Relics of an Ancient Virus Embedded in DNA Control Embryo Development | The science

Every human being begins with a single cell—a fertilized egg—and eventually becomes an impressive being made up of some 30 trillion cells, each specialized for a specific task: transporting oxygen in the blood, contracting muscles, transmitting thoughts to the brain. . This first cell is totipotent: it is capable of giving rise to a complete personality. According to animal studies, when it divides, the two resulting cells remain totipotent, but the next time it reproduces, everything changes. These four cells are no longer totipotent, but pluripotent: they can give rise to any type of cell in the body, but not the entire subject. A team from the National Center for Cancer Research (CNIO) in Madrid has discovered in mouse embryos a surprising participant in this fundamental phase of development: remnants of viruses from infections that occurred millions of years ago, embedded in the animals’ DNA.

More than 8% of the human genome corresponds to this viral genetic material, integrated since time immemorial. Researcher Sergio de la Rosa, the study’s first signatory, and his colleagues observed in mice that one of these past invaders, the endogenous retrovirus MERVL, acts as a conduit in this necessary transition of cells from totipotency to pluripotency. “Until recently, these viral remains were considered junk DNA, useless or even harmful genetic material,” he explained in a statement. “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 have evolved with us over millions of years, perform important functions, such as regulating other genes,” he said.

French pharmacologist Nabil Juder, leader of the CNIO group, has been studying the URI protein, which is associated with several types of cancer, such as liver and ovarian cancer, for more than two decades. Juder’s previous research has shown that levels of this protein beyond a narrow threshold can either trigger tumors or prevent them, depending on the context. Balance is important. Their new results show that the activity of the URI protein is key for other molecules in making a cell pluripotent. If URI does not act, totipotency remains. The researchers believe that understanding this process in embryonic development will help to understand similar mechanisms that operate in the development of cancer.

Work published this Wednesday in the journal Science achievements, shows that when the mouse embryo has only two totipotent cells, ancestral viruses integrated into the DNA take the lead. The viral-derived protein MERVL-gag binds to the URI and inactivates it. As embryonic development continues, viral protein levels decline and URIs may intervene, leading to pluripotency. “Our results demonstrate the symbiotic coevolution of endogenous retroviruses with host cells to ensure smooth and precise progression of early embryonic development,” the authors note in their study. Thanks to the remnant of the ancient virus, the embryo’s cells can travel to their destination.

Juder emphasized that this is “a completely new role for endogenous retroviruses.” In his opinion, this new knowledge could be useful in the field of regenerative medicine and the creation of embryo models for scientific research, since it opens up a new way to manipulate totipotent cells and produce stable cell lines in the laboratory.

People have a mystery

Biologist Martha Shahbazi emphasizes that totipotency in mouse embryos is lost at the four-cell stage, and they are no longer able to give rise to a full-fledged individual. “It’s unknown in humans because no one has done the experiment,” explains Shahbazi, a Spanish researcher who studies human embryos at the Laboratory of Molecular Biology in Cambridge, UK. “There is work that suggests that at the two-cell stage there are already molecular differences between them, but it is not known what this means in functional terms, in the formation capacity of the organism,” he adds.

Shahbazi points out that the CNIO team found that if the URI protein is eliminated, cells are blocked in the earliest phase of development: totipotency. “To use these cells for regeneration and to create embryonic models, the next step will be to demonstrate whether these cells have greater potential and to develop methods to mimic the early phases of development,” he warns.

Biologist Miguel Manzanares applauds the new work, in which he was not involved. “These endogenous retroviruses integrate into the genome and no longer move. They are like a fossilized footprint. The funny thing is that they are species specific. This event did not occur in the common ancestor of humans and mice, and the mechanism is conserved. They are specific to mice,” explains Manzanares from the Severo Ochoa Center for Molecular Biology (CSIC) in Madrid. The researcher emphasizes that endogenous retroviruses HERVL, equivalent in humans to murine MERVL, are also activated in human totipotent cells. Embryonic development at this early stage is similar in rodents and humans. “How can we explain that one of the main players in this process is species specific? This issue is on the agenda,” he says.

Researcher Francisco José Sánchez Luque emphasizes the flexibility of the evolutionary process of living things. “At first these were infectious, pathogenic viruses, but they became excellent material for the work of evolution. There are many regulatory sequences that have been redesigned to perform other functions, for example in the human immune system itself. Retrovirus sequences have been redesigned to protect against other retroviruses,” says Sánchez Luque, a biologist who heads the molecular genetics group of mobile and foreign DNA at the López-Neira Institute of Parasitology and Biomedicine in Granada. “This study shows that one of the retroviral proteins that was integrated into DNA was redesigned to regulate a very important process – the transition from one cell to two to four cells. This is a very delicate moment at the beginning of embryonic development, and it turns out that evolution has done this by reworking it. It is very possible that something similar happens in humans,” says the biologist.

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