Investigating the role of the chromatin remodeller XNP-1 in C. elegans

Abstract

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.

Date of Award	12 Jun 2024
Original language	English
Awarding Institution	University of St Andrews
Supervisor	Helder Ferreira (Supervisor)