All multicellular organisms originate from the fusion of a male and a female gamete cell, for example, the sperm and the egg cell. This results in the formation of a zygote which contains DNA from both gametes.
The zygote is special because this single cell is capable of developing into an embryo and ultimately an entire organism, unlike an already-differentiated cell like a skin cell which can only develop into skin tissue. This property of the zygote is called ‘totipotency’.
Whether the gametes’ DNA is already prepared for totipotency at fertilisation or whether it needs to be reprogrammed to enable the zygote’s totipotency, is a question crucial to developmental biology.
Scientists from Huntsman Cancer Institute (HCI) at the University of Utah have some answers.
They analysed the DNA methylation patterns of sperm cells, egg cells, three stages of embryo cells before its genome is active, and one stage after it is active.
When methyl groups attach to certain areas of DNA, gene activity in those areas gets “turned off”. Studying the DNA methylation pattern of an undifferentiated cell (the embryo cell), and comparing it with the pattern of a differentiated cell (the egg cell and the sperm cell) can tell us which genes need to be activated to make a cell totipotent.
Zebrafish was chosen for this study as it is an ideal organism: it generates a large number of egg cells and there is a longer gap before the zygote is activated. Zygotic genome activation (ZGA) is the point of transition from maternal to embryonic control of development.
Second, ZGA occurs at approximately the 2-cell stage in mice, and the 4- to 8-cell stage in humans, compared with the 1,000-cell stage (about 3 hours post-fertilisation) in zebrafish.
This gives scientists more time to examine the process of ZGA in zebrafish than in its mammalian counterparts.
The results were unexpected — the sperm cell’s methylation pattern matched that of the active embryo cell, while the egg cell needed to be reprogrammed before it reached this state. This means that at fertilisation, the DNA from the sperm is more “poised” for development than that of the egg cell.
“It was previously believed/expected that the egg at fertilisation would already be ready for ZGA, and that it was likely the sperm that needed to undergo changes. Our results provide the opposite outcome — the sperm is ready, not the egg,” Bradley R. Cairns explained in an email to this correspondent.
Dr. Cairns is a Senior Director of Basic Science at Huntsman Cancer Institute and co-author of the paper published in Cell this week.
Further, their study showed that the egg cell’s DNA is able to reprogramme itself to be ready for ZGA without using the sperm’s DNA as a template.
Diseases like cancer involve the misregulation of these cell processes, resulting in cells that get arrested at an early stage of differentiation, or cells that go backwards and become undifferentiated like embryo cells.
Once there is a clearer picture of how this misregulation takes place, better strategies can be devised to reverse this process.
“Studies on the zebrafish and the mouse allow us to look at eggs, and at how the process of totipotency is achieved in evolution, and give us guidance conceptually and technically on how the process might work in humans,” said Cairns.
“We now will approach the work in humans with much more focus and technical know-how.”
This article has been corrected for a typographical error
