Babraham scientists reveal how environmental signals can reprogramme stem cells
Epigenetics researchers at the Babraham Institute have identified the biological process that leads to global loss of the genome’s methylation memory when cells are reprogrammed at fertilisation to the so-called ‘ground-state’ development. Reported in the journal Cell Stem Cell, this new understanding of how epigenetic memory can be completely erased may prove useful in generating better quality cells for transplantation and cell-therapy purposes. The research also reveals how signals that come from the cell’s environment can help this reprogramming.
Epigenetics is revolutionising our understanding of genetic inheritance and also helping to explain how our genes can be influenced by the environment. Genomic methylation, which does not alter DNA sequence but essentially marks it in a stable lifelong manner, is accumulated during development and plays a vital role in committing cells to specialised roles in the body. These methylation marks must be erased at the start of each new generation, to restore the ability of a newly fertilised egg to develop into a new organism.
Understanding this mechanism of ‘wiping the slate clean’ is important to appreciate how the developmental capacity of cells is reset and also provides insights that will guide the use of stem cells for therapeutic purposes, which also requires remodelling of genomic methylation. It is known that when adult cells are reprogrammed to stem cell-like cells, they do not completely erase their ‘memory’. This unfortunately limits their use in stem cell therapy since these cells will have the tendency to develop into the types of specialised cells from which they were originally derived.
Stem cells receive signals from the environment that force them to become more specialised cells. The Babraham researchers blocked these environmental signals with drugs and found that they could induce this superior stem cell state with the treatment. In a parallel study published recently in Nature, researchers from the from The University of California San Francisco and The University of British Columbia in Canada found that treating stem cells with Vitamin C had similar effects, suggesting that nutritional factors may lead to better stem cells.
Dr Gabriella Ficz, lead author from the Babraham Institute said, "We were quite surprised by the strong mechanistic link between the external signals and the DNA methylation machinery. This work consequently opens up a whole range of questions related to what happens in the adult body where we know that aberrant methylation is associated with cancer. In addition, how these changes are mediated through the new DNA modification 5-hydroxymethylcytosine (5-hmC), similar to what we have observed in ES cells, remains a key focus in epigenetics research."
The Babraham Institute, which receives strategic funding from the Biotechnology and Biological Sciences Research Council (BBSRC), undertakes world-leading research to generate new knowledge of biological mechanisms underpinning ageing, development and the maintenance of health. 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. Babraham’s Epigenetics researchers were the first to describe the mechanistic role and localisation of 5-hmC in ES cells.
The development of novel, more sensitive sequencing technologies has enabled subtly different types of methylation to be detected, which has provided these new insights into how cells get reprogrammed. This is the first published study using a new analysis system called TrueMethyl™, developed by Cambridge Epigenetix Ltd., a spinout from the University of Cambridge. The system provides, for the first time quantitative, accurate and repeatable single-base resolution sequencing of the modified bases hydroxymethylcytosine (5-hmC) and methylcytosine (5-mC). Early studies indicate that these modifications may have distinct and important physiological functions.
Professor Wolf Reik, Group Leader at The Babraham Institute and senior author of the paper said, “Employing chemical oxidation gives very high conversion efficiencies and minimises sequence context effects, giving results of unparalleled quality. Consequently this new analytical method opens new avenues for basic research, pharmaceutical discovery and diagnostics. This technology was pivotal in enabling us to accurately measure 5-hmC and 5-mC during demethylation.”
Dr Simon Cook, Head of Knowledge Exchange and Commercialisation at Babraham and also a co-author on the study said, “This is an excellent example of how knowledge exchange between academic research institutes like Babraham and small companies like Cambridge Epigenetix can contribute to the development of new technology platforms that in turn drive new scientific discoveries – it’s good for the researchers, good for the company and good for UK science.”
In addition to BBSRC, this research was supported by the Wellcome Trust, the MRC, the EU, NoE Epigenesys and EU BLUEPRINT.
Publication Details: FGF signalling inhibition in ESCs drives rapid genome-wide demethylation to the epigenetic ground state of pluripotency (2013). Gabriella Ficz, Timothy A. Hore, Fatima Santos, Heather J. Lee, Wendy Dean, Julia Arand, Felix Krueger, David Oxley, Yu-Lee Paul, Jörn Walter, Simon J. Cook, Simon Andrews, Miguel R. Branco and Wolf Reik Cell Stem Cell (2013) http://dx.doi.org/10.1016/j.stem.2013.06.004
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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.
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.
Cambridge Epigenetix Ltd. is a spinout from the University of Cambridge and has received funding from Syncona Partners. Its founders and management team include leading members of the original senior team at Solexa, now Illumina. Further information is available at www.cambridge-epigenetix.com