Researchers at the Institute, working in collaboration with researchers at the Radboud University, Netherlands, have identified the main mechanism responsible for removing pre-set epigenetic instructions from the genome. This reprogramming occurs in the development of an embryo, the cells that eventually generate sperm and egg cells, and is also of importance for the ability to produce naïve stem cells for regenerative medicine purposes.
During early development, the genome undergoes global memory erasure. This can be likened to a clean-up operation where gene silencing tags are lost from the DNA. The absence of these ‘off’ tags opens up parts of the genome previously locked away. Understanding how this reprogramming happens is a core quest for researchers working in the field of epigenetics.
The researchers’ aim was to find out the relative contribution of three different processes which all result in a decrease of ‘off’ tags (methyl groups): active removal from the genome, a halt in the addition of new methyl groups to DNA or whether methylation is not maintained as DNA is replicated. To answer this, the researchers utilised both lab-based biology and mathematical modelling to unpick the dynamics of the demethylation process. The group’s expertise in measuring DNA methylation changes throughout the genome allowed them to add vital detail to existing predictive models and improve accuracy.
As described in a paper in Molecular Cell, they found that the main driver of methylation loss across the genome was lack of maintenance as the genome was replicated. The accurate modelling of each demethylation pathway allowed their respective contributions and dynamics to be discovered and thereby leads to a unified view of genome-wide demethylation mechanisms.
Dr Ferdinand von Meyenn, postdoctoral researcher at the Babraham Institute and co-first author on the paper said: “Epigenetic resetting during embryogenesis is essential for normal development and also limits the potential for transgenerational epigenetic inheritance. By combining our experimental data with a mathematical approach we now have a better understanding of these processes.” Dr Mario Iurlaro, also a postdoctoral researcher at the Babraham Institute and co-first author on the paper added: “Our approach allowed us to systematically dissect the different pathways responsible for DNA demethylation and identify the main cause as impaired maintenance of methylation during cell replication.”
Professor Wolf Reik, Head of the Epigenetics Programme at the Institute and a senior author on the paper, said: “The exciting thing about this work is that it provides new insights into the mechanisms of global erasure of epigenetic memory. Being able to understand the interplay and behaviour of each pathway gives us a new level of understanding of global epigenetic reprogramming during early embryonic development.”
The research was supported by the Biotechnology and Biological Sciences Research Council, the Wellcome Trust, EU BLUEPRINT and EpiGeneSys to Wolf Reik, a Swiss National Science Foundation Fellowship to Ferdinand von Meyenn and an INGENIUM Marie Curie Actions studentship to Mario Iurlaro.
Ferdinand von Meyenn (Babraham Institute), Mario Iurlaro (Babraham Institute) and Ehsan Habibi (Radboud University, Nijmegen, Netherlands) are co-first authors on this work.
Ferdinand von Meyenn, postdoctoral research fellow (Reik lab)
Mario Iurlaro, postdoctoral research fellow (Reik Lab)
Fátima Santos, senior research scientist (Reik Lab)
Edoardo Petrini, postdoctoral research fellow (Reik Lab)
Inês Milagre, postdoctoral research fellow (Reik Lab)
Wolf Reik, Head of Epigenetics programme and group leader at the Babraham Institute, and associated faculty at the Wellcome Trust Sanger Institute
von Meyenn, Iurlaro, Habibi et al. (2016) Impairment of DNA methylation maintenance is the main cause of global demethylation in naïve embryonic stem cells. Molecular Cell
Erase and start again
Wiping the slate clean: erasing cellular memory and resetting human stem cells
Image: Stas Walenga/Shutterstock.com
26 May 2016