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Two opposing gene expression patterns within ATRX aberrant neuroblastoma

ABSTRACT: 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).

ORGANISM(S): Homo sapiens

PROVIDER: GSE226770 | GEO | 2023/03/16

REPOSITORIES: GEO

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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.

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Profiling of SF188 ATRX isogenic glioma cells

Project description:Methylation profiling of SF188 paediatric high grade glioma cell line isogenic clones carrying CRISR/Cas9 frameshift deletions in ATRX

2019-06-01 | E-MTAB-7800 | biostudies-arrayexpress

Two opposing gene expression patterns within ATRX aberrant neuroblastoma

Project description:Two opposing gene expression patterns within ATRX aberrant neuroblastoma

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MYCN Amplification and ATRX Mutations are Incompatible in Neuroblastoma

Project description:Age and stage of disease at diagnosis is associated with outcome in neuroblastoma. A previous study identified ATRX point mutations and in-frame deletions in older patients with stage 4 disease. To validate the frequency of ATRX mutations and assess the relation of mutations and known prognostic variables, we collaborated with the Children’s Oncology Group and sequenced the entire ATRX genomic locus in 475 neuroblastoma tumor samples to validate the frequency of ATRX mutations and assess the relation of mutations and known prognostic variables. Older age at diagnosis, stage 4 disease, and unfavorable histology were significantly associated with mutations in the ATRX gene; MYCN amplification was mutually exclusive from ATRX mutations. To directly test if ATRX mutations and MYCN amplification are incompatible in neuroblastoma, we mutated the ATRX gene in MYCN amplified neuroblastoma cell lines and ectopically expressed MYCN in ATRX mutant neuroblastoma cell lines. Both approaches showed that ATRX and MYCN amplification are incompatible in neuroblastoma in culture and in vivo. To gain a better understanding of the underlying molecular and cellular mechanisms of this incompatibility, we performed a series of experiments including telomere analysis, epigenetic profiling, electron microscopic analysis and metabolic profiling. We discovered that induction of MYCN expression in ATRX mutant neuroblastomas cells leads to metabolic reprogramming, mitochondrial dysfunction, increased reactive oxygen species and replicative stress. We propose that this leads to synthetic lethality in ATRX mutant neuroblastomas because of the underlying replicative stress in those cells as a result of dysfunction of this essential histone chaperone.

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The chromatin remodeler ATRX binds to atypical chromatin domains at the 3â exons of ZNF genes to preserve H3K9me3 enrichment

Project description:Here, we report that ATRX co-localizes with the H3K9-methyl transferase SETDB1 (also known as ESET), the co-repressor TRIM28 (also known as KAP1), and the transcription factor ZNF274 at 3â exons of Zinc Finger Genes (ZNFs) containing an atypical H3K9me3/H3K36me3 chromatin signature. Disruption of ATRX and ZNF274 leads to a significant reduction of H3K9me3, particularly at the 3â ZNF exons and other atypical chromatin regions, higher percentages of DNA damage, and defects in cell cycle. Taken together, our studies suggest that ATRX binds the 3â exons of ZNFs to maintain genomic stability through the regulation of their H3K9me3 levels XL-MNase ChIP-seq of ATRX was performed in the erythroleukemic cell line K562 and the Neuroblastoma cell line LAN6. Two independent replicates using different ATRX antibodies were performed in K562. Additionally, Native ChIP-seq of H3K9me3 in LAN6, ATRX WT and ATRX KO K562 cells was performed. Input samples were sequenced as control.

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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.

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PCGP ATRX ChIP-Seq1 - samples

Project description:ChIP-Seq files for PCGP ATRX study paper titled "MYCN Amplification and ATRX Mutations are Incompatible in Neuroblastoma"

| EGAD00001004429 | EGA

PCGP ATRX WGBS1 - samples

Project description:WGBS files for PCGP NBL_MYCN_ATRX paper titled "MYCN Amplification and ATRX Mutations are Incompatible in Neuroblastoma"

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Epigenomic analysis of Atrx deficiency in murine glioma cells of orgin [Atrx ChIP]

Project description:The chromatin regulator ATRX is inactivated in large subsets of adult and pediatric glioma. Whether and how ATRX deficiency promotes oncogenesis by epigenomic dysregulation remains unclear. We found that Atrx loss, especially when coupled with Tp53 inactivation, promoted cell motility and modulated differentiation state in primary murine neuroepithelial progenitors, recapitulating characteristic disease phenotypes and molecular features. Moreover, Atrx deficiency induced widespread shifts in chromatin accessibility, histone composition, and gene transcription at vacant Atrx binding sites distributed across the genome. Finally, target genes mediating Atrx-deficient phenotypes in vitro exhibited similarly selective misexpression in ATRX-mutant human glioma tissues and cell lines. These findings demonstrate that, in appropriate physiological contexts, ATRX deficiency and its epigenomic sequelae are sufficient to induce disease-defining oncogenic phenotypes.

2017-12-31 | GSE100462 | GEO

Mapping RNA interactions of human ATRX with RepA fragment of Xist

Project description:Heterochromatin in the eukaryotic genome is rigorously controlled by the concerted action of protein factors and RNAs. Here, we investigate the RNA binding function of ATRX, a chromatin remodeler with roles in silencing of repetitive regions of the genome and in recruitment of the polycomb repressive complex 2 (PRC2). We identify ATRX RNA binding regions (RBRs) and discover that the major ATRX RBR lies within the N-terminal region of the protein, distinct from its PHD and helicase domains. Deletion of this ATRX RBR (ATRXRBR) compromises ATRX interactions with RNAs in vitro and in vivo and alters its chromatin binding properties. Genome-wide studies reveal that loss of RNA interactions results in a redistribution of ATRX on chromatin. Finally, our studies identify a role for ATRX-RNA interactions in regulating PRC2 localization to a subset of polycomb target genes.

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