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Single-cell epigenetic analysis reveals principles of chromatin states in H3.3-K27M gliomas

ABSTRACT: Single-cell epigenetic analysis reveals principles of chromatin states in H3.3-K27M gliomas

PROVIDER: PRJNA822422 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR18573000.fastq.gz	Fastqsanger.gz
	SRR18572995.fastq.gz	Fastqsanger.gz
	SRR18572996.fastq.gz	Fastqsanger.gz
	SRR18572997.fastq.gz	Fastqsanger.gz
	SRR18572998.fastq.gz	Fastqsanger.gz

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Human ESC-based modeling of pediatric gliomas by K27M mutation in histone H3.3 variant

Project description:Human diffuse intrinsic pontine gliomas (DIPG) are an aggressive form of pediatric brain tumors that arise in the pons in young children thus resulting in significant morbidity and very poor survival. Recent data suggest that mutations in the histone H3.3 variant are often found in these tumors, though the mechanism of their contribution to oncogenesis remains to be elucidated. Here we report that the combination of constitutive PDGFRA activation and p53 suppression as well as expression of the K27M mutant form of the histone H3.3 variant leads to neoplastic transformation of hPSC-derived neural precursors. Our study demonstrates that human ES cells represent an excellent platform for the modeling of human tumors in vitro and in vivo, which could potentially lead to the elucidation of the molecular mechanisms underlying neoplastic transformation and the identification of novel therapeutic targets. Human ES cells were differentiated to NPCs and lentivirally transduced with a combination of constitutively active PDGFRA (D842V), sh-p53, and WT or K27M mutant form of histone H3.3 variant.

2014-11-21 | E-GEOD-55541 | biostudies-arrayexpress

Paediatric Glioma Histone H3.3 K27M/G34R Mutations Drive Abnormalities in Phase-Separated PML Nuclear Bodies.

Project description:Point mutations in histone variant H3.3 (H3.3 K27M, H3.3 G34R) and the H3.3-specific ATRX/DAXX chaperone complex are frequent events in paediatric gliomas. It is clear that H3.3 point mutations affect many chromatin modifications but the exact oncogenic mechanisms are an area of active investigation. Histone H3.3 has been previously linked to PML, a gene which is frequently mutated in Acute Promyelocytic Leukaemia. We find that H3.3 point mutations disrupt the formation of PML nuclear bodies and this prevents differentiation down glial lineages. Similar to PML-mutated Acute Promyelocytic Leukaemias, H3.3-mutated patient-derived gliomas cells are also sensitive to drugs which target PML bodies. We identify PML as a contributor to oncogenesis in H3.3-mutated gliomas and our results indicate that PML-targeting strategies may prove effective at treating H3.3-mutated paediatric gliomas.

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Human ESC-based modeling of pediatric gliomas by K27M mutation in histone H3.3 variant

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Spontaneous DIPG Modeling Reveals Novel H3.3 K27M-Mediated Oncogenic Mechanisms Acting Through Epigenetic Effects

Project description:A mouse knock-in model engineered for Cre recombinase-activated expression of the endogenous mouse H3f3a allele generating an epitope-tagged H3.3 equipped with or without a K27M mutation to investigate H3.3 K27M effects on brain cell and tumor growth, gene expression and epigenetics. These samples are matched with H3K27me3 ChIPseq and RNAseq in GSE108364.

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Spontaneous DIPG Modeling Reveals Novel H3.3 K27M-Mediated Oncogenic Mechanisms Acting Through Epigenetic Effects [RNA-seq]

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Spontaneous DIPG Modeling Reveals Novel H3.3 K27M-Mediated Oncogenic Mechanisms Acting Through Epigenetic Effects [ChIP-seq]

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Single-cell epigenetic analysis reveals principles of chromatin states in H3.3-K27M gliomas

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