All animals have evolved due to viruses that infected primitive organisms hundreds of millions of years ago. Viral genetic material became part of the genome of the first multi-cellular beings and remains in our DNA today.
For the first time, researchers from the CNIO (Spanish National Cancer Research Center) describe in the journal Science Advances the role played by these viruses in a process that is vital for our development, occurring a few hours after fertilization: the transition to pluripotency, when the oocyte goes from having two to four cells.
Before this step, each of the two cells of the embryo is totipotent, capable of developing into an independent organism; the four cells of the next stage are pluripotent, as they can differentiate into cells of any specialized tissue of the body.
This finding is relevant for regenerative medicine and the creation of artificial embryos, as it provides a new way to generate stable cell lines in the totipotency phases. Djouder leads the Growth Factors, Nutrients, and Cancer Group at the CNIO.
Genetic material from the now so-called ‘endogenous retroviruses’ was integrated into the genomes of organisms that may have facilitated the Cambrian explosion, a period over 500 million years ago when the world’s seas underwent a biodiversity ‘boom.’ Over the past decade, genetic sequences from these viruses have been found to make up at least 8–10% of the human genome.
“Until recently, these viral remnants were considered to be ‘junk DNA,’ genetic material that was unusable or even harmful,” explains De la Rosa. “Intuitively, it was thought that having viruses in the genome could not be good. However, in recent years we are starting to realize 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.”
The research shows that the MERVL endogenous retrovirus regulates the pace in embryo development, particularly during the transition from totipotency to pluripotency, and explains the mechanism behind this.
“This is a completely new role for endogenous retroviruses,” says Djouder. “We discovered a new mechanism that explains how an endogenous retrovirus directly controls pluripotency factors.”
This new action mechanism involves URI, a gene that Djouder’s group is researching in depth. If URI is deleted in laboratory animals, embryos do not develop. De la Rosa discovered its link to the MERVL retrovirus.
One of the functions of URI is to enable the action of molecules essential for acquiring pluripotency. If URI does not act, neither do the pluripotency factors, and the cell remains in a state of totipotency. The endogenous retrovirus protein, MERVL-gag, modulates the action of URI.
The researchers found that during the totipotency phase, when there are only two cells in the oocyte, expression of the MERVL-gag viral protein is high; this protein binds to URI and prevents it from acting. However, the levels gradually change, allowing URI to act and pluripotency to emerge.
The findings reveal symbiotic co-evolution of endogenous retroviruses with their host cells to ensure the smooth and timely progression of early embryonic development. The three-way relationship between the viral protein, URI, and pluripotency factors is finely modulated, “to allow sufficient time for the embryo to adjust and coordinate the smooth transition from totipotency to pluripotency and cell lineage specification during embryonic development,” concludes Djouder.
