A bit like someone looking into a mirror reflected in another mirror, as one new life is developing as an embryo, the capacity to produce the next generation of life is already being established in that embryo. Research carried out between the groups of Wolf Reik and Peter Rugg-Gunn in the Epigenetics research programme at the Babraham Institute has investigated the early stages of the development of cells called primordial germ cells and developed strategies to generate these cells in the lab. Primordial germ cells give rise to sperm or egg cells and, in humans, are already present in embryos at the second week of development.
As reported in the latest issue of Developmental Cell, the researchers developed a method to generate primordial germ cell ‘lookalike’ cells to look in detail at what was happening at the epigenetic level, comparing what happens in cells from mice and humans. Epigenetics refers to reversible modifications to DNA that don’t affect the DNA sequence but alter how genes are read. The specific pattern of epigenetic marks in a cell type specifies identity and this epigenetic control is vital to what makes our cells different, for example a skin cell from a liver cell, when they all contain the same genetic instructions.
The development of primordial germ cells is characterised by widespread epigenetic remodelling. These cells need to ‘forget’ their own programmed instructions and create a blank slate for the blueprint of either a sperm or egg cell to be laid down.
Creating and analysing accurate ‘lookalike’ primordial germ cells opened the window on characterising the early stages of specification of these cells and the regulation of developmental timings. This insight has been previously limited by the difficulty of obtaining these cells from embryos. The generation of human ‘lookalike’ primordial germ cells is also of importance for future fertility studies and analysis of potential transgenerational epigenetic inheritance in humans.
As explained by lead researcher, Dr Ferdinand von Meyenn, postdoctoral researcher in the Epigenetics research programme at the Babraham Institute and first author on the paper: “Our method establishes a reliable system that can be used to explore the early stages of epigenetic reprogramming in primordial germ cell-like cells and how this is regulated in the generation of reproductive cells. This method also provides an experimental system for future fertility studies in humans. Our side by side analysis uncovers the dynamics of epigenetic programming occurring in germ cell development at single base resolution in human and mouse cells.”
Professor Wolf Reik, Head of the Epigenetics research programme, said: “Charting the different developmental timings in the early reprogramming events observed in the human and mouse-derived cells gives the first mechanistic insight into how these events are regulated which is tremendously exciting. The next steps are to capture what happens in the later stages of primordial germ cell development and the related epigenetic events. In particular, this new method will allow us to answer questions regarding transgenerational epigenetic inheritance in humans.”
This research was funded by the Biotechnology and Biological Sciences Research Council, The Wellcome Trust, the EU BLUEPRINT Consortium and the EpiGeneSys FP7 EC-funded Network of Excellence. Ferdinand von Meyenn was funded by a Postdoctoral Fellowship of the Swiss National Science Foundation.
Generation of sperm and egg cell precursors in a dish: Image of cell aggregates with mouse primordial germ cell-like cells labelled in green.
von Meyenn et al. (2016) Comparative principles of DNA methylation reprogramming during human and mouse in vitro primordial germ cell specification. Developmental Cell
Ferdinand von Meyenn, postdoctoral research fellow (Reik lab)
Rebecca Berrens, PhD student (Reik lab)
Simon Andrews, Head of Bioinformatics
Fátima Santos, senior research scientist (Reik lab)
Amanda Collier, PhD student (Rugg-Gunn lab)
Felix Krueger, Bioinformatician
Rodrigo Osorno, senior research fellow (Reik lab)
Wendy Dean, senior research scientist (Reik lab)
Peter Rugg-Gunn, group leader, Epigenetics programme
Wolf Reik, Head of Epigenetics programme and group leader at the Babraham Institute, and associated faculty at the Wellcome Trust Sanger Institute
As a publicly funded research institute, the Babraham Institute is committed to engagement and transparency in all aspects of its research. The research presented here used mice kept in the Institute’s Animal Facility. Prospermatogonia (cells present in the embryo that will eventually give rise to sperm cells) were isolated from embryonic samples for analysis of small RNAs. All animal work carried out as part of this study was covered by a Home Office project license under the Animal (Scientific Procedures) Act 1986, and was further reviewed by the Babraham Institute Animal Welfare, Experimentation, and Ethics Committee.
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10 October 2016