How does chromatin structure affect telomeres: using C. elegans to understand the functions of ATRX

Chromatin structure impacts all processes that require access to DNA. Thus, proteins that alter chromatin structure, particularly ATP-dependent chromatin remodelling enzymes are important mediators of DNA transcription, replication and repair.

The aim of this work is to understand the functions of the conserved chromatin remodelling protein, ATRX using the nematode worm, C. elegans. Mutation of human ATRX causes ATRX syndrome (a developmental disease) and has also been strongly linked to the alternative lengthening of telomeres (ALT) pathway in cancers. These diverse ATRX phenotypes have been difficult to reconcile using only tissue culture systems. However, C. elegans is a tractable developmental model organism that has been previously used to study ALT and has a clear ATRX homolog, XNP-1. Moreover, we have preliminary evidence that xnp-1 mutation results in long telomeres in C. elegans, which may be indicative of ALT. This project will study how XNP-1 works within a developmental context and test the hypothesis that its role in H3.3 deposition at telomeres is evolutionarily conserved with that of human ATRX. Most excitingly, using C. elegans opens up the use of forward genetics to identify suppressor mutants of xnp-1 loss. Such suppressor screens provide a unique and unbiased means of identifying XNP-1’s functional pathway which, in the long-term, may be of translational benefit for ATRX syndrome sufferers.

The student will receive training in a wide variety of skills including: microscopy, molecular biology, genetics and the generation and analysis of next-generation sequencing (NGS) data.

Interested candidates should follow the online application procedure. Initial enquiries should be directed to the Principal Investigator, Dr Helder Ferreira ([Email Address Removed] ).