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ATRX inactivation disrupts global chromatin state and topology to dysregulate neurodevelopmental pathways in glioma cells of origin [CTCF CUT&TAG]

ABSTRACT: Our analysis reports increase in CTCF occpancy in Atrx- murine NPCs as compared to Atrx+ cells

ORGANISM(S): Mus musculus

PROVIDER: GSE309142 | GEO | 2026/07/01

REPOSITORIES: GEO

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ATRX inactivation disrupts global chromatin state and topology to dysregulate neurodevelopmental pathways in glioma cells of origin

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ATRX inactivation disrupts global chromatin state and topology to dysregulate neurodevelopmental pathways in glioma cells of origin [Hi-C]

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ATRX inactivation disrupts global chromatin state and topology to dysregulate neurodevelopmental pathways in glioma cells of origin [CTCF CUT&TAG]

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Alternative Lengthening of Telomeres (ALT) and ATRX inactivation in high grade pediatric osteosarcomas

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SILAC-iPOND analysis of WT vs ATRX KO eHAP cells ± HU

Project description:Mutations in the ATRX chromatin remodeller predispose to a developmental genetic disorder and cancer, but how ATRX safeguards genome and telomere stability remains unresolved. Here, we uncover critical dependencies for the CTC1-STN1-TEN1 (CST) complex and RAD9A-HUS1-RAD1 (9-1-1) clamp in ATRX deficient cells. ATRX:CST synthetic lethality manifests following accumulation of telomeric G-rich ssDNA, which results in telomere loss and cell death. Conversely, we attribute ATRX:9-1-1 synthetic lethality to genome-wide ssDNA lesions, which compromise DNA replication. We further show that ATRX suppresses DNA damage during replication stress by counteracting the activity of the FAM111A protease. We demonstrate that roles of ATRX in telomere maintenance and replication are genetically separable, requiring its ATPase activity and PIP-box, respectively. We also show that such roles protecting genome stability are largely independent of the ATRX-DAXX interaction. Collectively, our data show that functions of ATRX in suppressing toxic ssDNA lesions are context-dependent and are key to global DNA replication and telomere integrity.

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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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