Resetting genetic instructions
Researchers have gained a much clearer view of how sperm and egg cells are genetically reset in order that they function properly during fertilization and development. The new study, published on 6 December 2012 in Molecular Cell, is the first genome-wide study to look at what happens to chemical tags that affect DNA activity during early stages of egg and sperm cell development.
The team show that the process of resetting, in which chemical tags in the parent cells are erased from the genome, occurs earlier in the development of sperm and egg than thought. They also show, crucially, that some regions of the genome escape the widespread erasure, carrying their tags to the next generation.
All the cells in the body of one individual share the same DNA sequence: the way in which the DNA sequence is interpreted by each cell - whether genes are switched on or off, for example - results in the formation of different cell types. Genes that are inactive often acquire a chemical tag, called a methyl group, that plays a role in controlling gene activity.
Such potentially reversible changes to genes can occur during the life of a cell and of an organism, and can be influenced by cues from outside. This type of research, investigating modifications to the DNA which do not alter the underlying DNA sequence, is called epigenetics.
The team examined the timing and extent of changes to the pattern of methyl groups in primordial germ cells - cells that are destined to become egg and sperm in the adult animal.
"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 that 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 regions is linked to the development of type 2 diabetes."
Dr Stefanie Seisenberger, lead author from the Babraham Institute, which receives strategic funding from the Biotechnology and Biological Sciences Research Council (BBSRC)
"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."
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
Part of the work performed in this study was carried out at the Wellcome Trust Sanger Institute under the new Associate Faculty scheme.
"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."
Professor Michael Wakelam, Director of the Babraham Institute
This research was supported by the BBSRC, Boehringer Ingelheim Fonds, MRC, Wellcome Trust and the EU.