A series of molecular events occur shortly after fertilization in all mammals’ early embryos, setting the stage for subsequent development. The embryonic genome takes over control of the cell’s activities from the maternal genome during this critical ‘wake up call.’ Zygotic genome activation occurs at the 8-cell stage in humans (ZGA). Human ZGA could only be studied in human embryos prior to this study; human stem cell models only represented the embryo at later stages of development. Researchers in the UK were forced to use non-human models of early development because embryonic research was heavily regulated in the country.
ZGA cells in mouse embryonic stem cells (ESCs) were discovered in 2012, allowing researchers to learn more about the mammalian ZGA. The Reik lab at the Institute has discovered a human counterpart almost a decade later. The discovery made by the lab provides a new avenue for studying preimplantation development’s earliest stages.
Research Fellow in the Reik lab, who is also the lead author on the paper, Dr. Jasmin Taubenschmid-Stowers, commented: “To date, researchers have studied mouse embryonic stem cells, but now that a human stem cell counterpart has been found, they hope to learn even more about genome activation in humans.
A copy of the genome is taken in the form of an RNA code, which is translated into proteins, in order for cells to function. Transcriptionome is the RNA code output that can be used to identify distinct cell populations. Transcriptome signatures associated with genome activation were identified using information from both human and mouse ESC studies, according to the findings of this study. They began looking for similar cells in their human ESC population using single cell techniques.
After analyzing human embryonic stem cell transcriptome data, researchers discovered a group of ESCs with the right features to match the 8-cell stage of genome activation. For future studies, they could use these ‘8-cell like cells’ (also known as 8CLCs) as a reliable model because they shared the same molecular outputs that indicate genome activation with human cells.
The team collaborated with Professor Jennifer Nichols from the Wellcome-MRC Cambridge Stem Cell Institute to further investigate the similarities between their 8CLCs and the 8-cell stage in human embryos. By working together, they were able to identify ZGA-associated proteins in both sets of cell samples. The ZGA-associated proteins of 8CLCs closely matched those found in human 8-cell embryos, according to the findings of the scientists.
According to Jasmin, “As a result of our collaboration with Professor Nichols and her team, we were able to identify specific proteins and compare them to our new stem cell counterparts in real, fixed human 8-cell embryo cells. This study confirmed that our 8C-like cells matched at the protein level as well, in addition to the transcriptomics data, providing validation that the 8-cell like cells matched embryo cells across multiple molecular layers. “
“Our focus is now to characterise these cells and understand their unique properties so that we can use 8-cell like cells as a tool to ask questions about the molecular changes that may cause developmental issues at this early stage.” said Professor Wolf Reik, Babraham Institute group leader.