500-Million-Year-Old Virus: A Key to Embryo Development?

Our genomes contain traces of ancient viruses that infected our ancestors millions of years ago. These viral remnants, known as endogenous retroviruses, make up about 8 to 10 percent of our DNA. But far from being junk, some of these viral genes have important functions in regulating our own genes, especially during early stages of embryonic development.

One of these stages is the transition from totipotency to pluripotency, which occurs a few hours after fertilization. Totipotent cells are capable of developing into any cell type in the body, including the placenta. Pluripotent cells are also able to differentiate into any tissue, but not the placenta. This transition is crucial for the formation of a complex organism from a single fertilized egg.

Scientists from the Spanish National Cancer Research Center (CNIO) have discovered that a protein from an endogenous retrovirus called MERVL plays a key role in regulating this transition in mouse embryos. Their findings, published in the journal Science Advances, reveal a new mechanism that explains how an ancient virus directly controls pluripotency factors.

MERVL-gag: A viral protein that sets the pace of embryo development

The researchers used mouse models to study the expression and function of MERVL-gag, a protein encoded by the MERVL endogenous retrovirus. They found that this protein is highly expressed in the early totipotency phase of embryo development, and then gradually decreases as the cells become pluripotent.

They also showed that MERVL-gag influences the activity of URI, a gene that is essential for maintaining pluripotency. URI acts as a brake on the expression of pluripotency factors, such as NANOG and OCT4, which are needed for the cells to remain unspecialized and flexible. By interacting with URI, MERVL-gag modulates its braking effect and allows the cells to switch from totipotency to pluripotency at the right pace.

“It is a totally new role for endogenous retroviruses,” says Nabil Djouder, senior author of the study and leader of the Growth Factors, Nutrients and Cancer Group at CNIO. “We discovered a new mechanism that explains how an endogenous retrovirus directly controls pluripotency factors.”

Implications for regenerative medicine and artificial embryos

The discovery of this novel role of MERVL-gag has implications for the field of regenerative medicine and the creation of artificial embryos, which aim to mimic natural embryonic development in vitro. Understanding how totipotent and pluripotent cells are generated and regulated is essential for developing new therapies for diseases that involve tissue damage or degeneration.

The researchers suggest that manipulating MERVL-gag expression could be a way to generate stable cell lines in the totipotency phases, which are currently difficult to obtain and maintain in culture. This could also help to create artificial embryos that resemble natural ones more closely.

“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,” says Sergio de la Rosa, first author of the study and biologist at CNIO. “It’s an extremely active field of research.”

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