Metabolic control of epigenetic stability and potential in pluripotent stem cells

Generation of patient specific stem cells with the potential to be used to treat chronic disease is a realistic prospect and forms the basis of the field of regenerative medicine. Efficient and safe protocols to programme stem cells for a specific task are essential for this. Metabolism is a key cellular regulator and may be of critical importance in stem cell biology. This research project seeks to understand the relationship between metabolism and the instructions which drive gene expression in stem cells and influence the extent and spectrum of cell types that may be derived from them. Ultimately, we aim to use this knowledge to develop novel strategies for future regenerative medicine applications, extending healthy aging and treating disease.

Metabolism is emerging as a key regulatory mechanism to control cellular function, potential, and state through the dynamic regulation of the epigenome. In particular embryonic development is characterised by significant metabolic, epigenetic and cellular changes associated with different developmental stages, suggesting that metabolism may play a key role in regulating cell fate decisions. But until now, the precise molecular interplay between metabolism and the epigenome remains poorly understood.
The main goal of this proposal is to understand the mechanisms that link metabolism with epigenetic changes and cellular potential in pluripotent stem cells (PSCs). I plan to generate a comprehensive dataset of metabolic states in human and mouse PSCs and assess the impact of induced metabolic changes on PSC potential, histone and DNA methylation, and the relevant epigenetic enzymes. Elucidating these mechanisms will reveal molecular principles involved in the regulation of the epigenome and affecting PSC potential and state. This knowledge will form the basis for novel PSC differentiation strategies for regenerative medicine and will also contribute to our understanding of metabolic disease states and aging.