ATRX safeguards cellular identity during C. elegans development

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. In addition, XNP-1 is required to repress the inappropriate activation of germline genes. Importantly, this germline misexpression correlates with most of the phenotypes observed in xnp-1 animals. Seemingly distinct xnp-1 phenotypes such as developmental abnormalities and telomeric defects are both suppressed by mutation of the germline transcription factor gsox-1 . These findings suggest that the majority of XNP-1-dependent phenotypes stem from its role in maintaining proper cellular identity, offering insights into the functions of ATRX in humans.