DNA from ancient virus essential for embryo development

Viruses have a bad wrap – think HIV; avian influenza and of course COVID-19. But it turns out they are essential components in the evolution of animals, including humans.

A least 8% of the human genome is made up of the remnants of genetic material from ancient retroviruses that infected organisms over the course of millions of years.

Researchers have now found that this viral DNA plays an important role in a key process in embryo development, according to a new study in mice published in the journal Science Advances. The findings have important implications for regnenerative medicine and the creation of artificial embryos.

When retroviruses, such as HIV, infect a cell they convert their RNA genome into DNA and insert it into their host’s genome to replicate. But if this happens inside a cell that produces sperm or eggs then the retrovirus becomes “endogenous”, meaning its genetic material is passed down from generation to generation.

Viral genetic material was integrated into the genomes of the first multicellular organisms, and they can be found in the genomes of humans and other animals today.

“Until recently, these viral remnants were considered to be ‘junk DNA’, genetic material that was unusable or even harmful,” says first author Sergio De la Rosa, a researcher at the Spanish National Cancer Research Centre, CNIO.

“Intuitively, it was thought that having viruses in the genome could not be good. However, in recent years we are starting to realise that these retroviruses, which have co-evolved with us over millions of years, have important functions, such as regulating other genes. It’s an extremely active field of research.”

This study found that MERVL (murine endogenous retrovirus-L) – which has a counterpart in humans, HERVL – sets the pace for embryo development in mice during a step that occurs a few hours after fertilisation.

This is the transition from totipotency to pluripotency – when the fertilised egg cell transitions from having 2 to 4 cells.

Totipotent cells can divide into all cell types in an organism, until it creates a complete organism, whereas pluripotent cells are able to divide into most or all cell types but can’t develop into an entire organism on their own.

Looking closer at a protein called URI, which has previously been found to be essential for embryo development, revealed that it enables the action of certain molecules, called pluripotency factors, that are essential for totipotent cells to become pluripotent.

They found that an endogenous retrovirus protein, called MERVL-gag, controls the action of URI.

“It is a totally new role for endogenous retroviruses,” says senior author Nabil Djouder, who leads the Growth Factors, Nutrients and Cancer Group at CNIO.

“We discovered a new mechanism that explains how an endogenous retrovirus directly controls pluripotency factors”.

De la Rosa adds: “It’s a smooth transition. When there is a high expression of viral protein, there are fewer pluripotency factors; as expression decreases, URI stabilises such factors,” says De la Rosa.

The findings are relevant for regnenerative medicine and the creation of artificial embryos, as the loss of URI could be a way to generate stable cell lines in the totipotency phase.

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