ATRX safeguards cellular identity during C. elegans development

Abstract

ATRX is a member of the SWI/SNF family of ATP-dependent chromatin remodellers. In humans, loss of ATRX function leads to ATRX syndrome, a neurodevelopmental disorder. ATRX mutation in human cell lines is associated with multiple phenotypes including activation of the alternative lengthening of telomere (ALT) pathway, upregulation of retrotransposons and increased sensitivity to replication stress. However, the principal role of ATRX and the reason why its mutation causes such diverse phenotypes is currently unclear. To address this, we studied the role of ATRX in the model organism Caenorhabditis elegans. We find that loss of XNP-1, the C. elegans homologue of ATRX, recapitulates many human phenotypes. Loss of XNP-1 causes ectopic activation of germline genes in somatic cells, indicating a loss of cellular identity control. Strikingly, mutation of the germline transcription factor gsox-1 suppresses both this misexpression and multiple xnp-1 phenotypes, including developmental delay and telomeric defects. These findings suggest that ectopic germline gene expression underlies the majority of XNP-1-dependent phenotypes, consistent with a role for XNP-1 in maintaining cellular identity, offering insights into the functions of ATRX in humans.