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ATRX loss couples genome instability at a G-rich repeat to dysregulation of human alpha-globin expression [scRNA-seq]

ABSTRACT: Germline mutations in the chromatin remodelling protein ATRX cause a severe developmental disorder associated with α-thalassemia. In addition, ATRX is amongst the twenty genes most frequently mutated in cancer. How ATRX mutations alter gene expression remains unclear. Using the α-globin locus as a model, here we show that ATRX deficiency downregulates α-globin in a subset of cells exhibiting DNA damage. A G-rich repeat at the α-globin locus serves as a potential site of G-quadruplex formation and DNA damage. ATRX binds this repeat co-transcriptionally, and its loss increases R-loop accumulation at this site, leading to local DNA damage and transcriptional disruption in cis. Deletion of this repeat abolishes this effect, while targeted DNA damage reinstates it. These findings reveal a mechanism linking ATRX’s role in genome stability to transcriptional regulation, and uncover a molecular basis of human genetic disease mediated by a long-range G-rich repeat.

ORGANISM(S): Homo sapiens

PROVIDER: GSE291201 | GEO | 2026/01/12

REPOSITORIES: GEO

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ATRX loss couples genome instability at a G-rich repeat to dysregulation of human alpha-globin expression [ChIP-seq]

Project description:Germline mutations in the chromatin remodelling protein ATRX cause a severe developmental disorder associated with α-thalassemia. In addition, ATRX is amongst the twenty genes most frequently mutated in cancer. How ATRX mutations alter gene expression remains unclear. Using the α-globin locus as a model, here we show that ATRX deficiency downregulates α-globin in a subset of cells exhibiting DNA damage. A G-rich repeat at the α-globin locus serves as a potential site of G-quadruplex formation and DNA damage. ATRX binds this repeat co-transcriptionally, and its loss increases R-loop accumulation at this site, leading to local DNA damage and transcriptional disruption in cis. Deletion of this repeat abolishes this effect, while targeted DNA damage reinstates it. These findings reveal a mechanism linking ATRX’s role in genome stability to transcriptional regulation, and uncover a molecular basis of human genetic disease mediated by a long-range G-rich repeat.

2026-01-12 | GSE291197 | GEO

ATRX-mediated chromatin association of histone variant macroH2A1 regulates alpha globin gene expression

Project description:The histone variant macroH2A generally associates with transcriptionally inert chromatin, however the factors that regulate its chromatin incorporation remain elusive. Here, we identify the SWI/SNF helicase, ATRX, as a novel macroH2A interacting protein. Unlike its role in assisting H3.3 chromatin deposition, ATRX acts as a negative regulator of macroH2A’s chromatin association. In human erythroleukemic cells deficient for ATRX, ChIP-sequencing studies reveal that macroH2A accumulates at the HBA gene cluster on the subtelomere of chromosome 16, coinciding with the loss of α globin expression. Collectively, our results implicate deregulation of macroH2A’s distribution as a contributing factor to the α thalassemia phenotype of ATRX syndrome. Mononucleosomes from K562 cells bearing integrated lentiviral shRNA constructs targeting either luciferase (shluc) or ATRX (sh92) were isolated and ChIP'd with mH2A1 antibody. DNA from shluc Input and the two mH2A1 ChIPs were isolated and sequenced on Illumina's Hiseq.

2012-03-08 | E-GEOD-35339 | biostudies-arrayexpress

ATRX loss couples genome instability at a G-rich repeat to dysregulation of human alpha-globin expression [ChIP-seq]

Project description:ATRX loss couples genome instability at a G-rich repeat to dysregulation of human alpha-globin expression [ChIP-seq]

| PRJNA1232184 | ENA

ATRX loss couples genome instability at a G-rich repeat to dysregulation of human alpha-globin expression [scRNA-seq]

Project description:ATRX loss couples genome instability at a G-rich repeat to dysregulation of human alpha-globin expression [scRNA-seq]

| PRJNA1232191 | ENA

G-quadruplex stabilizer CX-5461 effectively combines with ionizing radiation to selectively target ATRX-deficient malignant glioma [RNA-seq]

Project description:Mutational inactivation of α-thalassaemia/mental retardation X-linked (ATRX) represents a defining molecular feature in large subsets of adult and pediatric malignant glioma. ATRX deficiency gives rise to abnormal G-quadruplex (G4) DNA secondary structures at GC-rich regions of the genome, altering chromatin accessibility and enhancing DNA damage. Building on earlier work, we sought to assess the extent to which pharmacological G4 stabilization selectively enhances DNA damage and cell death in preclinical models of ATRX-deficient glioma. Deploying the G4 stabilizer CX-5461 in patient-derived glioma stem cells (GSCs) in vitro and in GSC murine flank and intracranial xenografts in vivo, we evaluated efficacy as both a single agent and in combination with ionizing radiation (IR), a central element of current treatment standards. CX-5461 promoted dose-sensitive lethality in ATRX-deficient GSCs relative to ATRX-intact controls. Mechanistic studies revealed that CX-5461 disrupted histone variant H3.3 deposition, enhanced replication stress and DNA damage pathways, activated p53-independent apoptosis, and induced G2/M arrest selectively in ATRX-deficient GSCs. These data were corroborated in vivo, where we notably demonstrated that combinational treatment leads to profound tumor growth delay and prolonged survival exclusively in ATRX-deficient flank tumors. In its totality, our work substantively demonstrates efficacy and defines mechanisms of action for a novel therapeutic strategy targeting ATRX-deficient malignant glioma, laying the groundwork for clinical translation.

