Faulty cellular reprogramming and the corresponding unleashing of rogue DNA elements has been found to be at the heart of male sterility in mice. The research, published today in Nature Structural & Molecular Biology, involved the Institute’s epigenetics experts working with colleagues at the MRC Centre for Regenerative Medicine and the European Bioinformatics Institute.
The genetic information of a species is usually held under lockdown, preventing undesirable typos in the genetic code of our genes. However, during some situations this repression must be released, for example in the creation of sperm and egg cells in the developing embryo. The research identified that in mice lacking two key proteins required to reinstate gene lockdown, jumping sections of DNA, called transposons, take advantage of this freedom to activate the expression of genes in their vicinity. In the study, the undesirable gene expression initiated by the transposons caused precursor sperm cells to fail to develop properly in mice, causing sterility.
Just like books in a library, most of our genes are maintained in a closed state unless they are being read and copied. One way in which our genes are silenced is by the addition of chemical tags, a reversible silencing process called methylation. By laying down patterns of gene silencing, the genome ensures appropriate gene expression for different cell types. To extend the library analogy, this is similar to restricting a library user to a particular subset of books rather than the full range. The methylation process is also effective at silencing and preventing the disruptive activity of transposons in the genome. Surprisingly, approximately 70% of the mouse genome is made up of these mobile DNA pieces but only 2% of the transposons in the genome are potentially active.
The generation of sperm and egg precursors from the cells making up the early embryo requires the resetting of information annotated on the genome through DNA methylation, a process called genome reprogramming. Methylation information is deleted and then reinstated to establish the correct gene ‘reading list’ for precursor cells to become a developed sperm or egg. Male mice lacking either of two proteins central to re-establishing genome methylation are sterile. After confirming that neither protein had a key role in precursor sperm cells directly, the researchers found that sperm development failed in these mice because of defective genome reprogramming as the precursor sperm cells developed in the mouse embryo. Profiling where methylation was laid down throughout the genome, especially at transposon-containing locations, identified that loss of correct genome methylation allowed a family of transposons to be activated. These transposons drove expression of neighbouring genes, genes which wouldn’t usually be expressed during normal sperm development, and cells therefore fail to develop properly.
“DNA methylation reprogramming is essential for the interpretation of one genome into the many different cell types of an organism.” said Professor Wolf Reik, Head of the Epigenetics research programme at the Babraham Institute and a senior author on the paper. “However, it’s a risky situation because it creates an environment where transposon activity can cause all sorts of unwanted effects. There’s a flip side though. Over the course of evolution we have transposons to thanks for the creation of novel, useful genes so sometimes their disruption of genomes can be positive.”
The obvious question is whether male infertility in humans could be explained by the same effect? Paper author Dr Rebecca Berrens thinks it’s possible. “The rewiring of the genome in early sperm cells is expected to be similar in mice and humans and we know that human sterility can be caused by transposon activity although the exact mechanism is unknown. It’s an exciting time for epigenetics research as we start to unpick these types of mechanisms to explain phenotypes.”
Vasiliauskaitė, L., Berrens, R.V., Ivanova, I., Carrieri, C., Reik, W., Enright, A.J., O’Carroll, D.. Defective germline reprogramming rewires the spermatogonial transcription. Nature Structural & Molecular Biology
This work received funding from the European Research Council under the European Union’s Seventh Framework Programme. The Babraham Institute receives strategic funding from the Biotechnology and Biological Sciences Research Council (BBSRC).
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Affiliated authors (in author order)
Rebecca Berrens - Epigenetics Programme, Babraham InstituteWolf Reik - Group Leader, Epigenetics Programme, Babraham Institute
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All mice used in this study were male; and bred and maintained in EMBL Mouse Biology Unit, Monterotondo, and subsequently in the Centre for Regenerative Medicine, Edinburgh. All procedures were done in accordance to the current Italian legislation (Art. 9, 27. Jan 1992, nu116) under license from the Italian health ministry or the UK Home Office regulations, respectively.
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The Babraham Institute receives strategic funding from the Biotechnology and Biological Sciences Research Council (BBSRC) through an Institute Core Capability Grant to undertake world-class life sciences research. Its goal is to generate new knowledge of biological mechanisms underpinning ageing, development and the maintenance of health. Research focuses on signalling, gene regulation and the impact of epigenetic regulation at different stages of life. By determining how the body reacts to dietary and environmental stimuli and manages microbial and viral interactions, we aim to improve wellbeing and support healthier ageing.
30 April 2018