The new research, published today (3 April) in the journal Nature, details how a newly discovered form of epigenetic regulation controls the development of embryonic stem (ES) cells.
The research, funded by BBSRC, MRC, the University of Cambridge and EPIGENOME, has important implications for regenerative medicine as it could offer new methods for controlling how ES cells differentiate in every cell in the human body and, potentially, to the growing field of induced pluripotent stem (iPS) cells where adult stem cell are ‘reprogrammed’.
Embryonic stem (ES) cells are pluripotent cells present in the early embryo, which have the capacity to differentiate into all the specialised cells that make up the adult body. As an embryo develops, the cells respond to signals and differentiate to acquire a particular fate, for example a skin cell. Cell fate is governed not only by the genome, but also by chemical changes to DNA that alter the DNA structure but not its sequence. These ‘epigenetic’ tags are one of the ways that genes get switched on or off in different places at different times, enabling different tissues and organs to arise from a single fertilised egg and also helps to explain how our genes can be influenced by the environment.
The new research reveals that a new type of epigenetic modification, 5-hydroxymethylcytosine (5hmC), plays a critical role mediating the external signals that instruct a cell how to develop; this tiny chemical tag (5hmC) is attached to or removed from the genetic sequence depending on the message received, switching genes on or off. The researchers managed to identify the location of this tag throughout the genome, using high throughput sequencing methods. They observed for so called pluripotency-related genes that, as 5hmC decreases, another previously known epigenetic modification, 5-methylcytosine (5mC) increases – this shift has consequences in determining how genes function and hence a cell’s developmental fate.
The pluripotency window for stem cells is short-lived but essential for the environment and pre-defined genetic programme to exert influence on the direction that each cell should take to build a healthy embryo. Hydroxy-methylation appears to be linked to a higher degree of pluripotency; when the process of generating 5hmC tags in the stem cell genome was disrupted, the researchers saw the pluripotency-related genes were down-regulated, causing the cells to be more ‘receptive’ to signals that promote differentiation than would normally be the case for stem cells.
The two epigenetic modifications, 5mC and 5hmC, were seen to have other opposing behaviour in the genome, which might be important for maintaining flexibility of stem cells in order to respond accurately to external cues.
Knowing how hydroxymethylation works in embryonic stem cells might also help with reprogramming adult cells into induced pluripotent stem cells (iPS cells), since removal of methylation is important in generating these cells. Hence increasing the amounts of hydroxymethylation during reprogramming might make the process more efficient and error-free. This might help with developing improved strategies for regenerative medicine.
Professor Wolf Reik, who led the study at the Babraham Institute, which receives strategic funding from the Biotechnology and Biological Sciences Research Council (BBSRC) said, “This work provides an exciting new perspective on what makes embryonic stem cells special. It shows how the balance between opposing epigenetic marks is important for the ability of stem cells to differentiate into different tissues. We may be able to use the new epigenetic mark, hydroxymethylation, for improved strategies for reprogramming any cell into a stem cell, and hence in regenerative medicine.”
While advancing our understanding of the biology behind ‘reprogramming’, these findings may also help to explain how epigenetic changes occurring during ageing can cause disease, since conditions like heart disease and autoimmune disorders may be associated with failure of epigenetic regulation. It is known that 5hmC is most abundant in ES cells and in the brain. This study opens up many questions on the role that 5hmC may play in a non-dividing brain cell, modulating gene expression, and its relationship with memory formation and neurological disorders. Gabriella Ficz, joint lead author of this research said, “Our work reveals important aspects about the epigenetics of stem cells but looking at our data I couldn’t stop wondering about the involvement of this new modification in ageing and complex diseases like diabetes, autoimmune disorders and schizophrenia as well as cancer and obesity. It is an exciting time for epigenetic research!”
Miguel R. Branco, joint lead author commented, “The recent discovery of this new DNA modification has attracted a quickly growing interest from the scientific community. Whilst it is still early days and we will have to dig deeper to better understand its role, our work has unveiled important links between hydroxymethylation, methylation and the regulation of pluripotency genes.”
Professor Douglas Kell, BBSRC Chief Executive, said, “Fundamental biological processes such as epigenetic regulation have important and far-reaching consequences. As this research shows, epigenetics offers both the potential to underpin new therapies in the future but also to help us to understand how the normal functioning of our bodies operates.”
The Babraham Institute undertakes world-leading life sciences research to generate new knowledge of biological mechanisms underpinning ageing, development and the maintenance of health. Professor Michael Wakelam, Director of the Babraham Institute, said, “These innovative studies from the Reik laboratory are part of the Babraham Institute’s central mission to understand lifelong health and wellbeing.” This research at Babraham was supported by the BBSRC, the MRC, the University of Cambridge and by the EPIGENOME Network of Excellence.
Notes to editors
Publication details: Dynamic regulation of 5-hydroxymethylcytosine in mouse ES cells and during differentiation. Gabriella Ficz, Miguel R. Branco, Stefanie Seisenberger, Fátima Santos, Felix Krueger, Timothy A. Hore, C. Joana Marques, Simon Andrews & Wolf Reik. DOI: 10.1038/nature10008
About the Babraham Institute
The Babraham Institute is an institute supported by the Biotechnology and Biological Sciences Research Council (BBSRC) near Cambridge, undertaking international quality research to generate new knowledge of biological mechanisms underpinning ageing, development and the maintenance of health. The Institute’s research is focused on understanding the biological events that underlie the normal functions of cells and the implication of failure or abnormalities in these processes. Research focuses on signalling and genome regulation, particularly the interplay between the two and how epigenetic signals can influence important physiological adaptations during the lifespan of an organism. By determining how the body reacts to dietary and environmental stimuli and manages microbial and viral interactions, we aim to improve wellbeing and healthier ageing. www.babraham.ac.uk
BBSRC is the UK funding agency for research in the life sciences. Sponsored by Government, BBSRC annually invests around £470M in a wide range of research that makes a significant contribution to the quality of life in the UK and beyond and supports a number of important industrial stakeholders, including the agriculture, food, chemical, healthcare and pharmaceutical sectors.
BBSRC provides institute strategic research grants to the following:
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- Institute for Animal Health
- Institute for Biological, Environmental and Rural Studies (Aberystwyth University)
- Institute of Food Research
- John Innes Centre
- The Genome Analysis Centre
- The Roslin Institute (University of Edinburgh)
- Rothamsted Research
The Institutes conduct long-term, mission-oriented research using specialist facilities. They have strong interactions with industry, Government departments and other end-users of their research.
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