Stem cell discovery at Babraham Institute creates opportunity to study our genomic wake-up call

Shortly after fertilisation, the early human embryo undergoes a major ‘wake-up call’.

At this stage - while it is just eight cells in size - the embryo’s genome takes over control of the cell’s activities from the maternal genome.

It is a key developmental moment, in which the genome is reset and reorganised, and large numbers of embryonic genes are expressed for the first time.

If it proves unsuccessful, further development of the embryo fails - or there may be implications for later developmental stages.

Now researchers at the Babraham Institute have discovered a stem cell population that provides a new way to study the awakening of the human genome.

It is hoped these unique cells could advance our knowledge of the earliest events in our development.

The newly-identified subset of human embryonic stem cells provide the closest model available to study this process without the need for human embryos.

Until now, existing human stem cell models had only represented the embryos at later stages of development.

That meant research into this moment - known as zygotic genome activation (ZGA) - could only be carried out with human embryos, the use of which is naturally highly regulated, or through alternative, non-human models.

The breakthrough from the Reik Lab at Babraham comes a decade after the 2012 discovery of cells representing the genome activation stage of development in mouse embryonic stem cells (ESCs), which has allowed researchers to learn more about mammalian ZGA.

It is hoped we can now advance our knowledge of the earliest events during preimplantation development, map key changes and study the implications of genome activation errors on developmental disorders and embryo loss.

Dr Jasmin Taubenschmid-Stowers, lead author and research fellow in the Reik lab, part of the institute’s epigenetics research programme, said: “Studying mouse embryonic stem cells has allowed researchers to learn about the general process of genome activation, but we could learn even more about this important step in human development thanks to our discovery of a human stem cell counterpart.”

Cells take copies of the genome in the form of an RNA code, which is translated into proteins to enable them to function.

The RNA code output - known as the transcriptome - can be used to identify different populations of cells.

In this study, published in the journal Cell Stem Cell, researchers used existing human data sets and information from mouse ESC studies to identify characteristic transcriptome marks that could be linked to genome activation.

Using single cell techniques to search for similar cells in a population of human ESCs, they found a subset with the right transcriptome marks to be a potential match for the eight-cell stage, when the major wave of genome activation occurs.

Calling these ‘eight-cell like cells’ or 8CLCs, they used published human data to further validate and confirm that they shared the same molecular outputs seen in genome activation, in order to show they could be used as a reliable model for future studies.

Professor Jennifer Nichols from the Wellcome - MRC Cambridge Stem Cell Institute helped the Babraham researcher explore the extent of the similarities.

They selected and searched for proteins in both sets of cells that were indicative of ZGA and found a close match between ZGA-associated proteins in 8CLCs with those in human eight-cell embryos.

As Jasmin explains: “The collaboration with Professor Nichols and her team was vital as we could identify selected proteins and really look at those in real, fixed human eight-cell stage embryo cells compared to our new stem cell counterparts. This work confirmed that our 8C-like cells matched at the protein level too, in additional to the transcriptomics data, providing validation that the eight-cell like cells matched embryo cells across multiple molecular layers.”

Prof Wolf Reik, Babraham Institute group leader, said: “Our focus is now to characterise these cells and understand their unique properties so that we can use eight-cell like cells as a tool to ask questions about the molecular changes that may cause developmental issues at this early stage.”

Prof Reik is to take up the role of director of Altos Labs’ Cambridge Institute of Science at Granta Park in the summer, following the biotech company’s record-breaking launch, which attracted $3bn of backing.

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