| Abstract |
Epigenetic alterations and genome instability are hallmark of ageing. However, partially due to a lack of robust models and technologies, the precise nature of these age-associated genetic and epigenetic alterations and their functional relevance in the plasticity of the phenotype are unclear. We have developed a new mouse model, in which we are able to switch on/off basal autophagy in adulthood and have found that reduced autophagy accelerates ageing and that this premature ageing phenotype can be 'segmentally' rescued by subsequent autophagy restoration. Strikingly, this 'rejuvenation' is accompanied by increased tumorigenesis. We reason that age-associated metabolic stress (reduced basal autophagy) induces genomic and epigenomic alterations, the latter of which could be either reversible or irreversible, and that those alterations collectively provide a selective pressure under optimal conditions (i.e., upon age-reversal). Taking advantage of our new immunoprecipitation-free epigenome profiling method, which is capable of assaying the epigenomic profiles from low-input tissues, we will determine the dynamic nature of the age-associated epigenetic changes and genetic mutations during ageing and age-reversal in mice. This technology will also be applied to detect the age-associated genetic changes that occur adjacent to specific epigenetic marks: we envisage that functionally relevant mutations may be enriched or diminished after the age-reversal. These approaches will provide an insight into the mechanism behind the establishment of genomic instability through these epigenomic states. In parallel, we will also develop a high-throughput single-cell epigenome sequencing platform to refine cell type specificity, which, together with our rejuvenation model, will potentially identify functional components as well as 'passenger' (epi-)genetic events in ageing at a single-cell level. |
