Investigating the role of the chromatin remodeller XNP-1 in C. elegans
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ATRX is a member of the SWI/SNF family of chromatin remodellers. ATRX loss causes pleiotropic phenotypes, including the neurodevelopmental disorder ATR-X syndrome, de-repression of the alternative lengthening of telomere pathway, increased LTR retrotransposon expression and sensitivity to replication stress. How ATRX activity suppresses these phenotypes within a developmental context is unclear. Here, we use the model organism Caenorhabditis elegans to investigate the role of XNP-1, the ATRX homologue in worms. Unlike in other organisms, previous studies have shown that XNP-1 is not embryonic lethal, and only has slightly reduced fertility compared to a wildtype strain at 20°C. Only when grown at 25°C does XNP-1 loss cause sterility. We used this fact to explore the role of XNP-1/ATRX and how it suppressed such diverse phenotypes within a developmental context, which would not have been possible in other experimental systems. We found that XNP-1 represses LTR retrotransposon expression during germline development, in a mechanism independent of SET-25, a H3K9 trimethylase, but dependent on the replication-independent histone variant HIS-72. However, we discovered that LTR retrotransposon misexpression is unlikely to cause the developmental defects observed in xnp-1 mutants. We then took a more unbiased transcriptomic approach to investigate gene expression changes upon XNP-1 loss in embryos and the first larval stage. We found that XNP-1 represses the ectopic expression of germline genes, probably in a parallel pathway to the SynMuvB family of transcriptional regulators. Finally, we identified the causative mutation in a suppressor line previously isolated in a forward genetic screen. This enabled us to theorise on possible molecular roles XNP-1 may play at higher temperatures. Overall, we propose a model where germline misexpression is sufficient to cause the reduced brood size observed upon XNP-1 loss at 20°C, and where this misexpression contributes to the sterility phenotype observed upon XNP-1 loss at 25°C.
Thesis, PhD Doctor of Philosophy
Embargo Date: 2026-01-23
Embargo Reason: Thesis restricted in accordance with University regulations. Restricted until 23 January 2026
Description of related resourcesInvestigating the role of the chromatin remodeller XNP-1 in C. elegans (Thesis Data) Olver, J., University of St Andrews, 23 Jan 2026. DOI: https://doi.org/10.17630/3cdce624-5259-4253-819b-d9873cab2896
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