Quantitative Analysis of Transcriptional Changes in Atrx Conditional Knockout Mice
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE273097 | GEO | 2024/10/01
REPOSITORIES: GEO
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Project description:Loss of the Atrx chromatin remodeling protein causes dysfunction and death of post-mitotic retinal interneurons in mice. Embryonic conditional deletion of Atrx from multipotent retinal progenitor cells results in the selective loss of the retinal inhibitory interneurons, namely amacrine and horizontal cells. The cell death occurs postnatally after the development of these cell types, peaking at postntal day 17 in the mouse retina. Identification of molecular factors and pathways that mediate the health and survival of these neurons may suggest novel therapeutic strategies for neuroprotection in ATR-X syndrome and other neurodegenerative diseases. We performed gene expression profiling of wildtype and Atrx conditional knockout mouse retina tissues to identify putative targets of Atrx and molecular pathways that underlie the neurodegenerative phenotype.
2016-09-09 | GSE78877 | 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:ATRX is a chromatin remodelling protein of the SWI/SNF family, mutations in which cause alpha thalassemia X-linked (ATRX) intellectual disability syndrome and are highly associated with a number of cancers characterized by alternative lengthening of telomeres. ATRX functions with the histone chaperone DAXX to facilitate deposition of the histone variant H3.3 at heterochromatic regions such as telomere and pericentric repeats, resulting in a unique form of heterochromatin characterized by both trimethylation of histone H3 at lysine 9 (H3K9me3) and H3.3. How ATRX is recruited to these regions remain unclear.To better understand it, we therefore used immunoprecipitation-coupled to mass spectrometry (IP-MS) to identify potential factors that interact with ATRX and may promote its localization and function. Based on our proteomics results, we identified known ATRX-interacting proteins, DAXX and MRE11. We also identified a number of proteins that have been genetically linked to G-quadruplex structures. Interestingly, we identified members of DNA replcation machinery MCM complex (e.g. MCM2, MCM4, MCM6, and MCM7) and the faciliates chromatin transcription (FACT) comeplex as novel ATRX-interacting proteins. We then verified the interaction of ATRX to MCM proteins and FACT subunits by co-immunoprecipition/immunoblot and proximity ligation assay.
2020-06-03 | MSV000085543 | MassIVE
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
Project description:ATRX is a member of the SWI2/SNF2 family of chromatin remodeling proteins and primarily functions at heterochromatic loci via its recognition of M-bM-^@M-^XrepressiveM-bM-^@M-^Y histone modifications (e.g., H3K9me3). Despite significant roles for ATRX during normal neural development, as well as its relationship to human disease, ATRX function in the central nervous system is not well understood. Here, we describe ATRXM-bM-^@M-^Ys ability to recognize an activity-dependent combinatorial histone modification, H3K9me3S10ph, in post-mitotic neurons. In neurons, this M-bM-^@M-^\methyl/phosM-bM-^@M-^] switch occurs exclusively following periods of stimulation and is highly enriched at heterochromatic repeats associated with centromeres. Using a multifaceted approach, we reveal that H3K9me3S10ph bound Atrx represses non-coding transcription of centromeric minor satellite sequences during instances of heightened activity. Our results indicate an essential interaction between ATRX and a previously uncharacterized histone modification in the central nervous system and suggest a potential role for abnormal repetitive element transcription in pathological states manifested by ATRX dysfunction. For Atrx ChIP-seq, IPs were performed on three control vs. three KCl stimulated (all representing biological, and not technical replicates) primary cultured mouse cortical neurons at DIV 8. All samples were normalized to background input levels. For H3K9me3S10phos ChIP-seq, biological singlecates (control vs. forskolin) were analyzed against respective inputs.
2015-01-02 | E-GEOD-64062 | biostudies-arrayexpress
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
Project description:We investigated the role of the chromatin remodeling protein ATRX on chromatin accessibility of HCMV genomes during the IE phase of lytic infections
2024-08-28 | GSE262839 | GEO
Project description:ATRX is a member of the SWI2/SNF2 family of chromatin remodeling proteins and primarily functions at heterochromatic loci via its recognition of ‘repressive’ histone modifications (e.g., H3K9me3). Despite significant roles for ATRX during normal neural development, as well as its relationship to human disease, ATRX function in the central nervous system is not well understood. Here, we describe ATRX’s ability to recognize an activity-dependent combinatorial histone modification, H3K9me3S10ph, in post-mitotic neurons. In neurons, this “methyl/phos” switch occurs exclusively following periods of stimulation and is highly enriched at heterochromatic repeats associated with centromeres. Using a multifaceted approach, we reveal that H3K9me3S10ph bound Atrx represses non-coding transcription of centromeric minor satellite sequences during instances of heightened activity. Our results indicate an essential interaction between ATRX and a previously uncharacterized histone modification in the central nervous system and suggest a potential role for abnormal repetitive element transcription in pathological states manifested by ATRX dysfunction.
2015-01-02 | GSE64062 | GEO
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: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.
2016-04-05 | E-GEOD-70920 | biostudies-arrayexpress