Scientists from the Babraham Institute have gained a new understanding of how molecular signals and switches control how an embryo develops into an adult. The new research, published today 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 cells 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 pluripotencyrelated 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 couldnt 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 Institutes 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.

ublication details: Ficz G, Branco MR, Seisenberger S, Santos F, Krueger F, Hore TA, Marques CJ, Andrews SR, Reik W (In press) Dynamic regulation of 5-hydroxymethylcytosine in mouse ES cells and during differentiation. Nature http://dx.doi.org/10.1038/nature10008

Contact details: The Knowledge Exchange Office Email:kec@babraham.ac.uk Tel: +44 (0)1223 496206

The Babraham Institute Babraham Research Campus Cambridge CB22 3AT United Kingdom Notes to Editors: About the Babraham Institute: The Babraham Institute undertakes world-class life sciences research to generate new knowledge of biological mechanisms underpinning ageing, development and the maintenance of health. Our research focuses on cellular signalling, gene regulation and the impact of epigenetic regulation at different stages of life. By determining how the body reacts to dietary and environmental stimuli and manages microbial and viral interactions, we aim to improve wellbeing and support healthier ageing. The Institute is strategically funded by the Biotechnology and Biological Sciences Research Council (BBSRC), part of UK Research and Innovation, through an Institute Core Capability Grant and also receives funding from other UK research councils, charitable foundations, the EU and medical charities. Website: http://www.babraham.ac.uk The Biotechnology and Biological Sciences Research Council(BBSRC)is the UK funding agency for research in the life sciences. Sponsored by Government, BBSRC annually invests around 450 million in a wide range of research that makes a significant contribution to the quality of life for UK citizens and supports a number of important industrial stakeholders including the agriculture, food, chemical, health and well-being and pharmaceutical sectors. BBSRC carries out its mission by funding internationally competitive research, providing training in the biosciences, fostering opportunities for knowledge transfer and innovation and promoting interaction with the public and other stakeholders on issues of scientific interest in universities, centres and institutes. Website: bbsrc.ukri.org/ Babraham Bioscience Technologies Ltdis responsible for managing the Babraham Research Campus Bioincubator. BBT brings together all the elements to support innovation and enable the successful exploitation of research in the biomedical sector based on technologies emanating from the Babraham Institute and bioventures relocating to the campus. BBT has taken a prominent role regionally, initiating and leading partnerships to promote knowledge and skills flow and has established a reputation for successfully translating innovative science into viable business opportunities through partnerships for wealth creation.

Website:www.babraham.com

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