Linking metabolism to ageing: a new role for histone lysine acetylation

Healthy ageing is influenced by diet and light/dark cycles that control the interconnected metabolic and circadian cycles within cells. We study baker's yeast, which has a metabolic cycle and ages similarly to humans, providing a tractable system to discover the processes that coordinate cycles and ageing. Research aimed at discovering new ways of improving healthy ageing is rising to prominence, with work addressing the basic biology of ageing likely to underpin future medical advances. Much of our knowledge of the molecular processes involved in ageing has come from work using simple eukaryotes as model organisms. Furthermore, many of the genes and processes involved in ageing are conserved across evolution. We plan to investigate a new pathway linked to ageing at the fundamental level of gene expression, and the control of ageing by the metabolic state of the cell.

In this project we will use a single-cell eukaryote, the yeast Saccharomyces cerevisiae. Yeast has many advantages for this work. We can synchronize yeast in their metabolic cycle meaning that we can study whole populations of cells with identical metabolic states. Yeast is one of the only systems in which it is possible to directly study the effect of metabolism on gene expression. Genes are packaged into chromatin, a complex of DNA and protein that influences gene expression. The chromatin is chemically modified in a reaction driven by the metabolic state of the cell, allowing gene expression and metabolism to be coordinated. It is generally believed that these chemical modifications influence the first step of gene expression, known as transcription, the copying of the genetic information in the DNA to the intermediate molecule RNA, which the then used as a template for the synthesis of proteins. We have discovered a new link between the chromatin and the last step of gene expression, the translation of the genetic information carried in RNA molecules into protein. This discovery was made possible by our ability to study particular regions of the chromatin that undergo chemical modifications in yeast, not possible in other organisms. This also enabled us to link this particular site of chemical modification on the chromatin to ageing in yeast.

The purpose of this project is to understand how the chromatin influences translation of proteins and ageing. The characteristics of a cell, including how it ages, are controlled by proteins, in particular the amount of protein synthesized during translation. The production of proteins is central to cellular cycles and ageing, and is controlled by diet/nutrients, but the detailed processes are not understood. Defining these processes will contribute in the future to rational drug design aimed at alleviating symptoms of age-related conditions. Neurodegenerative conditions, for example, arise due to defects in the structures adopted by proteins, causing loss of normal function and cell death. The accumulation of defective proteins can be alleviated by altering how fast they are produced, and in yeast this leads to improved long-term viability of cells.

In summary, we have discovered a novel nutrient-dependent target in chromatin that controls how fast proteins are produced and propose to dissect exactly how this is achieved. This work has important implications for understanding how diet and rhythmic cycles influence protein production and the molecular mechanisms behind age-related conditions.

The field studying chromatin and histone post-translational modifications (PTMs) is extensive but we understand very little about the functions associated with specific residues/PTMs on histones or how they are coordinated with the metabolic state of the cell. Metabolic intermediates are co-factors for enzymes that deposit/remove PTMs. In S.cerevisiae it is possible to create residue substitutions in the histones, allowing us to uncover a novel link between ageing, lysine 18 acetylation on histone H3 (H3K8ac) and the synthesis of proteins in the cytoplasm. Protein synthesis is the most energy-consuming processes in the cell and is subject to tight control, linked to cell growth. We hypothesize that a failure to correctly modify chromatin, leading to the increased use of resources for protein synthesis and the associated generation of harmful by-products, could have devastating long-term effects for the cell, explaining the link to ageing.

We aim to dissect these relationships in yeast, in which pathways controlling ageing are conserved and which can be synchronized during a metabolic diurnal rhythm, known as the yeast metabolic cycle (YMC), enabling us to study all stages of gene expression with high spatial and temporal resolution and at known metabolic state. We will sample synchronized yeast at 16 time points, representing 8 majors shifts in metabolism and gene expression during the YMC, and using state-of-the-art techniques and the underpinning bioinformatics/computational biology already established in the laboratory including NET-seq (nascent transcription), 3' end-seq (transcripts) and ribosome profiling and mass spectrometry (translation) in WT strains and strains expressing A, R, Q and L substitutions at acetylated lysines on histone H3, we will dissect how cycling acetyl-CoA and H3K18ac coordinate protein synthesis. Overall, our findings will provide important new insights into metabolic control of gene expression and the biology of longevity.

This work relates to the BBSRC Priority Area of Bioscience for Health and to the specific BBSRC priorities: Data Driven Biology and Healthy Ageing across the Lifecourse.
The primary immediate beneficiaries will be the scientific community, as discussed in academic beneficiaries. A major output from this project will be several very large 'omics' datasets and we aim to develop the tools and approaches needed to extract the most from these datasets and to generate new biological understanding. Through our recent publications and the preliminary data underpinning this application, we already have a successful track record in doing this. We are particularly keen on integrating four areas of biology in this work with their associated datasets generated as part of this project and by other groups working in these areas: metabolism and rhythms, epigenetics, gene expression and ageing. This will require us to develop innovative computational approaches to integrate, analyse and interpret our data generated by multiple 'omics' technologies with existing datasets and those to be generated by other groups working in these areas. This will enable us to gain maximum value and new scientific leads and to benefit UK science.

The longer term impact of this work is rooted in increasing our understanding of pathways involved in ageing. Strategies to improve the health of older people have the potential to transform societies, providing huge economic, social and medical impact. The use of yeast to provide insights into the fundamental biological mechanisms and physiological processes involved in ageing, particularly the link between metabolism and the chromatin, the idea of a homeostatic mechanism impacting on protein synthesis and the role of epigenetics in the control of this mechanism impact on this strategic area.

Longer-term beneficiaries will include:

The commercial sector. We have very strong track record in taking results from yeast and worms, the two model organisms we work with, and translating these into commercial opportunities. Oxford Biodynamics Ltd. (www.oxfordbiodynamics.com) and Chronos Therapeutics (www.chronostherapeutics.com) were set up based on the work in my group on yeast ageing and epigenetics. Yeast displaying an age-related phenotype can be screened for small molecules that alleviate the short lifespan with potential for use in human ageing.

Policy makers. It is necessary for policy makers to appreciate the importance of basic research in model organisms in underpinning successful drug discovery, as we have already successfully demonstrated with our local spin outs. Information from this project should contribute to policy on resource allocation at many levels. We will continue to engage with policy makers to emphasize the importance of blue skies and primary research on the biology of ageing through engaging with groups such as the Royal Society of Biology (of which I am a fellow), Age UK and at meetings of the British Society for Research on Ageing and parallel international organizations.

The Third Sector. Through our website we will provide ageing funders and charity fund raisers with news on our ageing research to inform policy and for use in material to stimulate giving which will in turn increase the UK's capacity in ageing research.

The Wider Public. Increased public understanding of science of ageing and its relationship to metabolism and epigenetics is a non-quantifiable but important benefit. The PI has an active track record in public engagement, for example recently giving an interactive lecture on epigenetics as part of the Christmas Lectures series run by Oxford University for year 9 students from a range of local schools (http://podcasts.ox.ac.uk/series/christmas-science-lectures) in addition to giving many talks in schools and other outreach events. The PI is well placed to exploit public engagement profiles to maximize impact.