Research provides insight into DNA reprogramming during egg and sperm cell development
Scientists at the Babraham Institute have gained a new understanding of when and how the DNA in developing egg and sperm cells is ‘reset’, in preparation for making a new embryo. It is well known that small chemical groups can be added to DNA to alter gene activity, these modifications to the DNA are acquired during development in the womb and throughout adult life and can arise from changes in environment. Most of these modifications are removed in immature egg and sperm cells to ‘reset’ the DNA and to erase any ‘environmental memory’, but some remain.
Decoding this reprogramming has major implications for our understanding of development and how these modifications can be inherited from one generation to another. All the cells in the body of one individual have the same DNA sequence (genome) and it is how the DNA sequence is interpreted that results in the formation of different cell types, for example different genes can be switched on and off. Inactive genes often have a small chemical modification, called a methyl group, added to them outside the coding sequence which promotes this regulation.
This study, published today (6 December) in the journal Molecular Cell, is the first genome-wide study to look at what happens to the methyl groups during early stages of egg and sperm cell (primordial germ cell) development. This type of research, investigating modifications to the DNA which do not alter the underlying DNA sequence, is called epigenetics.
Dr Stefanie Seisenberger, lead author from the Babraham Institute, which receives strategic funding from the Biotechnology and Biological Sciences Research Council (BBSRC), explained, “We produced a high resolution map showing the location and timing of methyl group removal from primordial germ cell DNA. We discovered that the majority of demethylation occurred much earlier than people previously thought and this has allowed us to shed light on the process of methyl group removal in mammals, a mechanism which has remained elusive for many years. An even more exciting finding is that we have identified regions of DNA that avoid demethylation and are therefore candidates for how environmental information can be transferred from parent to offspring. Interestingly, one of these areas has a link with type 2 diabetes.”
Professor Wolf Reik, senior author of the paper, a Group Leader at the Babraham Institute and an associate faculty member at the Wellcome Trust Sanger Institute, added, “Several recent studies in other laboratories have confirmed that environmental information can be transferred from parent to offspring in mammals, for example mice fed a high-fat diet produce offspring with altered metabolic regulation, but it is not known how this occurs. One interesting observation from our study, which backs up work performed elsewhere, is that incomplete removal of methyl groups from DNA occurs more frequently in sperm than egg forming cells, suggesting that fathers have a bigger part to play in epigenetic inheritance than previously thought. This has implications not only for understanding mechanisms of inheritance and development but also our susceptibility to obesity and diseases like diabetes.”
Part of the work performed in this study was carried out at the Wellcome Trust Sanger Institute under the new Associate Faculty scheme. Professor Michael Wakelam, Director of the Babraham Institute, commented, “This is an excellent example of fruitful scientific collaboration between research institutes bringing about an improvement of our knowledge of how we develop, and thus paving the way for future epigenetics research into the inheritance of age-related diseases such as diabetes.” This research was supported by the BBSRC, Boehringer Ingelheim Fonds, MRC, Wellcome Trust and the EU.
The dynamics of genome-wide DNA methylation reprogramming in mouse primordial germ cells
Stefanie Seisenberger, Simon Andrews, Felix Krueger, Julia Arand, Jörn Walter, Fátima Santos, Christian Popp, Bernard Thienpont, Wendy Dean and Wolf Reik Molecular Cell http://dx.doi.org/10.1016/j.molcel.2012.11.001
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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.
The Wellcome Trust Sanger Institute The Wellcome Trust Sanger Institute is one of the world's leading genome centres. Through its ability to conduct research at scale, it is able to engage in bold and long-term exploratory projects that are designed to influence and empower medical science globally. Institute research findings, generated through its own research programmes and through its leading role in international consortia, are being used to develop new diagnostics and treatments for human disease. http://www.sanger.ac.uk/ About the Wellcome Trust The Wellcome Trust is a global charitable foundation dedicated to achieving extraordinary improvements in human and animal health. It supports the brightest minds in biomedical research and the medical humanities. The Trust's breadth of support includes public engagement, education and the application of research to improve health. It is independent of both political and commercial interests. www.wellcome.ac.uk
The Boehringer Ingelheim Fonds (BIF) is a public foundation - an independent, non-profit organization for the exclusive and direct promotion of basic research in biomedicine. The foundation supports up-and-coming scientists whose research projects experimentally elucidate the basic phenomena of human life. BIF also organizes two International Titisee Conferences per year. At BIF, we are convinced that great scientific ideas and developments need a stimulating context, freedom and a sound financial fundament. We do our best to provide all this for our fellows in our various fellowship and grant programmes.
About the Medical Research Council (MRC) For almost 100 years the Medical Research Council has improved the health of people in the UK and around the world by supporting the highest quality science. The MRC invests in world-class scientists. It has produced 29 Nobel Prize winners and sustains a flourishing environment for internationally recognised research. The MRC focuses on making an impact and provides the financial muscle and scientific expertise behind medical breakthroughs, including one of the first antibiotics penicillin, the structure of DNA and the lethal link between smoking and cancer. Today MRC funded scientists tackle research into the major health challenges of the 21st century.
About EU EpiGeneSys As an FP7 European Community-funded Network of Excellence, EpiGeneSys's goals go further than simply funding a research project-our extensive training program is helping to build a bridge between the fields of epigenetics and systems biology and our public education mission will communicate the science in an accessible and interesting fashion while awakening young pupils' interest in research.
About EU BLUEPRINT BLUEPRINT is a large-scale research project receiving close to 30 million euro funding from the EU. 41 leading European universities, research institutes and industry entrepreneurs participate in what is one of the two first so-called high impact research initiatives to receive funding from the EU.