Nature Communications· 2026Q1
ATRX deficiency drives aberrant type I interferon signalling through cGAS-dependent transcriptional dysregulation
- 2citations
- Q1SCImago
- 2026year
Short summary
Loss of ATRX function, identified in patients with white matter disease and learning difficulties, enhances type I interferon signaling through a non-canonical, cGAS-dependent mechanism that dysregulates gene expression.
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Key points
- ATRX deficiency, observed in patients with neurological disorders, enhances type I interferon signaling.
- This enhanced signaling is mediated by a cGAS-dependent mechanism independent of cGAS's DNA sensing role.
- Loss of ATRX function alters the chromatin association of DAXX and H3.3.
- cGAS is crucial for the nucleosome composition and gene expression changes caused by ATRX deficiency.
AI-generated from the title and abstract; the full text is not read.
Abstract
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. In two unrelated patients demonstrating cerebral white matter disease, learning difficulties and a persistent upregulation of interferon stimulated gene expression in whole blood, we identified the same Y1758C missense substitution in ATRX. Using patient-derived cells, engineered fibroblasts and neuronal models, we show that this substitution, and other loss of function mutations in ATRX, result in enhanced type I interferon signalling through a cGAS-dependent mechanism uncoupled from the DNA sensing activity of cGAS. Loss of ATRX function leads to alterations in the chromatin distribution of DAXX and H3.3, with cGAS essential for the changes in nucleosome composition and gene expression mediated by ATRX deficiency. Thus, our study highlights a previously unrecognized link between ATRX dysfunction and inflammation involving a non-canonical role of cGAS.
The authors' abstract, as published at the source. Nature Communications, 2026 · DOI ↗
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ImmunologyImmunology and Microbiology