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Homo sapiens

ABSTRACT: ATRX mutant neuroblastoma is sensitive to EZH2 inhibition via modulation of neuronal differentiation

PROVIDER: PRJNA390893 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR10228530.fastq.gz	Fastqsanger.gz
	SRR10228531.fastq.gz	Fastqsanger.gz
	SRR10228532.fastq.gz	Fastqsanger.gz
	SRR10228533.fastq.gz	Fastqsanger.gz
	SRR10228534.fastq.gz	Fastqsanger.gz

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Similar Datasets

ATRX mutant neuroblastoma is sensitive to EZH2 inhibition via modulation of neuronal differentiation.

Project description:Mutations and structural alterations of the SWI/SNF-like chromatin remodeler ATRX have been reported at high frequency in a number of adult and pediatric tumors1. However, the consequences of ATRX (Alpha Thalassemia/Mental Retardation, X-linked) mutations in cancer and their underlying epigenetic sensitivities remain ill defined. Particularly intriguing are the large N-terminal deletions of ATRX in neuroblastoma that generate in-frame fusion (IFF) proteins1Â–3 devoid of key chromatin interaction domains. Here we demonstrate that neuroblastoma cells harbouring ATRX IFFs have distinct gene expression programs compared to neuroblastoma cells that are wild type for ATRX. This is due in part to H3K27me3-mediated silencing of REST (RE1 Silencing Transcription Factor) target genes involved in neuronal differentiation. In turn, we find that ATRX IFF cells display exquisite sensitivity to EZH2 inhibition in both adherent and tumorsphere conditions, due in part to derepression of neurogenesis genes, including REST targets. Examination of the epigenomic landscape of a pediatric neuroblastoma tumor harboring an ATRX IFF revealed that H3K27me3 occupies a subset of REST target genes that are transcriptionally silenced, and are sensitive to EZH2 inhibition in our cell-based assays. Thus, our study greatly advances our understanding of indolent neuroblastoma and identifies EZH2 inhibition as a potential therapy for patients with ATRX mutant disease. Further, these studies may be applicable to other ATRX mutant pediatric malignancies, particularly those carrying similar structural alterations of ATRX.

| EGAS00001002507 | EGA

ATRX mutant neuroblastoma is sensitive to EZH2 inhibition via modulation of neuronal differentiation

Project description:We report on the characterization of ATRX in-frame fusion neuroblastoma and identify that ATRX IFF proteins re-locate from H3K9me3 enriched regions to active chromatin, such as the promoter of neural repressor REST. We further identify that REST is upregulated in ATRX IFF NB and that several neurogenesis and REST target genes are transcriptionally downregulated. Through ChIP-seq analysis, we observe that REST is bound to ATRX IFF Down genes, which have higher levels of H3K27me3. We further show that ATRX in-frame fusion neuroblastoma cells are sensitive to EZH2 inhibitors through de-repression of H3K27me3 bound neuronal function genes, includiing a subset of REST targets.

2019-10-15 | GSE100148 | GEO

ATRX mutations mediate an immunogenic phenotype and macrophage infiltration in neuroblastoma.

Project description:ATRX is one of the most frequently mutated genes in high-risk neuroblastoma. ATRX mutations are mutually exclusive with MYCN amplification and mark a recognizable patient subgroup, presenting in older children with chemotherapy-resistant, slowly progressive disease. The mechanisms underlying how ATRX mutations drive high-risk and difficult-to-treat neuroblastoma are still largely elusive. To unravel the role of ATRX in neuroblastoma, we generated isogenic neuroblastoma cell line models of both ATRX loss of-function and ATRX in-frame multi-exon deletions, representing different types of alterations found in patients. RNA-sequencing analysis consistently showed significant upregulation of pathways implicated in inflammatory responses and epithelial-to- mesenchymal transition in the ATRX-mutant cell lines. In vivo, ATRX mutations mediate macrophage recruitment in xenograft models. This was further confirmed in patient-derived xenograft models. In support of this, bioinformatic analysis of previously published neuroblastoma patient data sets revealed an immunogenic phenotype and higher score of macrophages (with no distinction between M1 and M2 macrophage populations) and dendritic cells, but not lymphocytes, in ATRX-mutant versus ATRX wildtype tumors. Histopathological assessment of diagnostic samples from patients with ATRX mutant disease confirmed these findings with more macrophage infiltration compared to MYCN-amplified tumors. In conclusion, these results highlight that in contrast to MYCN-amplified neuroblastoma, which is associated with a cold immune microenvironment, ATRX-mutated neuroblastoma is characterized by a distinct immunogenic phenotype.