2024-03-18 | GSE261563 | GEO

Mechanism suppressing transcription of the globin genes in Danio rerio nonerythroid cells

Project description:In genomes of modern fish and amphibia α- and β- globin genes are grouped at a single locus that may resemble the ancestral one and is syntenic to α-globin locus of modern warm-blooded vertebrates. In Danio rerio, the major locus of α/β globin genes comprises two subclusters, one of them harboring genes expressed in adult and the other – genes expressed in embryonic and larval erythrocytes. The results of our previous study suggested that the adult subcluster of this locus has evolved into α-globin gene domain of vertebrate animals. Here we studied how adult and embryo-larval genes of Danio rerio major globin gene locus are repressed in fibroblasts. The results obtained suggest that that at least some of the globin genes present within the adult subcluster are repressed by Polycomb similarly to human α-globin genes. Furthermore, within two α/β gene pairs repression of α-type and β-type genes appears to be mediated by different mechanisms as increasing the level of histone acetylation can activate transcription of only β-type genes.

2020-07-17 | GSE154562 | GEO

A SNF2 protein targets variable copy number repeats and thereby influences allele-specific expression

Project description:ATRX is an X-linked gene of the SWI/SNF family whose role in vivo is currently unknown. Mutations in ATRX cause syndromal mental retardation. ATRX binds to tandem repeat (TR) sequences both in heterochromatin (e.g. telomeres) and euchromatin. Genes associated with these TRs can be dysregulated when ATRX is mutated and the degree to which their expression changes is determined by the size of the TR, producing skewed allelic expression. This explains the nature of the affected genes, the variable phenotypes seen with identical ATRX mutations and also illustrates a new mechanism underlying variable penetrance. Many of the TRs in ATRX targets are G-rich and predicted to form non-B DNA structures (including G quadruplex) in vivo. We have shown that ATRX binds G quadruplex structures in vitro suggesting a mechanism by which ATRX may play a role in various nuclear processes and how this is perturbed when ATRX is mutated. 4 Human Erythroblast, 1 HEP3B and 1 Fibroblast ChIP-ChIP Sample For ChIP-Seq: one human erythroblasts, one mouse ES, one human erythroblast reference Sample, and one mouse ES input reference Sample.

2010-11-02 | E-GEOD-22162 | biostudies-arrayexpress

G-quadruplex stabilizer CX-5461 effectively combines with ionizing radiation to selectively target ATRX-deficient malignant glioma [CUT&Tag]

Project description:Mutational inactivation of ?-thalassaemia/mental retardation X-linked (ATRX) represents a defining molecular feature in large subsets of adult and pediatric malignant glioma. ATRX deficiency gives rise to abnormal G-quadruplex (G4) DNA secondary structures at GC-rich regions of the genome, altering chromatin accessibility and enhancing DNA damage. Building on earlier work, we sought to assess the extent to which pharmacological G4 stabilization selectively enhances DNA damage and cell death in preclinical models of ATRX-deficient glioma. To investigate the effect of G4 stabilization on histone variant H3.3 deposition on the genome, we treated patient-derived glioma stem cells (GSCs) with G4 stabilizer CX-5461 and performed cleavage under targets and tagmentation (CUT&Tag) for H3.3. Our analyses show that G4 stabilizer CX-541 disrupts H3.3 deposition in ATRX-deficient GSCs and likely enhances replication stress and DNA damage.

2024-03-18 | GSE261562 | GEO

ATRX-mediated chromatin association of histone variant macroH2A1 regulates alpha globin gene expression

2012-03-08 | GSE35339 | GEO

G-quadruplex stabilizer CX-5461 effectively combines with ionizing radiation to selectively target ATRX-deficient malignant glioma

Project description:Mutational inactivation of ?-thalassaemia/mental retardation X-linked (ATRX) represents a defining molecular feature in large subsets of adult and pediatric malignant glioma. ATRX deficiency gives rise to abnormal G-quadruplex (G4) DNA secondary structures at GC-rich regions of the genome, altering chromatin accessibility and enhancing DNA damage. Building on earlier work, we sought to assess the extent to which pharmacological G4 stabilization selectively enhances DNA damage and cell death in preclinical models of ATRX-deficient glioma. In this study, we assessed the extent to which G4 stabilization impacted genome-wide deposition of H3.3 in patient-derived glioma stem cells (GSCs). In order to evaluate the overlap of these H3.3 deposition sites with regions of the genome that bind ATRX, we performed cleavage under targets and tagmentation (CUT&Tag) for ATRX using GSC line TS 543. Our analyses show that G4 stabilizer CX-541 disrupts H3.3 deposition at regions of the genome that frequently bind ATRX.

2025-05-29 | GSE276481 | GEO

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