Stefanie Seisenberger, Simon Andrews, Felix Krueger, Julia Arand, Jörn Walter, Fátima Santos, Christian Popp, Bernard Thienpont, Wendy Dean and Wolf Reik.
The Dynamics of Genome-wide DNA Methylation Reprogramming in Mouse Primordial Germ Cells
Molecular Cell Published 28 December 2012, AOP 6 December 2012
All the cells within an organism have an identical set of genes. Nevertheless, each cell can adopt one of many different functions, for example a muscle cell functions very differently to a brain cell. This is regulated by which genes are switched on or off and the study of these molecular switches is called epigenetics. One of the hallmarks of epigenetics is DNA methylation, which involves small chemical groups (methyl groups) becoming attached to the DNA and these are usually associated with inactive genes.
DNA methylation marks are tremendously important during the development of embryos. As an embryo grows, all the cells which are generated take on a certain cellular identity and eventually become highly specialised cells in adult life. DNA methylation marks are involved in promoting this cellular identity.
The cells generated in the developing embryo which give rise to sperm or egg in adult life are called primordial germ cells (PGCs). These cells inherit a DNA methylation pattern (from the tissue from which they arise -the epiblast) and this has to be erased in order to provide a clean slate for the next generation, in preparation for making a new embryo. On the molecular level, this means that DNA methylation marks are reset or “reprogrammed” in PGCs on a global scale but not much is known about this process.
In this work, we have investigated the precise dynamics of how methylation marks are erased in PGCs. First we found that methylation erasure happens earlier than previously thought. Second, we observed that methylation erasure takes place while these cells divide and expand and this way we have gained some mechanistic insight into how this global process is achieved. Third, we analysed which genes are active (or expressed) in PGCs and we found that a complex network of genes is switched on which establishes a developmental potential similar to an embryonic stem cell. When PGCs develop further, this network is switched off again and instead a gamete-specific network is turned on, which drives PGCs further towards their fate as sperm or egg. Lastly, we have also identified regions that seem to escape reprogramming. This is a significant finding because environmental influences (such as diet or stress) can influence DNA methylation patterns and in the case of a pregnant mother can also affect the developing embryo and even the cells within the embryo that will eventually form the next generation grandchildren. This way “environmental memory” on the DNA can be passed on to future generations if not successfully erased. Our work provides a detailed description of epigenetic reprogramming in the germ line and an advanced understanding of how epigenetic information can be passed on to future generations.
This research was conducted in collaboration with Wendy Dean and Simon Andrews at the Babraham Institute. The Reik lab investigates how epigenetic factors regulate cellular identity in germ cells and embryonic stem cells and collaborates closely with the Sanger Institute, where part of this work was carried out. This research was supported by the BBSRC, Boehringer Ingelheim Fonds, MRC, Wellcome Trust and the EU.
About the lead author
Stefanie Seisenberger holds a PhD in Developmental Genetics awarded for her work on epigenetic profiling carried out at the Babraham Institute in Cambridge together with Wolf Reik. The Reik laboratory is a pioneer in epigenetic profiling and Stefanie has optimised a number of techniques for this purpose as part of her PhD and contributed to the epigenetic analysis of embryonic stem cells and germ cells. Stefanie completed a Biology degree at the Ludwig Maximilan University in Munich (Germany) and first came to Cambridge in 2006 to complete her final year project with a stipend from the German Academic Exchange Service (DAAD). This work was carried out in Mark Carrington’s group at the Department of Biochemistry, where Stefanie studied the role of a surface protein in Trypanosoma brucei, the causative agent of human sleeping sickness. After finishing her degree, Stefanie turned to epigenetics and with a PhD fellowship from the Boehringer Ingelheim Fonds and additional stipends from the BBSRC and the Cambridge European Trust, she started her work on epigenetic profiling with Wolf Reik. Stefanie was awarded her PhD in 2011 and is currently a postdoc in the Reik laboratory investigating how DNA methylation marks are reset in germ cells and how this can affect subsequent generations.
Babraham Institute - Babraham Research Campus - Cambridge - United Kingdom