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Epigenetic switch helps keep early embryo cells on the right track

Key points:

• An international team of researchers have identified how a protein complex Polycomb Repressive Complex 2 (PRC2) controls the very first cell fate decision towards either placenta or foetus during human embryonic development.
• PRC2 is a protein well known for switching genes off in several types of cell, but researchers have shown for the first time that PRC2 is active at an early stage in development.
• These latest findings sheds light on how the very first cell lineages are allocated, and show that perhaps the role of PRC2 should be revisited in other cases where it had been dismissed.

A study describing how stem cells resembling the early embryo are restricted in their ability to differentiate into certain tissue lineages has been published today in by an international consortium of researchers from KU Leuven (BE), the ̨��swag ̨��swag (UK), Radboud University (NL), Ghent University (BE) and the ̨��swag of Molecular Biotechnology of the Austrian Academy of Science (AU). Understanding the molecular conditions that allow embryonic cells to keep their options open is important for our knowledge of human development, and successful implantation during pregnancy.

The research identifies an unexpected role for an important regulator of gene expression at the key decision point during which unspecialised cells make their first fate decision. This occurs within the first week of human development, when cells in the embryo either become embryonic cells, and will form the body of the embryo, or they become placental cells to support the growth of the embryo. This decision is driven by reversible epigenetic changes to the cell’s DNA that control which genes are switched on or off. The correct orchestration of switching genes on and off is essential for successful development and is responsible for cells acquiring different identities.

Access to human embryos for research is limited but researchers are able to study aspects of human development in the lab using human embryo-like cells called human naïve pluripotent stem cells.

In the study, the authors performed the most comprehensive investigation so far in human pluripotent stem cells to examine the properties of the epigenetic switches and how they are controlled. By uniting information about the genes, epigenetics, and proteins in the stem cells, the team discovered that a protein complex called PRC2 (Polycomb Repressive Complex 2) was especially active at this developmental stage. The researchers were also able to study key aspects of human development in the lab using a very powerful, recently developed human embryo-like model system called blastoids, in which the researchers could further validate their findings.

Polycomb proteins are a well-studied group of molecules that influence access to the DNA in a cell. “The protein complex PRC2 was known to have a role later in development, but it is the first time that we have observed that PRC2 plays a role in such early stages of human embryonic development.” says Professor Hendrik Marks, Group Leader at Radboud University. “Previously, it was assumed that it was not important at these early stages. Identifying an important role for PRC2 in early development sheds light on how the very first cell types arise in the human embryo”, adds Professor Vincent Pasque (KU Leuven).

When the researchers inactivated PRC2, human naïve pluripotent stem cells made more placental cells. Remarkably, PRC2 inactivation also accelerated blastoid development, where stem cells organise into 3D embryo-like structures, raising the possibility that the timing and efficiency of blastoid formation for research purposes could be controlled and improved.

“Since naïve human pluripotent stem cells can make all cell types, it was believed that there must be no epigenetic controls in place to influence cell identity” explains doctoral researcher Irene Talon (KU Leuven). “However, we found that the protein complex PRC2 acts as a barrier that prevents the conversion of the human naïve pluripotent stem cells into placenta cells”.

Scientists have long wanted to gain insights into how different cell types are made early during human embryogenesis because this step is crucial for the embryo to successfully implant into the uterus and to establish a healthy pregnancy.  “Our research opens up the ability to better control stem cell specialisation and blastoid development, which is useful for studying in the laboratory how the initial placental cells are formed. In the longer term, the new knowledge might improve our understanding of how embryos successfully implant in the uterus at the earliest stages of pregnancy, and why this can sometimes go wrong”, concludes Dr Peter Rugg-Gunn, group leader at the ̨��swag ̨��swag.

Today’s publication shows the power of studying stem cells to understand human development, but more discoveries can only be achieved if researchers have high quality, and well-understood cell models. The Rugg-Gunn lab has recently made remarkable progress towards a complete understanding of the conditions that induce and maintain different pluripotent stem cell states.

Their findings address two different stages of generating pluripotent stem cells; the reprogramming process, and maintaining the desired cell state. Earlier this year, they identified an epigenetic factor essential for encouraging cells to become naïve pluripotent stem cells. Once reprogrammed, cells are kept in specific conditions to maintain their unspecialised state, the Rugg-Gunn lab found that naïve pluripotent stem cells rely on the signalling molecule TGFβ for their stable unspecialised state.

Adam Bendall, PhD researcher in the Rugg-Gunn lab, added: “It is really exciting to see our new results and how they build on our previous findings. We have gone from having a very basic understanding of naïve pluripotent stem cells, to being able to pinpoint some of the key players in their regulation.”

Notes to Editors

This news article was adapted from a press release issued jointly by KU Leuven, the ̨��swag ̨��swag, Radboud University, Ghent University and the ̨��swag of Molecular Biotechnology of the Austrian Academy of Science.

̨��swagation reference

Zijlmans, Talon, Verhelst, Bendall et al. Integrated Multi-Omics Reveal Polycomb Repressive Complex 2 Restricts 2 Human Trophoblast Induction, , 2022

̨��swag ̨��swag press contact:

Honor Pollard, Communications Officer, honor.pollard@babraham.ac.uk

Image description:

Fluorescent microscopy image of a human blastoid, which is an artificial embryo-like structure formed from stem cells that can model early embryogenesis in a dish. Cells corresponding to the early placenta are marked in blue, and cells corresponding to the early embryo are marked in yellow.

Credit: Photo courtesy of Alok Javali, Heidar Heidari Khoei and Nicolas Rivron, ̨��swag of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna, Austria.

̨��swag ̨��swag affiliated authors (in author order):

Adam Bendall, PhD student, Rugg-Gunn lab

Andrew Malcolm, PhD student, Rugg-Gunn lab

Laura Biggins, Bioinformatician, Bioinformatics facility

Amanda Collier, former PhD student, Rugg-Gunn lab

Charlene Fabian, PhD student, Rugg-Gunn lab

Peter Rugg-Gunn, group leader, Epigenetics programme

̨��swag funding

This research was supported by The ̨��swag Foundation–Flanders (FWO), the KU Leuven ̨��swag Fund, the Biotechnology and Biological Sciences ̨��swag Council (BBSRC) and the Wellcome Trust.

About the ̨��swag ̨��swag

The ̨��swag ̨��swag undertakes world-class life sciences research to generate new knowledge of biological mechanisms underpinning ageing, development and the maintenance of health. Our research focuses on cellular 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. The ̨��swag is strategically funded by the Biotechnology and Biological Sciences ̨��swag Council (BBSRC), part of UK ̨��swag and Innovation, through ̨��swag Strategic Programme Grants and an ̨��swag Core Capability Grant and also receives funding from other UK research councils, charitable foundations, the EU and medical charities.

About BBSRC

The Biotechnology and Biological Sciences ̨��swag Council (BBSRC) is part of UK ̨��swag and Innovation, a non-departmental public body funded by a grant-in-aid from the UK government.

BBSRC invests in world-class bioscience research and training on behalf of the UK public. Our aim is to further scientific knowledge, to promote economic growth, wealth and job creation and to improve quality of life in the UK and beyond.

Funded by government, BBSRC invested £451 million in world-class bioscience in 2019-20. We support research and training in universities and strategically funded institutes. BBSRC research and the people we fund are helping society to meet major challenges, including food security, green energy and healthier, longer lives. Our investments underpin important UK economic sectors, such as farming, food, industrial biotechnology and pharmaceuticals.