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PFA Ependymoma-associated protein EZHIP inhibits PRC2 through a H3 K27M like mechanism (RNA-seq)

ABSTRACT: PFA Ependymoma-associated protein EZHIP inhibits PRC2 through a H3 K27M like mechanism (RNA-seq)

PROVIDER: PRJNA513969 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR8422940_1.fastq.gz	Fastqsanger.gz
	SRR8422940_2.fastq.gz	Fastqsanger.gz
	SRR8422941_1.fastq.gz	Fastqsanger.gz
	SRR8422941_2.fastq.gz	Fastqsanger.gz
	SRR8422942_1.fastq.gz	Fastqsanger.gz

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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

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

PFA ependymoma-associated protein EZHIP inhibits PRC2 activity through a H3 K27M-like mechanism.

Project description:Posterior fossa type A (PFA) ependymomas exhibit very low H3K27 methylation and express high levels of EZHIP (Enhancer of Zeste Homologs Inhibitory Protein, also termed CXORF67). Here we find that a conserved sequence in EZHIP is necessary and sufficient to inhibit PRC2 catalytic activity in vitro and in vivo. EZHIP directly contacts the active site of the EZH2 subunit in a mechanism similar to the H3 K27M oncohistone. Furthermore, expression of H3 K27M or EZHIP in cells promotes similar chromatin profiles: loss of broad H3K27me3 domains, but retention of H3K27me3 at CpG islands. We find that H3K27me3-mediated allosteric activation of PRC2 substantially increases the inhibition potential of EZHIP and H3 K27M, providing a mechanism to explain the observed loss of H3K27me3 spreading in tumors. Our data indicate that PFA ependymoma and DIPG are driven in part by the action of peptidyl PRC2 inhibitors, the K27M oncohistone and the EZHIP 'oncohistone-mimic', that dysregulate gene silencing to promote tumorigenesis.

| S-EPMC6513997 | biostudies-literature

H3 K27M and EZHIP impede H3K27-methylation spreading by inhibing allosterically stimulated PRC2 [EZHIP]

Project description:In this study, we report that EZHIP and H3 K27M preferentially interact with an allosterically activated form of PRC2 in vivo. The formation of H3 K27M- and EZHIP-PRC2 complexes occurs at CpG islands containing H3K27me3 and impedes PRC2 and H3K27me3 spreading. Moreover, we find that H3 K27M inhibits PRC2 in trans and can reduce H3K27me3 levels independent of chromatin incorporation. While EZHIP is not found outside of placental mammals, we find that expression of human EZHIP reduces H3K27me3 in Drosophila melanogaster through a conserved molecular mechanism.

2020-10-12 | GSE151979 | GEO

H3 K27M and EZHIP impede H3K27-methylation spreading by inhibing allosterically stimulated PRC2 [K27M]

2020-10-12 | GSE151980 | GEO

Histone H3 wild-type DIPG/DMG overexpressing EZHIP extend the spectrum diffuse midline gliomas with PRC2 inhibition beyond H3-K27M mutation

Project description:Characterisation of a new subgroup of DMG lacking H3-K27M mutation that is defined by H3K27me3 loss and EZHIP overexpression that can be detected by IHC. These tumors are distinct from EZHIP-positive posterior fossa ependymomas and are associated with a dismal prognosis. We propose that these EZHIP/H3-WT tumors need to be considered similar to canonical DIPG/DMG, thus extending the spectrum of DMG with PRC2 inhibition beyond H3-K27M mutation

2020-03-20 | E-MTAB-8888 | biostudies-arrayexpress

Ependymoma associated protein EZHIP inhibits PRC2 through a H3 K27M like mechanism (ChIP-Seq Ring1b)

Project description:to understand the genome wide alterations in PRC2-mediated K27me3 and PRC1 distribution caused by oncohistone K27M mutation or novel PRC2 inhibitor – EZHIP

2019-04-08 | GSE124741 | GEO

Ependymoma associated protein EZHIP inhibits PRC2 through a H3 K27M like mechanism (ChIP-Seq H2K27me3)

Project description:to understand the genome wide alterations in PRC2-mediated K27me3 and PRC1 distribution caused by oncohistone K27M mutation or novel PRC2 inhibitor – EZHIP

2019-04-08 | GSE124740 | GEO

Ependymoma associated protein EZHIP inhibits PRC2 through a H3 K27M like mechanism (ChIP-Seq CBX2)

Project description:to understand the genome wide alterations in PRC2-mediated K27me3 and PRC1 distribution caused by oncohistone K27M mutation or novel PRC2 inhibitor – EZHIP

2019-04-08 | GSE124739 | GEO

PFA Ependymoma-associated protein EZHIP inhibits PRC2 through a H3 K27M like mechanism (RNA-seq)

Project description:To understand the EZHIP-mediated transcriptional profile in mouse embryonic fibroblasts

2019-04-08 | GSE124839 | GEO