Scientists from the Yeo group, working with Professor Tony Perry from the University of Bath and Dr Matthew VerMilyea of Ovation Fertility in the US, have discovered that genes in human embryos rapidly become active after fertilisation, opening a new window on the start of human embryonic life.
When sperm meets egg, a whole cascade of events must kick off to merge the two gametes (with one set of chromosomes each) into a one cell embryo (containing two copies of each chromosome) ready to start dividing into more and more cells and grow into a living being. The egg is 1000s of times larger than the sperm; it’s the largest, or one of the largest single cells in the body. A hen’s egg, or even an ostrich egg, is a single cell! So most of the ‘machinery’ to kick things into action exists in the egg. But sperm and egg genes are inactive and need to be ‘awakened’ in the new embryo.
Textbooks currently tell us that that no new gene transcription* occurs until the 4 cell stage. We show this to be fundamentally wrong. Using very rare single cell human embryos from an IVF clinic in Texas – in fact because of a change in procedure these no longer exist – we have shown that transcription actually begins at the one cell stage, far earlier than previously thought. This promises to change the way we think about our developmental origins.
[*Transcription can be thought of as the awakening of the genes found on the maternal and paternal chromosomes as it produces instructions to make new proteins that go on to set the cellular machinery into action.]
The research, published today in Cell Stem Cell, used a method called RNA-sequencing to make a detailed inventory of tell-tale products of gene activity, called RNA transcripts. It revealed that hundreds of genes awaken in human one-cell embryos. Previous techniques had not been sensitive enough to detect this but the state-of-the art RNA-sequencing used in this study was able to reveal even small changes.
This is the first good look at the beginning of a biological process that we all go through – the transit through the one-cell embryo stage
said Professor Perry.
Without genome awakening, development fails, so it’s a fundamental step.
The team found that many genes activated in one-cell embryos remain switched on until the four-to-eight cell stage, at which point they are switched off.
It looks as if there is a sort of genetic shift-work in early embryos: the first shift starts soon after fertilisation, in one-cell embryos, and a second shift takes over at the eight-cell stage
says Professor Perry.
What does human genome awakening tell us
Understanding the process of genome awakening is important: it is a key piece of the jigsaw of development that promises a better understanding of disease, inheritance and infertility. The scientists found some activated genes that might be expected to play roles in early embryos, but the roles of others were unknown and could point to embryonic events that we don’t yet understand.
The team’s findings also shine a light on how the genes are activated.
Although the trigger for activation is thought to come from the egg, it’s not known how; now we know which genes are involved, we can locate their addresses and use molecular techniques to find out
said Professor Perry.
Remarkably, candidates that might trigger gene activation include factors usually associated with cancer, such as some well-known oncogenes. This led the researchers to speculate that the natural, healthy role of factors that are known to misbehave in cancer, is to awaken genes in one-cell embryos. If this proves to be correct, the team’s findings could illuminate events that initiate cancer, providing new diagnostic and preventive opportunities.
The team also looked at unhealthy one-cell embryos that do not go on to develop, and found that many of their genes fail to activate. Abnormal embryos have been used to evaluate methods of human heritable genome editing, but the new findings suggest they may be inappropriate as a reliable test system.
The findings also have clinical implications for the inheritance of acquired traits, such as obesity: parents who gain weight seem to pass the trait to their kids. It is not known how such acquired traits are transmitted, but altering gene activation after fertilisation is a possible mechanism. Others, including Susan Ozanne’s group, have provided evidence that in mice, preconception obesity can change the epigenetics of the egg/sperm enough so there is actually an increased risk in metabolic disease in the offspring.
If the same is true for humans (more difficult to work out!) then we should be able to see signatures of this in the new transcription of a single cell embryo. This is likely to be one of our next research questions.
Dr Giles Yeo
An open access copy of the paper is available online.