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Genome stability established through epigenome plasticity during ageing and rejuvenation

Reference	BB/S013466/1
Principal Investigator / Supervisor	Professor Masashi Narita
Co-Investigators / Co-Supervisors	Professor Hiroshi Kimura, Professor Tuomas Knowles, Professor Yasuyuki Ohkawa
Institution	University of Cambridge
Department	Cancer Research UK Cambridge Institute
Funding type	Research
Value (£)	497,604
Status	Current
Type	Research Grant
Start date	01/05/2019
End date	30/04/2023
Duration	48 months

Abstract

unavailable

Summary

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.

Impact Summary

Genetic instability and epigenetic drift are hallmarks of ageing but their individual and combined functional relevance are highly elusive. This is largely due to a lack suitable animal models and versatile low-input epigenomic technologies. Our proposal covers these elements, taking advantage of our new age-reversal mouse model and a single-cell epigenetic profiling technology, ChILT. These will be highly beneficial to researchers not only in the ageing field, but also any researchers who are interested in 'cellular heterogeneity'. In addition, we will utilise microfluidics to develop high throughput epigenomic techniques, which will also inspire microfluidics and microgel researchers. Since the mouse model utilises autophagy perturbation, this will also be benefit to researchers in the field of autophagy research. We will strengthen the active collaborations between the Japanese and UK teams, or within each team. This is an interdisciplinary project, and all researchers directly involved in the projects will have a unique opportunity to further develop and extend their career paths. Through combined teaching efforts in the international team, students (both under- and post-graduates) will be exposed to cutting-edge research methods and concepts. We aim to publish our new results in Open Access, peer-reviewed, high impact scientific journals and will regularly present our data at high-profile meetings. Genomic data will be disseminated through open access repositories such as GEO Datasets. Any new mouse models will be available to the research community. Communication of significant findings will be enhanced with support from dedicated PR teams at the University of Cambridge and CRUK, in addition to social media platforms, such as Twitter (@CRUKCambridge, @narita_lab). Cambridge benefits from a thriving biotech environment from small-medium enterprise (SME) to large pharmaceutical companies such as AstraZenica, who currently occupy space within the CRUK CI facility. We will look to leverage the results of this study and foster academic-industrial links with segments of this community to accelerate translation into the clinic and society. Through this study, we will actively seek to identify a molecular signature, which controls the ageing process and that is potentially pharmacologically exploitable. Therefore, our study may eventually benefit the general public.

Committee	Not funded via Committee
Research Topics	X – not assigned to a current Research Topic
Research Priority	X – Research Priority information not available
Research Initiative	UKRI-Japan Society for the Promotion of Science (JSPS) Joint Call [2018]
Funding Scheme	X – not Funded via a specific Funding Scheme

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