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ATRX Deficiency Drives Aberrant Type I Interferon Signalling Through cGAS-Dependent Transcriptional Dysregulation [Cut&Tag: ATRX]

ABSTRACT: The X-linked α-thalassaemia intellectual disability syndrome (ATRX) protein is a chromatin remodeller involved in transcriptional regulation and genome stability. While the importance of ATRX in development and malignancy is well recognised, its role in innate immunity is less well defined. Here we describe three unrelated patients with ATR-X syndrome carrying missense mutations in the ATPase domain of ATRX, each manifesting features of severe inflammation accompanied by persistent upregulation of interferon-stimulated gene expression in whole blood. Studies in patient-derived cells, CRISPR-engineered fibroblasts and neuronal models demonstrate that ATRX loss-of-function mutations drive enhanced type I interferon signalling through a cGAS-dependent mechanism uncoupled from the DNA sensing activity of cGAS. Mechanistically, ATRX deficiency disrupts the chromatin distribution of DAXX and H3.3, with cGAS essential for the changes in nucleosome composition and gene expression mediated by loss of ATRX. Thus, our study highlights a previously unrecognized link between ATRX dysfunction and inflammation involving a non-canonical role of cGAS.

ORGANISM(S): Homo sapiens

PROVIDER: GSE329644 | GEO | 2026/08/24

REPOSITORIES: GEO

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Project description:In mammals, DNA methylation is essential for protecting repetitive sequences from aberrant transcription, translocation, and homologous recombination. However, DNA hypomethylation occurs during specific developmental stages (e.g. preimplantation embryos) and in certain cell types (e.g., primordial germ cells). The absence of dysregulated repetitive elements in these cells suggests the existence of alternative mechanisms that prevent genome instability triggered by DNA hypomethylation. In this report, we seek to elucidate the factors that play a critical role in ensuring genome stability by focusing on DAXX and ATRX, two proteins that have been linked to transcriptional control and epigenetic regulation. We carried out ChIP-seq and RNA-seq analyses to compare the genome-wide binding and transcriptome profiles of DAXX and ATRX in mouse ES (mES) cells triple knocked out for the three mammalian DNA methyltransferases (DNMTs) (TKO cells) to those in wildtype mES cells. Our data indicate that DAXX and ATRX are distinct in their chromatin-binding profiles and highly co-enriched at tandem repetitive elements. Global DNA hypomethylation, as was the case in TKO cells, further promoted the recruitment of the DAXX/ATRX complex to tandem repeat sequences including IAP (intracisternal A‐particle) retrotransposons and telomeres. Inhibition of DAXX or ATRX in cells with hypomethylated genomes (e.g., TKO cells, mES cells cultured in ground-state conditions, and preimplantation embryos) increased aberrant transcriptional de-repression of repeat elements and dysfunction at telomeres. Furthermore, we provide evidence that DAXX/ATRX-dependent silencing may occur through DAXX’s interaction with SUV39H1 and increased H3K9me3 on repetitive sequences. Our study suggests that DAXX and ATRX are important for safeguarding the genome, particularly in silencing repetitive elements in the absence of DNA methylation. We tested the hypothesis that the DAXX/ATRX complex participates in protecting repetitive elements in the absence of DNA methylation. To this end, we investigated genome-wide chromatin targeting of DAXX and ATRX in wildtype mES cells, and in mES cells that exhibit extensive loss of DNA methylation due to homozygous knockout of all three DNA.

Dataset Information

ATRX Deficiency Drives Aberrant Type I Interferon Signalling Through cGAS-Dependent Transcriptional Dysregulation [Cut&Tag: ATRX]

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