Scientists at the Babraham Institute in Cambridge have made a breakthrough in understanding how mammalian genomes are modified in the egg and sperm and are reprogrammed after fertilisation. The research has implications for better understanding fertility.

Around 15 per cent of couples worldwide have difficulty conceiving a child and in around five per cent of cases the reasons for infertility remain elusive.

Attention is now turning to epigenetic changes, which are important regulators for many biological processes including the development of sperm and eggs.

This research, in collaboration with the National Institute for Child Health and Development in Tokyo, may bring new understanding to cases of infertility where there is no obvious underlying cause and pave the way for improvements in diagnosis of infertility and Assisted Reproductive Technologies (ART) in humans.

At the heart of embryonic reprogramming are chemical changes (methylation) to the genome, which influence gene expression without altering the genetic sequence, yet can be inherited. Methylation marks are one of the ways that genes get switched on or off in different places at different times, enabling different tissues to develop from a single fertilised egg.

If these ‘epigenetic’ methylation marks are not copied correctly from the egg and sperm in the developing embryo, mistakes could be retained for the individual’s lifetime, potentially leading to errors in epigenetic patterns and human disorders.

The research, reported in the journal Nature Genetics, details for the first time a genome-wide methylation map of mammalian oocytes (eggs), which will provide scientists with a greater understanding of how we develop into healthy individuals and maintain wellbeing during ageing.
 
Dr Gavin Kelsey, senior author of the paper and a group leader at the Babraham Institute, which receives strategic funding from the Biotechnology and Biological Sciences Research Council explained: “A greater understanding of how methylation landscapes are set up has far reaching implications not only for understanding mechanisms of inheritance and development but also our susceptibility to age-related diseases since conditions like heart disease, diabetes and obesity may be associated with errors in epigenetic regulation.
 
“The research may also bring new insight to reproductive problems, helping to pinpoint some of the epigenetic impairments suspected to underlie infertility where there is no obvious cause. This research lays the foundations for understanding post-fertilisation reprogramming of embryos and may contribute knowledge to improve assisted reproductive technologies in humans.”
 
The research also brings new understanding of epigenetic regulation and ‘genomic imprinting’ in mammals, a process where particular genes are used depending on whether they come from the mother or father.

Central to this are ‘epigenetic’ methylation tags, which modify DNA structure and appear to give the chromosomes a ‘memory’ of their parental origin. Major epigenetic reprogramming occurs in germ cells (eggs and sperm) to erase and reset parental imprints and in early pre-implantation development. After fertilisation, methylation is extensively reprogrammed in the developing embryo, except at imprinted genes which have to retain the methylation tags inherited from the egg or sperm.
 
If one copy of a gene is epigenetically ‘turned off’ and the remaining working gene has a mutation, problems may arise. A number of imprinting diseases have been reported in humans and animals born after the use of ART, although their incidence remains low - for example, a loss of methylation of the mother’s copy of a certain gene leads to Beckwith-Wiedemann syndrome, an over-growth disorder with a higher risk of developing childhood cancer.

Consequently understanding more about the methylation landscape of mammalian eggs and early embryos may help inform strategies for assisting with human reproduction and may lead to new possibilities in pre-implantation genetic diagnosis.
 
This landmark methylation map of germ cells and embryonic development may also have implications for the assisted reproduction of livestock. It will also be an invaluable resource for the research community, which will enable scientists to determine how much of the genome is imprinted, bringing greater understanding about the regions of the genome that are resistant or prone to methylation and the role of this in mammalian development.
 
This research was supported by the Babraham Institute, which undertakes international quality life sciences research to generate new knowledge of biological mechanisms underpinning ageing, development and the maintenance of health, the BBSRC and also was supported by grants from The Medical Research Council and the Centre for Trophoblast Research in Cambridge.

• PHOTOGRAPH SHOWS: Dr Gavin Kelsey, senior author of the paper and a group leader at the Babraham Institute