Disruption of developmental enhancer and PRC2 function by K27M in childhood glioma
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA645695 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12203113.fastq.gz | Fastqsanger.gz | |||
| SRR12203114.fastq.gz | Fastqsanger.gz | |||
| SRR12203115.fastq.gz | Fastqsanger.gz | |||
| SRR12203116.fastq.gz | Fastqsanger.gz | |||
| SRR12203117.fastq.gz | Fastqsanger.gz |
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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. ATAC-seq chromatin accessibility profiling in drosophila S2 cells
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Project description:Heterozygous histone H3.3K27M mutation is a primary oncogenic driver of Diffuse Midline Glioma (DMG). H3.3K27M inhibits the Polycomb Repressive Complex 2 (PRC2) methyltransferase complex, leading to a global reduction and redistributing of the repressive H3 lysine 27 tri-methylation. This rewiring of the epigenome is thought to promote gliomagenesis. We established novel, isogenic DMG patient-derived cell lines that have been CRISPR-Cas9 edited to H3.3 WT or H3.3K27M alone and in combination with EZH2 and EZH1 co-deletion, inactivating PRC2 methyltransferase activity of PRC2 and eliminating H3K27me3. RNA-seq and ATAC-seq analysis of these cells revealed that K27M has a novel epigenetic effect that appears entirely independent of its effects on PRC2 function. While the loss of the PRC2 complex led to a systemic induction of gene expression (including HOX gene clusters) and upregulation of biological pathways, K27M led to a balanced gene deregulation but having an overall repressive effect on the biological pathways. Importantly, the genes uniquely deregulated by the K27M mutation, independent of methylation loss, are closely associated with changes in chromatin accessibility, with upregulated genes becoming more accessible. Notably, the PRC2-independent function of K27M appears necessary for tumorigenesis as xenografts of our H3.3K27M/EZH1/2 WT cells developed into tumors, while H3.3/EZH1/2 KO cells did not. We demonstrate that K27M mutation alters chromatin accessibility and uniquely deregulates genes, independent of K27 methylation. We further show the mutation's role in altering biological pathways and its necessity for tumor development.
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Project description:Heterozygous histone H3.3K27M mutation is a primary oncogenic driver of Diffuse Midline Glioma (DMG). H3.3K27M inhibits the Polycomb Repressive Complex 2 (PRC2) methyltransferase complex, leading to a global reduction and redistributing of the repressive H3 lysine 27 tri-methylation. This rewiring of the epigenome is thought to promote gliomagenesis. We established novel, isogenic DMG patient-derived cell lines that have been CRISPR-Cas9 edited to H3.3 WT or H3.3K27M alone and in combination with EZH2 and EZH1 co-deletion, inactivating PRC2 methyltransferase activity of PRC2 and eliminating H3K27me3. RNA-seq and ATAC-seq analysis of these cells revealed that K27M has a novel epigenetic effect that appears entirely independent of its effects on PRC2 function. While the loss of the PRC2 complex led to a systemic induction of gene expression (including HOX gene clusters) and upregulation of biological pathways, K27M led to a balanced gene deregulation but having an overall repressive effect on the biological pathways. Importantly, the genes uniquely deregulated by the K27M mutation, independent of methylation loss, are closely associated with changes in chromatin accessibility, with upregulated genes becoming more accessible. Notably, the PRC2-independent function of K27M appears necessary for tumorigenesis as xenografts of our H3.3K27M/EZH1/2 WT cells developed into tumors, while H3.3/EZH1/2 KO cells did not. We demonstrate that K27M mutation alters chromatin accessibility and uniquely deregulates genes, independent of K27 methylation. We further show the mutation's role in altering biological pathways and its necessity for tumor development.
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