Architecture of the genome: a genetic investigation of chromosome-positioning mechanisms. (360G-Wellcome-082377_Z_07_Z)

The intranuclear organization of chromosomes is critical for many aspects of genome function, affecting gene expression, DNA repair, and the organization of DNA replication. It is therefore imperative that we understand the mechanisms and cellular components that control chromosome architecture. We have pioneered a screening method that combines advanced imaging with yeast genetics to identify cellular components important for chromosome positioning, using a microscope system funded by a recent Wellcome Trust Equipment grant. Our pilot analysis has identified the chromatin assembly factor Asf1 and the Ctf18 ring-loading complex as crucial for correct positioning of the chromosome ends or telomeres. The first objective of this research programme is to use genetic, genomic, and proteomic approaches to understand the mechanisms by which Asf1 and Ctf18 affect telomere positioning. Second, we will undertake a genome-scale survey of the cellular components responsible for positioning and organizing telomeres. The information gained will contribute to the third part of the programme, in which we will analyse the localisation of non-telomeric chromosome domains, and identify the molecular components involved in global chromosome positioning. Overall, this research programme forms a cutting-edge investigation of the mechanisms controlling eukaryotic chromosome architecture.