Chromatin and Ageing
Chromatin is the complex of DNA and proteins that can be found in the nucleus of a cell. The basic unit of chromatin is the nucleosome that consists of DNA wrapped around an octamer of highly conserved histone proteins. The nucleosomes help to compact the DNA, but also serve as a gatekeeper for access to the genetic material. Over the last two decades, research revealed that the regulation of chromatin is at the heart of every DNA-dependent process, like transcription, replication and repair. This regulation, which is mediated by posttranslational modifications, is often referred to as epigenetics. Misregulation of epigenetic control has been implicated in many diseases, most notably cancer.
Recent advances have shown that chromatin changes dramatically during ageing. The expression of histone proteins is decreasing and levels of histone and chromatin modifying enzymes are altered upon ageing. In particular, modifications that influence the overall chromatin architecture are changing: The heterochromatic marks H3K9 and K27 methylation are decreasing, whereas acetylation of H4K8/12 are increasing. Overall, the chromatin becomes more accessible and hence more prone to inappropriate binding of transcription machinery or DNA damaging agents to the DNA.
Focus of the lab
We are using a combination of biochemical, genetics and genomics to address the question of chromatin alterations during ageing. We use two different model systems, the unicellular yeast S. cerevisiae and mammalian tissue culture systems. Importantly, many features of ageing are conserved during evolution from yeast to mammalian cells. Therefore, we exploit the genetic tractability and short replicative lifespan (determined by the number of offspring an individual yeast cell can produce) of yeast to perform system-wide screens for factors that influence chromatin architecture during the ageing process. We aim at understanding a network that is controlling the changes in chromatin structure. Ultimately, we would like to understand, whether, how and when we could perturb this network during the ageing process to revert the changes observed.