PFA (posterior fossa group A) ependymomas are a lethal glial malignancy of the hindbrain found in infants and toddlers. Lacking any highly recurrent somatic mutations, PFAs have been proposed as a largely epigenetically driven tumor type. An almost complete lack of model systems has inhibited discovery of novel PFA therapies. Both in vitro and in vivo, the PFA hypoxic microenvironment controls the availability of specific metabolites to diminish histone methylation, and to increase both histone demethylation and acetylation at H3K27. PFA ependymoma initiates from a cell lineage in the first trimester of human development where there is a known hypoxic microenvironment. Unique to PFA cells, transient exposure to ambient oxygen results in irreversible cellular toxicity. PFA tumors exhibit a low basal level of H3K27me3, and paradoxically inhibition of H3K27 methylation shows significant and specific activity against PFA. Targeting metabolism and/or the epigenome presents a unique opportunity for rational therapy for infants with PFA ependymoma.
2020-03-18 | GSE146858 | GEO
Project description:Posterior fossa A (PFA) ependymomas are lethal malignancies of the hindbrain in infants and toddlers. Lacking highly recurrent somatic mutations, PFA ependymomas are proposed to be epigenetically driven tumors for which model systems are lacking. Here we demonstrate that PFA ependymomas are maintained under hypoxia, associated with restricted availability of specific metabolites to diminish histone methylation, and increase histone demethylation and acetylation at histone 3 lysine 27 (H3K27). PFA ependymomas initiate from a cell lineage in the first trimester of human development that resides in restricted oxygen. Unlike other ependymomas, transient exposure of PFA cells to ambient oxygen induces irreversible cellular toxicity. PFA tumors exhibit a low basal level of H3K27me3, and, paradoxically, inhibition of H3K27 methylation specifically disrupts PFA tumor growth. Targeting metabolism and/or the epigenome presents a unique opportunity for rational therapy for infants with PFA ependymoma.
| S-EPMC10782558 | biostudies-literature
Project description:Epigenome analysis of ependymoma cell lines
| PRJNA436983 | ENA
Project description:Genome sequencing studies have uncovered the most frequent mutations in cancer and novel targets for therapy. While successful in many tumors, this approach has failed in others. Lethal infant ependymomas (Group A) lies at the far end of this spectrum with no recurrent focal genomic alterations, no recurrent somatic mutations, and no clear driver for targeted therapy. Despite a paucity of genetic aberrations, Group A ependymomas demonstrate widespread epigenetic alterations. We therefore sought to interrogate the oncogenic drivers of ependymoma by characterizing the enhancer landscapes of 30 primary tumors. Super enhancer (SE) mapping revealed novel ependymoma oncogenes such as PAX6, SKI, and FGFRL1 and uncovered subgroup specific SE lesions across ependymoma, specifically, in Group A such as PAX3, MEIS1, and IGF2BP1. Finally, we identified SE associated gene dependencies that maintain FGFR1 and WEE1 expression in ependymoma, demonstrating the utility of SE lesions to predict novel targets for cancer therapy.
2018-11-15 | GSE75017 | GEO
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:YAP/TAZ drives ependymoma-like tumour formation in mice
| PRJNA622645 | ENA
Project description:Phase separation of YAP fusion proteins drives supratentorial ependymoma
| PRJNA854642 | ENA