Atrx deletion in neurons leads to sexually-dimorphic dysregulation of miR-137 and spatial learning and memory deficits
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE129975 | GEO | 2020/06/30
REPOSITORIES: GEO
Similar Datasets
Project description: Not available
| S-EPMC7326465 | biostudies-literature
Project description:Atrx deletion in neurons leads to sexually-dimorphic dysregulation of miR-137 and spatial learning and memory deficits
| PRJNA533318 | ENA
Project description:ATRX, a chromatin remodeler protein, is recurrently mutated in H3F3A-mutant pediatric glioblastoma (GBM) and IDH-mutant grade 2/3 adult glioma. Previous work has shown that ATRX-deficient GBM cells show enhanced sensitivity to irradiation, but the etiology remains unclear. We found that ATRX binds regulatory elements of cell cycle phase transition genes in GBM cells, and there is a marked reduction in Checkpoint Kinase 1 (CHEK1) expression with ATRX loss, leading to early release of G2/M entry after irradiation. ATRX-deficient cells exhibit enhanced activation of master cell cycle regulator ATM with irradiation. Mice intra-cranially implanted with ATRX-deficient GBM cells demonstrate doubling of median survival compared to the ATRX-Wild Type controls when treated with ATM inhibitor AZD0156 and radiation. This study demonstrates that ATRX-deficient high-grade gliomas (HGGs) display epigenetic dysregulation of cell cycle phase transitions, which opens a new window for therapies targeting this unique phenotype.
2022-01-18 | GSE178114 | GEO
Project description:ATRX, a chromatin remodeler protein, is recurrently mutated in H3F3A-mutant pediatric glioblastoma (GBM) and IDH-mutant grade 2/3 adult glioma. Previous work has shown that ATRX-deficient GBM cells show enhanced sensitivity to irradiation, but the etiology remains unclear. We found that ATRX binds regulatory elements of cell cycle phase transition genes in GBM cells, and there is a marked reduction in Checkpoint Kinase 1 (CHEK1) expression with ATRX loss, leading to early release of G2/M entry after irradiation. ATRX-deficient cells exhibit enhanced activation of master cell cycle regulator ATM with irradiation. Mice intra-cranially implanted with ATRX-deficient GBM cells demonstrate doubling of median survival compared to the ATRX-Wild Type controls when treated with ATM inhibitor AZD0156 and radiation. This study demonstrates that ATRX-deficient high-grade gliomas (HGGs) display epigenetic dysregulation of cell cycle phase transitions, which opens a new window for therapies targeting this unique phenotype.
2022-01-18 | GSE178113 | GEO
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.
2020-03-09 | PXD017806 | Pride
Project description:Purpose: the chromatin-remodeler ATRX is frequently mutated in a range of human malignancies including pediatric and adult gliomas, and its loss underlies induction of alternative lengthening of telomeres (ALT) pathway for chromosome-end maintenance. But how ATRX exters its glioma suppresor role remains unclear. Here, we combine RNAi and somatic deletion approaches to demonstrate ATRX as a glioma suppressor controlling neural differentiation. Loss of ATRX promotes gliomagenesis by blocking neuronal progenitors from undergoing terminal maturation. Our findings provide the molecular and cellular mechanism underline ATRX's function in gliomagenesis.
2015-10-01 | GSE73447 | GEO
Project description:The genome consists of non-B-DNA structures such as G-quadruplexes (G4) that are involved in the regulation of genome stability and transcription. Telomeric-repeat containing RNA (TERRA) is capable of folding into G-quadruplex and interacting with chromatin remodeler ATRX. Here we show that TERRA modulates ATRX occupancy on repetitive sequences and over genes, and maintains DNA G-quadruplex structures at TERRA target and non-target sites in mouse embryonic stem cells. TERRA prevents ATRX from binding to subtelomeric regions and represses H3K9me3 formation. G4 ChIP-seq reveals that G4 abundance decreases at accessible chromatin regions, particularly at transcription start sites (TSS) after TERRA depletion; such G4 reduction at TSS is associated with elevated ATRX occupancy and differentially expressed genes. Loss of ATRX alleviates the effect of gene repression caused by TERRA depletion. Immunostaining analyses demonstrate that knockdown of TERRA diminishes DNA G4 signals, whereas silencing ATRX elevates G4 formation. Our results uncover an epigenetic regulation by TERRA that sequesters ATRX and preserves DNA G4 structures.
2022-11-09 | GSE194038 | GEO
Project description:Heterochromatin Protein 1 (HP1) is a major regulator of chromatin structure and function. In animals, the network of proteins interacting with HP1 is mainly associated with constitutive heterochromatin marked by H3K9me3. HP1 physically interacts with the putative orthologue of the SNF2 chromatin remodeler ATRX, which controls deposition of the histone variant H3.3 in mammals. In Arabidopsis thaliana, we show that the orthologue of ATRX participates in H3.3 deposition and characterize the function of conserved domains of plant ATRX. We show that the plant Like HP1 (LHP1) interacts with ATRX through domains that evolved specifically in land plants ancestors. Interaction between ATRX and LHP1 affects the expression of a limited subset of genes controlled by the POLYCOMB REPRESSIVE COMPLEX 2 (PRC2), including the flowering time regulator FLC. In the context of flowering time, ATRX function requires the novel LHP1-interacting domain and the ATPase of the ATRX SNF2 helicase. We conclude that distinct evolutionary pathways led to interaction between ATRX and HP1 in mammals or its counterpart LHP1 in plants, resulting in distinct modes of transcriptional regulation.
2018-06-26 | GSE101777 | GEO
Project description:In mammals, dosage compensation entails inactivation of an entire X chromosome in female cells. X-chromosome inactivation (XCI) depends on the long noncoding RNA Xist and its recruitment of Polycomb Repressive Complex 2 (PRC2). How PRC2 specifically interacts with Xist and other Polycomb targets remains unclear. Using XCI as a model, we take an unbiased proteomics approach to search for new Xist and PRC2 regulators. We identify ATRX, a chromatin remodeler associated with mental retardation, alpha thalassemia, and cancer in humans. We show that ATRX is a high-affinity RNA-binding protein. ATRX directly interacts with RepA/Xist RNA and is required for loading of PRC2 onto the RNA in vivo. The Xist gene is a hotspot of ATRX occupancy. Without ATRX, PRC2 cannot load onto Xist RNA nor spread in cis along the X-chromosome. Epigenomic profiling reveals a dependency of PRC2 on ATRX that extends beyond XCI. Depleting ATRX results in genome-wide disruptions to PRC2 localization and trimethylation of histone H3-lysine 27 (H3K27me3). PRC2 is displaced from genes and relocalized to intergenic space, causing reduced H3K27me3 and concomitant changes in expression of Polycomb targets. We conclude that ATRX is a required specificity determinant for PRC2 targeting and function.
2014-11-07 | GSE56981 | GEO
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