This Mysterious Bit of “Junk” DNA Could Play A Vital Role In Promoting Health

Some millions of years ago, a far distant ancestor of all animals encountered a virus that inserted its own genetic material into the creature. Over the course of animal evolution, these bits of viral DNA accrued with every new encounter and were passed down the generations.

Today anywhere from eight to 10 percent of the human genome originates from viruses. Scientists used to think these holdover viral genes (also sometimes called endogenous retroviruses) were nothing but junk — hence the term “junk DNA.” But emerging research in recent years suggests they’re anything but a genetic waste of space. For example, some genes within this DNA shape animal anatomy, help correctly bundle chromosomes inside a cell’s nucleus, or aid the immune system’s responses to viruses.

In a study published Wednesday in the journal Science Advances, researchers at the Spanish National Cancer Research Center (CNIO) found some junk DNA may be crucial to embryonic development, a molecular turning point steering cells from a state of infinite potential to a more targeted trajectory.

Embryonic development

The junk DNA at the heart of this switch is called MuERV-L (or MERVL) endogenous retroviruses. The researchers found in mice, MERVL-gag, a retroviral protein of MERVL endogenous retroviruses, interacts with a gene called URI, which influences whether or not an embryo develops smoothly and at the right pace.

"It is a totally new role for endogenous retroviruses," Nabil Djouder, a cell biologist at CNIO who led the study, said in a press release. "We discovered a new mechanism that explains how an endogenous retrovirus directly controls” an embryonic cell’s ability to develop into many different cell types, what’s referred to as pluripotency.

URI, also known by its mouthful unconventional prefoldin RPB5 interactor, is part of the class of molecules called prefoldins whose job it is to ensure our cells’ proteins fold correctly and don’t clump together, akin to the backstage theater crew maintaining order behind the scenes.

Studies in mice found that when URI was too active in a cell, it led to cancer; when it was genetically removed in adult mice, this led to organ failure. In studies with worms and fruit flies, erasing other prefoldin genes prevented embryos from growing altogether. This has raised questions of whether URI as well was involved in embryonic development.

MERVL endogenous retroviruses, on the other hand, are known to be active when a fertilized egg (or zygote) divides into a two-celled embryo, individually called blastomeres. At this point, these cells are totipotent, meaning they have the power and the potential to become any type of cell in the body. But to prevent blastomeres from going off the embryonic rails, becoming anything they want in an uncoordinated fashion, certain genes are turned on to coax the cells toward becoming specialized cell types, like muscle or nerve.

According to some studies, MERVL endogenous retroviruses are one of the first genes turned on in early embryos and seem to help drive genes related to totipotency. Interestingly, activating MERVL in pluripotent stem cells reverses them into an early embryo-like state. However, messing with MERVL can lead to big problems, like cells being unable to segregate into specific types. But just like with URI, how this fascinating piece of junk DNA is able to hold so much sway over an embryonic cell’s fate is still a bit of a mystery.

A new mechanism

To see if there’s a missed connection between the two, Djouder and his colleagues at CNIO played around deleting and turning on and off MERVL endogenous retroviruses — particularly the protein MERVL-gag — as well as the URI gene in mouse embryos.

They found the URI acts like a sort of molecular bodyguard for two other genes associated with development and pluripotency, called OCT4 and SOX2, respectively. It protects them from damage and allows the embryo to make the switch from totipotency to pluripotency. MERVL-gag, however, is the junk DNA hired gun taking out URI and keeping the early embryo totipotent.

But all this happens in a smooth, sequential order. In the beginning, when the early embryo is totipotent, MERVL-gag is circulating in high amounts and keeps URI silenced by binding to it. Eventually, its levels decline, which frees up URI to go back to protecting OCT4 and SOX2, allowing the early embryo to continue expanding its way to a tingling mass of pluripotent cells.

While this research is far from over, the scientists see this molecular mechanism opening up a whole range of possibilities, such as creating more stable embryonic stem cells (or ESCs), which are cells that possess unlimited self-renewal capabilities, turning into any cell type in the body.

“Such engineered ESCs could find diverse applications, including regenerative medicine, disease modeling, and the creation of artificial embryos,” the authors write in their paper.

While artificial embryos are a more thorny, ethical, Blade Runner 2049-esque issue to consider, perhaps it shows that all that doesn’t glitter may actually be some genetic gold.