Exploring the links between diet, metabolites and gene regulation to improve our understanding of mechanisms that maintain and support lifelong health.
A key way in which our cells and bodies respond to the nutritional environment is through epigenetic information. Epigenetics refers to the systems that control the activity of our genes over the long term. These epigenetic systems package our DNA, determining whether genes are accessible and 'on', or inaccessible and 'off'. Epigenetic systems are an essential part of how our genes are controlled throughout our lives: key epigenetic marks are set up early in development and help define different cell types in the body, including as cells differentiate from stem cells, and help ensure cells function properly. With advancing age, epigenetic information can change and deteriorate, partly in response to lifestyle factors, leading to the potential for impaired cell function and renewal. We are interested in the links between diet, metabolites and how genes are controlled by epigenetic systems over our lifetimes, and whether we can use epigenetic information to improve the resilience of cells.
Aim 1: How changes in the balance of cellular metabolites affect epigenetic systems
In our first aim, we investigate the links between metabolites within cells and epigenetic information on our DNA. Epigenetic systems require a supply of cellular metabolites and variation in the metabolic state of cells, for example in relation to nutrients, could alter the stability of epigenetic marks on our genes. We will use yeast cells and cultured mammalian cells to explore how changes in the balance of cellular metabolites affects epigenetic systems and whether we can adapt the balance to promote epigenetic stability, cell function and ageing health.
Aim 2: How epigenetic states are established and maintained
In our second aim, we study when and how in early development major epigenetic information is set up. Epigenetic systems are particularly dynamic and plastic at the earliest stages of embryonic development as the different cell lineages are first determined, and errors that occur at these early stages can have life-long adverse effects. Although we understand a good deal about these mechanisms from work in model organisms like the mouse, we need to know whether human development depends on similar systems. We have pioneered models that mimic implantation of human embryos which, together with methods we have developed to profile epigenetic information in individual cells, allow us for the first time to investigate how epigenetic systems help determine early human development and set up epigenetic states for life.
Aim 3: How epigenetic states change over the life course
In our third aim, we look at how epigenetic information changes over the life-course and affects how tissues can regenerate. Applying what we have learnt from aim 1, we will take forward knowledge gained from our study of yeast and cultured mammalian cells about balancing cellular metabolites to see how it can improve how whole animals (mice) age and respond to nutritional challenges. Progressing aim 2, we will test how epigenetic systems set up early in development influence the regeneration of stem cells, for example using organoids that mimic the development and regeneration of a complex tissue like the intestine.