2025-02-10 | GSE277158 | GEO

Targeting EZH2 in MYCN-amplified Neuroblastoma [ChIP-seq]

Project description:Purpose: Identify new targets in MYCN-amplified Neuroblastoma Methods: ChIP-Seq experiments were performed on Kelly and LAN-1 neuroblastoma cells by using the following antibodies: anti-EZH2 (Cell Signaling 5246S); anti-H3K27me3 (Millipore 07-449); anti-H3K4me3 (Abcam ab8580). We evaluated the global EZH2 PRC2-dependence by identifiying direct genome-wide target genes for EZH2, H3K27me3 and H3K4me3. Results: We found that EZH2 serves a PRC2-dependent function in neuroblastoma, repressing neuronal differentiation. Moreover, EZH2-regulated genes were strongly repressed in MYCN-amplified and high-risk primary tumors. Conclusion: Our study supports testing EZH2 inhibitors in patients with MYCN-amplified neuroblastoma.

2017-12-02 | GSE85430 | GEO

Mus musculus

Project description:Atrx facilitate normal neuronal differentiation

| PRJNA297036 | ENA

SW480 cells undergoes postmitotic neuron-like differentiation in response to EZH2 knockdown

Project description:Formerly we found that combined inhibition of class I HDACs, DNMTs, EZH2 and LSD1 with chemical inhibitors in a variety of cancer cells caused neuronal differentiation. Our recent study demonstrated that functional knockdown of EZH2 alone in SW480 cells can also lead to significant neuronal differentiation. We used microarray to analyze global gene expression change in SW480 cells after neuronal differentiation induced by EZH2 knockdown.

2018-12-31 | GSE118593 | GEO

Homo sapiens

Project description:EZH2 regulates neuroblastoma cell differentiation via NTRK1 promoter epigenetic modifications

| PRJNA385803 | ENA

ATRX histone binding and helicase activities have distinct roles in neuronal differentiation

Project description:We have identified the distinct effects on neuronal differentiation of two different mutations of ATRX. We generated E14 mouse embryonic stem cell lines with mutations in the histone binding domain of ATRX (PHDmut) or in the helicase domain (K1584R). Neurodifferentiation is both delayed and compromised in PHDmut and K1584R, and manifest differently from complete ATRX loss. We performed ATRX ChIP-seq which showed changes in occupancy of ATRX in PHDmut and K1584R. Our CUT&RUN and RNA-Seq reveal that mutations or deficiency of ATRX result in separate patterns of dysregulation in gene expression and PRC2 binding, suggesting different roles of each ATRX domain in neuronal differentiation

2022-09-01 | GSE193910 | GEO

Two opposing gene expression patterns within ATRX aberrant neuroblastoma

Project description:To study the role of distinct ATRX aberrations in neuroblastoma we created isogenic ATRX aberrant models using CRISPR-Cas9 in several neuroblastoma cell lines and one tumoroid. We created ATRX knock-out models, ATRX in-frame exon 2-10 deletions and ATRX in-frame exon 2-13 deletions. Additionally, we included patient-derived models data (i.e. cell line data and one tumoroid).

2023-03-16 | GSE226770 | GEO

ARID1A-deficient Bladder Cancer is Dependent on PI3K Signaling, and can be Targeted via EZH2 and/or PI3K Pharmacologic Inhibition: Therapeutic Implications

Project description:ARID1A-mutant bladder cancer is dependent on PI3K signaling and is sensitive to EZH2 and/or PI3K inhibition. Clinical trials in molecularly selected patients should be considered.

2022-08-22 | GSE203033 | GEO

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