The diet dilemma: can you eat what you like and live happily ever after?

Various signaling pathways mediate the effects of DR on health, however, the epigenetic changes associated with DR that likely mediate long-term consequences are vastly unexplored. In consequence, considerable debate surrounds the mechanism of long term DR action, not helped by the fact that lifespan itself is an inaccurate and pleotropic reporter. Using a direct readout through transcriptomics should facilitate dissection of the multiple overlapping epigenetic mechanisms that clearly potentiate DR. DR alters lifespan in remarkably similar ways across eukaryotes diverged by millions of years, allowing the use of genetically powerful model organisms such as yeast to elucidate underlying mechanisms.

Our lab has developed improved methods for transcriptomic and chromatin analysis in ageing yeast, and discovered clear impacts of histone modification on the ageing transcriptome. This project will initially define the transcriptomic changes associated with ageing under various DR regimens. It will then examine the importance of histone modifications in mediating short and long-term consequences of DR using a range of histone modification mutants including acetyltransferases, methyltransferases and deacetylases with known roles in gene expression regulation or ageing phenotypes. Selected mutants that impair DR-mediated gene expression change will be used to assess the fitness trade-off between short-term food utilization and longevity. Finally, based on these studies, experiments will be designed to reconstitute the long term epigenetic changes mediated by DR providing a first step towards viable long-term DR-mimetic therapies.

Techniques: Yeast genetics and ageing cell purification; RNAseq, ChIPseq and bioinformatics.

Website: http://www.babraham.ac.uk/our-research/epigenetics/jon-houseley