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Metabolic regulation of the epigenome drives lethal infantile ependymoma [Cut&Run]

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE146858 | GEO | 2020/03/18

REPOSITORIES: GEO

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Metabolic Regulation of the Epigenome Drives Lethal Infantile Ependymoma

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

Metabolic Regulation of the Epigenome Drives Lethal Infantile Ependymoma

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

EZHIP / CXorf67 mimics K27M mutated oncohistones and functions as an intrinsic inhibitor of PRC2 function in aggressive posterior fossa ependymoma

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

Spatial transcriptomics reveal unnresolved wound repair as potential driver of PFA Ependymoma progression

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

EZHIP / CXorf67 mimics oncohistones to inhibit PRC2 in PFA ependymoma

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

Cxorf67-FLAG co-immunoprecipitation analysis from 293T cells

Project description:The regulation of gene expression is controlled in part by post-translational modifications to histone proteins. Methylation at histone H3, lysine 27 (H3K27), which is catalyzed by Polycomb repressive complex 2 (PRC2), is associated with silenced chromatin. Previous studies have identified dysregulation of H3K27 methylation in pediatric diffuse intrinsic pontine gliomas (DIPGs), the majority of which feature mutation of lysine 27 to methionine. This “oncohistone” potently inhibits PRC2 activity and leads to a global reduction in H3K27 methylation. Similar to DIPG, posterior fossa type A (PFA) ependymomas also show low levels of H3K27 methylation. Although PFAs do not possess the H3K27M oncohistone mutation, they do show increased expression of Cxorf67. Interestingly, Cxorf67 contains a C-terminal sequence that resembles the sequence surrounding H3K27, and we find that this portion of Cxorf67 inhibits PRC2 activity to an even greater extent than the H3K27M oncohistone. Thus, we suggest re-naming Cxorf67 as EZHIP (Enhancer of Zeste Homologs Inhibitory Protein). Furthermore, when expressed in 293T cells, Cxorf67 interacts with several members of PRC2 and induces changes in H3K27 methylation patterns that mirror the changes in H3K27 methylation induced by expression of H3K27M. We propose that PFAs have dysregulated H3K27 methylation by a mechanism that involves inhibition of PRC2 by Cxorf67, which could drive tumorigenesis.

2019-04-09 | PXD013390 | Pride

RNAseq analysis of childhood posterior fossa subgroup A ependymoma

Project description:Posterior fossa subgroup A (PFA) ependymoma is a brain tumor of childhood with a high rate of recurrence. Here we have performed RNAseq on a longitudinal cohort of patient samples obtained at presentation and at recurrence(s), in order to identify the biological correlates of treatment failure and tumor evolution.

2023-06-01 | GSE226957 | GEO

High and low cell density areas in posterior fossa ependymoma type A have a distinct transcriptome

Project description:Posterior fossa type A (PF-EPN-A, PFA) ependymoma are aggressive tumors that mainly affect children and have a poor prognosis. Histopathology shows significant intratumoral heterogeneity, ranging from loose tissue to often sharply demarcated, extremely cell dense tumor areas. Spatial transcriptomics of six cases allow for a comparison of the transcriptome of high and low cell density areas.

2024-01-31 | GSE249189 | GEO

PFA ependymoma cancer study

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.

| EGAS00001004312 | EGA

Expression data from human ependymoma

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

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