Endogenous retroviruses give way to pluripotency during the embryonic stage.

Hundreds of millions of years ago, animals evolved thanks to certain viruses that infect primitive organisms. Viral genetic material was integrated into the genome of the first multicellular creatures and is still present in DNA today. Over the past decade, the genetic sequences of these viruses have been discovered to make up at least 8 to 10 percent of the human genome.

In this sense, CNIO researchers have described for the first time the role that these viruses play in a key process of human development that occurs a few hours after fertilization: step towards pluripotency, when there are two to four cells in the egg. Before this stage, each of the two cells of the embryo is totipotent, that is, it can develop into an independent organism. On the other hand, the four cells of the next phase are not totipotent, but pluripotent, since they can differentiate into cells of any specialized tissue of the body.

Ancient viruses

This genetic material left behind endogenous retroviruses It was combined with the genome of living creatures that witnessed the Cambrian Explosion, which occurred more than 500 million years ago, when the planet’s seas experienced an explosion of biodiversity.

“Until recently, these viral remains were considered “junk DNA,” useless or even harmful genetic material,” explains Sergio De la Rosa, first signatory of the study published in the journal Science Advances. “Intuitively, it was believed that the presence of viruses in the genome could not be good. But in recent years we are realizing that these retroviruses, which developed with us For millions of years, they have performed important functions, such as regulating the functioning of other genes. “This is a very active area of ​​research,” he adds.

Research shows that The endogenous retrovirus MERVL sets the pace of embryo development, especially at a certain stage of the transition from totipotency to pluripotency, and explains the mechanism by which this occurs. It is associated with the URI gene.

“This is a completely new role for endogenous retroviruses,” he says. Nabil Juder, senior author of the study. “We have discovered a new mechanism that explains how an endogenous retrovirus directly controls pluripotency factors,” he notes.

Several years ago it was discovered that if ARVI is eliminated in laboratory animals, embryos they didn’t develop. De la Rosa wanted to know why, and that’s how he discovered its connection to the retrovirus MERVL. Their results suggest that one of the functions of URI is to mediate the action of essential molecules to acquire pluripotency; If the URI does not work, the pluripotency factors do not work. and the cell remains in a state of totipotency. And this led to the discovery that it was the endogenous retrovirus MERVL-gag protein, which in turn modulated the action of URI.

Transition

The researchers observed that during the totipotency phase, the expression of the viral MERVL-gag protein is high; This protein binds to the URI and prevents its action. But gradually the levels change, so Viral MERVL-gag protein levels drop and URI can take effect, the moment of emergence of pluripotency. “It’s a smooth transition: when you have high viral protein expression, you have fewer pluripotency factors; When ERV expression decreases, you allow URI to stabilize these factors,” says De la Rosa.

Research shows Symbiotic coevolution of endogenous retroviruses with host cellsto ensure the smooth and timely development of early embryonic development. “The three-way communication between viral protein, URI, and pluripotency factors is very finely modulated to allow the embryo sufficient time to adapt and coordinate the smooth transition from totipotency to pluripotency and cell lineage specification during embryonic development,” Juder concludes.

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