ATRX deficiency drives aberrant type I interferon signalling through cGAS-dependent transcriptional dysregulation
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 link between ATRX dysfunction and inflammation involving a non-canonical role of cGAS.
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BibTeX
@article{eldaher2026atrx,
title = {{ATRX deficiency drives aberrant type I interferon signalling through cGAS-dependent transcriptional dysregulation}},
author = {Marie-Thérèse A. El-Daher and Eve L. White and Andreas Fellas and Graeme Grimes and Simone Pelliciari and Gaofeng Zhu and Tom A. Tait and Carolina Uggenti and Natalie Blair and Erisa Nita and Philippe Gautier and Hywel Dunn-Davies and Sophie Glen and Somdutta Dhir and Mathieu P. Rodero and Gillian I. Rice and Luis Seabra and Richard Clark and Angie Fawkes and Joseph A. Marsh and Minke HW Huibers and Joost B. Koedijk and Erika Van Nieuwenhove and John H. Livingston and Evangeline Wassmer and Swati Naik and Julie Vogt and Bertrand Isidor and Tom D. Deegan and Alice Lepelley and Rebekah Tillotson and Patrick Revy and Richard J. Gibbons and Yanick J. Crow},
journal = {Nature Communications},
year = {2026},
month = oct,
doi = {10.1038/s41467-026-78094-8},
url = {https://www.nature.com/articles/s41467-026-78094-8},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - ATRX deficiency drives aberrant type I interferon signalling through cGAS-dependent transcriptional dysregulation
AU - Marie-Thérèse A. El-Daher
AU - Eve L. White
AU - Andreas Fellas
AU - Graeme Grimes
AU - Simone Pelliciari
AU - Gaofeng Zhu
AU - Tom A. Tait
AU - Carolina Uggenti
AU - Natalie Blair
AU - Erisa Nita
AU - Philippe Gautier
AU - Hywel Dunn-Davies
AU - Sophie Glen
AU - Somdutta Dhir
AU - Mathieu P. Rodero
AU - Gillian I. Rice
AU - Luis Seabra
AU - Richard Clark
AU - Angie Fawkes
AU - Joseph A. Marsh
AU - Minke HW Huibers
AU - Joost B. Koedijk
AU - Erika Van Nieuwenhove
AU - John H. Livingston
AU - Evangeline Wassmer
AU - Swati Naik
AU - Julie Vogt
AU - Bertrand Isidor
AU - Tom D. Deegan
AU - Alice Lepelley
AU - Rebekah Tillotson
AU - Patrick Revy
AU - Richard J. Gibbons
AU - Yanick J. Crow
PY - 2026
DA - 2026/10/08
JO - Nature Communications
DO - 10.1038/s41467-026-78094-8
UR - https://www.nature.com/articles/s41467-026-78094-8
AB - 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 link between ATRX dysfunction and inflammation involving a non-canonical role of cGAS.
SN - 2041-1723
ER -