Genes are switched on in the human embryo from the get-go

The finding that some genes are active from the get-go challenges the textbook view that genes don't become active in human embryos until they are made up of four-to-eight cells, two or three days after fertilisation.

The newly discovered activity begins at the one-cell stage – far sooner than previously thought – promising to change the way we think about our developmental origins.

The research, published today in Cell Stem Cell, was co-led by Professor Tony Perry at the University of Bath, Dr Giles Yeo at the University of Cambridge and Dr Matthew VerMilyea at Ovation Fertility, US.

Using a method called RNA-sequencing, the team applied precision analysis to individual human eggs and one-cell embryos 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. Because the gene activity starts small, previous techniques had not been sensitive enough to detect it. But 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, from the Department of Biology and Biochemistry at Bath. "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,” said Professor Perry.

What human genome awakening tells us

At the moment of human fertilisation, sperm and egg genomes – the collection of all of their genes – are inactive: the sperm and egg rely on transcripts produced when they were being formed for instructions that regulate their characteristics.

Transcripts provide essential instructions in all cells, and embryo cells are no exception. This means that it is essential for parental (sperm and egg) genomes to awaken in the new embryo. But when and how does this happen?

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.

The link with cancer

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 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.

As Dr Yeo from the Medical Research Council Metabolic Diseases Unit at Cambridge suggests, "If true, we should be able to see this altered gene activation signature at the one cell stage."

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.

ENDS

 

For further information, please contact Professor Tony Perry at the University of Bath, email perry135@aol.com or the University of Bath press office at press@bath.ac.uk or (+44) 1225 383841. To speak to Dr Giles Yeo, email Amy Hall: amy@catalysthcm.com. To speak to Dr Tex VerMilyea at Ovation Fertility, email Amy Hall: (+1) 214.893.8214

 

• The manuscript and an image are available to download at: https://tinyurl.com/yc2da64e

 

• Link to the paper: Post-embargo “Human embryonic genome activation initiates at the one-cell stage” is published in Cell Stem Cell: https://doi.org/10.1016/j.stem.2021.11.012

 

• Image caption: Mouse one-cell embryo showing two pronuclei: the human version is similar, and their busy preparation for future development remains a mystery. Credit: Perry Lab.

 

University of Bath

The University of Bath is one of the UK's leading universities both in terms of research and our reputation for excellence in teaching, learning and graduate prospects.

 

The University is rated Gold in the Teaching Excellence Framework (TEF), the Government’s assessment of teaching quality in universities, meaning its teaching is of the highest quality in the UK.

 

In the Research Excellence Framework (REF) 2014 research assessment 87 per cent of our research was defined as ‘world-leading’ or ‘internationally excellent’.  From developing fuel-efficient cars of the future, to identifying infectious diseases more quickly, or working to improve the lives of female farmers in West Africa, research from Bath is making a difference around the world.  Find out more: http://www.bath.ac.uk/research/

 

Well established as a nurturing environment for enterprising minds, Bath is ranked highly in all national league tables. We are ranked 8th in the UK by The Guardian University Guide 2022, and 9th in The Times & Sunday Times Good University Guide 2022 and 10^th in the Complete University Guide 2022. Our sports offering was rated as being in the world’s top 10 in the QS World University Rankings by Subject in 2021.

 

About the MRC Metabolic Diseases Unit

The MRC Metabolic Diseases Unit is based at the Wellcome-MRC Institute of Metabolic Science. It supports research to improve understanding of the basic mechanisms responsible for obesity and related metabolic diseases. This knowledge underpins the development of interventions to prevent and treat these conditions.

 

About the University of Cambridge

The University of Cambridge is one of the world’s top ten leading universities, with a rich history of radical thinking dating back to 1209. Its mission is to contribute to society through the pursuit of education, learning and research at the highest international levels of excellence.

 

The University comprises 31 autonomous Colleges and 150 departments, faculties and institutions. Its 24,450 student body includes more than 9,000 international students from 147 countries. In 2020, 70.6% of its new undergraduate students were from state schools and 21.6% from economically disadvantaged areas.

 

Cambridge research spans almost every discipline, from science, technology, engineering and medicine through to the arts, humanities and social sciences, with multi-disciplinary teams working to address major global challenges. Its researchers provide academic leadership, develop strategic partnerships and collaborate with colleagues worldwide.

 

The University sits at the heart of the ‘Cambridge cluster’, in which more than 5,300 knowledge-intensive firms employ more than 67,000 people and generate £18 billion in turnover. Cambridge has the highest number of patent applications per 100,000 residents in the UK.  www.cam.ac.uk

 

About Ovation Fertility

Ovation^® Fertility is a national network of reproductive endocrinologists and scientific thought leaders focused on reducing the cost of having a family through more efficient and effective fertility care.  Ovation’s IVF and genetics laboratories, along with affiliated physician practices, work collaboratively to raise the bar for IVF treatment, with state-of-the-art, evidence-based fertility services that give hopeful parents the best chance for a successful pregnancy.  Physicians partner with Ovation to offer their patients advanced preconception carrier screening; preimplantation genetic testing; donor egg and surrogacy services; and secure storage for their frozen eggs, embryos and sperm.  Ovation also helps IVF labs across America improve their quality and performance with expert off-site lab direction and consultation.  Learn more about Ovation’s vision of a world without infertility at: www.OvationFertility.com.

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