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ATRX histone binding and helicase activities have distinct roles in neuronal differentiation

ABSTRACT: We have identified the distinct effects on neuronal differentiation of two different mutations of ATRX. We generated E14 mouse embryonic stem cell lines with mutations in the histone binding domain of ATRX (PHDmut) or in the helicase domain (K1584R). Neurodifferentiation is both delayed and compromised in PHDmut and K1584R, and manifest differently from complete ATRX loss. We performed ATRX ChIP-seq which showed changes in occupancy of ATRX in PHDmut and K1584R. Our CUT&RUN and RNA-Seq reveal that mutations or deficiency of ATRX result in separate patterns of dysregulation in gene expression and PRC2 binding, suggesting different roles of each ATRX domain in neuronal differentiation

ORGANISM(S): Mus musculus

PROVIDER: GSE193910 | GEO | 2022/09/01

REPOSITORIES: GEO

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Genome-wide ChIP seq of H3.3 in WT and ATRX KO mouse ES cells

Project description:Regions of H3.3 binding in WT and ATRX KO mouse ES cells were identified by ChIP seq Chip-seq experiements were performed in WT and ATRX KO E14 mouse ES cells

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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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Functional loss of ATRX and telomerase activates Alternative Lengthening of Telomeres (ALT)

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The chromatin remodelling factor ATRX suppresses R-loops in transcribed telomeric repeats

Project description:ATRX is a chromatin remodelling factor found at a wide range of tandemly repeated sequences including telomeres (TTAGGG)n. Acquired mutations in ATRX are found in nearly all tumours which maintain their telomeres via the alternative lengthening of telomere (ALT) pathway and ATRX is known to suppress this pathway. Here we show that recruitment of ATRX to telomeric repeats is dependent on their number, their orientation and, critically, on their transcription. Importantly, the transcribed telomeric repeats form RNA-DNA hybrids (R-loops) whose abundance correlates with the recruitment of ATRX. Here we show loss of ATRX is also associated with an increase in R-loop formation. These findings suggest that the presence of ATRX at telomeres may reflect a central role in suppressing deleterious DNA secondary structures which form at transcribed telomeric repeats, and this may account for the increases in DNA damage, stalling of replication and homology directed repair previously observed upon loss of ATRX function.

2017-09-08 | GSE96768 | GEO

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