Overview and broad aims
Epigenetic tags are essential in regulating gene activity. They provide a memory of decisions during development, safeguard cell states, and prepare cells for future events. Although epigenetic programmes are remarkably stable in most cells, erosion of epigenetic states can undermine cellular identity, causing errors in development or loss of tissue integrity in later life. Our research explores how epigenetic tags are set up during development and how they are modified by what we eat and as we age.
The metabolites within our cells are likely to be a major factor determining epigenetic states. This is because these metabolites work with the enzymes that add or remove epigenetic tags on our genes. Changes in metabolite levels in relation to age, nutrition and other environmental factors could profoundly impact the epigenome. We aim to harness knowledge of the metabolic inputs into epigenetic tags to identify interventions that may benefit lifelong health.
Progress and research highlights in 2023 and 2024
One of our key aims is to understand how nutrients affect how well we age. Calorie restriction has been shown in many organisms to improve ageing health but, as a long-term intervention, is likely to be undesirable in human populations. Working in yeast, we have found that we can enhance ageing health by changing diet without restricting calories (). By exploring the underlying cellular metabolic pathways, we have been able to create mutations in two sensor proteins, allowing yeast to ageing healthily even on an unlimited, rich diet. Because these are highly-conserved sensors, we are exploring whether we can similarly improve ageing health in more complex animals: fruit flies (working with colleagues in the Signalling programme), and ultimately in mouse models.
One of the key cellular metabolites is acetyl-CoA, which serves many purposes in the cell in response to the cell’s energy status, as well as being required for placing epigenetic tags – acetylation – on the histone proteins that DNA is complexed with in the nucleosome units of chromosomes. In this way, the level of acetylation on histones can respond to nutrients; conversely, histones could constitute a reservoir for acetyl-CoA for other cellular functions. We have explored this by detailed metabolic analysis in mouse cells (), confirming that histone acetylation is indeed nutrient responsive, but has a limited capacity to feed into the metabolic demands of the cell.
Just which and how many epigenetic tags histones carry is important in determining whether genes are active, silent, or poised for activity when developmental cues induce new differentiation events. The poised state is typified by ‘bivalent nucleosomes’, in which histones paradoxically carry both ‘activating’ and ‘repressive’ epigenetic tags. Until now, we have limited understanding of what gene regulatory proteins recognise bivalent nucleosomes, but by developing new techniques to construct bivalent nucleosomes, we have for the first time been able to identify proteins uniquely binding to the combination of active and repressive marks (). Unexpectedly, we find that these dual binders include proteins that add acetylation to histones, providing a potential link to cellular energy status, and the shifts in metabolism that occur as cells differentiate.
How embryonic cells coordinate development into different lineages in the early human embryo is poorly understood, as we are unable to access and manipulate embryos at these stages. One such important lineage is the amnion, a thin membrane that encloses the embryo. Previous work has used human pluripotent stem cells (hPSCs) as a model to investigate how the amnion develops but found that the signals required are shared with other cells, such as surface ectoderm which gives rise to tissues like the skin. Further optimisation of this culture system now reveals that cell density can be decisive in determining whether they become amnion or ectoderm (). This advance will help facilitate development of methods to produce others tissues from hPSCs.
Impact highlights
Supported by grants from Wellcome and ScienceWise, and together with the Human Developmental Biology Initiative, members of the programme supported a public dialogue project exploring the future of human embryo research, and to understand public views on the 14-day rule. The findings attracted substantial interest from groups such as the International Society for Stem Cell ÐÓ°ÉÔ´´ (ISSCR), and the media. Peter Rugg-Gunn gave evidence to the Human Embryology and Fertilisation Authority (HFEA) and has been appointed to the HFEA’s Scientific and Clinical Advances Advisory Committee.
There has been rapid development in our ability to derive human ‘embryo-like’ models from stem cells (SCBEMs), but they raise ethical questions and their legal status is undefined. Epigenetic researchers contributed to a dialogue and policy project on SCBEMs with Cambridge Reproduction, and Peter Rugg-Gunn reviewed a Parliamentary Office of Science and Technology research briefing (POSTnote). Peter serves on UK and committees including ISSCR that are developing guidelines for research using these models. The UK group published a Code of Practice in July 2024 which gained widespread attention in scientific and public media.
We have been translating outcomes of our work, with patent filings in nutrient sensing in ageing (Houseley); embryo implantation models (Rugg-Gunn); cell reprogramming activators and methods (Christophorou); and single-cell multi-omics methods (Rugg-Gunn).
Looking ahead
We expect to make progress in understanding early events in human embryogenesis, with the development of new culture systems that mimic the process of embryo implantation. We shall apply powerful new methods we are developing that enable us to profile multiple epigenetic tags in individual cells, to understand how epigenetic processes help define the first lineages in the human embryo, and set up epigenetic states of lifelong importance. Reprogramming of cell fate is pivotal to tissue regeneration; we expect to uncover mechanisms by which histones operating outside of the cell can promote regeneration of damaged tissues.