Inside every embryo, the army of the dead invades on the fourth day

Millions of years ago, retroviruses invaded the human genome. Today, some of these viral remnants continue to threaten the developing embryo, while others struggle to defend it.

There is an ancient and eternal battle going on within the DNA of every embryo.

When a sperm cell meets an egg cell, fertilization takes place and a embryo. During the first few days, the tiny early-stage embryo (a tiny blob made up of eight cells) is controlled by the egg’s genes.

It is on the third day of gestation that the embryo takes control of its development and activates its own Genoa. Or, in other words, and as computational biologist Manu Singh describes it “the army of the dead invades on the fourth day”.

This army is made up of ancient genetic sequences, having once belonged to infectious retroviruswhich have been incorporated into human DNA for millions of years, passing from generation to generation.

Currently they are almost harmless, but some of these genetic sequences still have the power to cause harm if activated. This damage involves the copying of these sequences, which insert into different parts of the genome, compromising the DNA and increasing the risk of it being harmed. changes.

However, the little embryo is not completely helpless. According to a study recently published in PLOS Biologya research team, led by Singh, discovers a curious “quality control mechanism” whereby the embryonic stem cells “fight” each other, ensuring the survival of the least affected cells.

Surviving cells are protected by the remains of another old retrovirusa designated genetic sequence HERVH. Cells in which HERVH is activated are able to counteract damage-causing sequences.

Without HERVH, a sort of bodyguard for embryonic cells, the cells are more vulnerable to DNA damage. In these cases, and once overloaded with malicious retroviruses, they end up sacrificing themselves and sparing the developing fetus.

“I consider it like two dragonson one side we have one who fights for death, and on the other we have one who fights for the living,” he explains. Singh, assistant professor of multidisciplinary sciences at the Max Planck Institute in Göttingen, Germany. “It’s a classic example of fighting fire against fire.”

About 40% of modern genetic material comes from ancient retroviruses, and all of them were able to insert themselves into parts of the genome where they did not belong.

Most of these mobile sequences, called transposable elementsended up losing their ability to “jump” between different parts of the genome.

Today, there is only one family of permanently active transposable elements in humans: the intercalated long nuclear elements, also called LINE 1.

LINE-1 is activated as soon as the embryo’s genome takes control of its own development. These elements are able to replicate and insert themselves randomly into different parts of the genome. Most of the time, it ends up being inserted in non-coded areas, without impacting the embryo.

But it’s not always the case. According to Singh, “sometimes LINE-1 inserts itself into a significant portion of DNA and compromises the cell’s ability to produce essential proteins.”

This DNA damage in turn triggers a innate immune response by the cell, which is trying to protect itself. But this defense process is difficult and exhausting for a small growing cell.

When the damage is too great, the cell surrenders and “commits suicide” through a process of programmed cell death, known as apoptosis.

This phenomenon occurs at a crucial moment in the development of the embryo.

In the short time between fertilization and implantation, embryonic stem cells are pluripotent, meaning they have the ability to differentiate into any type of cell. As they divide, they give rise to daughter cells, which are also pluripotent.

However, if a cell accumulates too much DNA damage, it loses the ability to replicate. “These cells must die for development to continue,” he explains. Carol B. Warestem cell biologist and professor at the University of Washington.

This new study is the result of a robust computational analysis, which involved researchers from Germany, Spain and the UK, with the aim of understanding the role of retroviruses in embryonic developmentto know how they help and/or harm you.

In this investigation, Singh’s team collected data on embryonic stem cells from fertilization to implementation.

The cells were grouped according to their similarity in terms of gene expression and according to markers which determine its future within the embryo.

For example, between cells that will be part of the ectoderm, precursor of skin and brain cells, or of the endoderm, which will evolve into cells of respiratory and digestive tissues.

Interestingly, a group of cells emerged that did not match any of the groups.

However, all had markers linked to DNA damage and apoptosis, a cellular process that eliminates stressed cells. Signh suspects that this damage could be related to LINE-1. These cells were then classified as “Rejects”.

On the fifth day of the embryo, after fertilization, the Singh-led team discovered that REject cells survive alongside healthy cells and sacrifice themselves to protect them. However, surviving cells express HERVHsomething that REjects are not able to do.

Although HERV is another old retrovirusit was shown to be able to suppress LINE-1 and protect pluripotent cells from damage, thus ensuring their survival.

“It’s kind of a romantic relationship,” Singh says. “These retroviruses invaded our body to kill and are now working to protect our system against other retroviruses.”

The five-day-old embryo is surrounded by an outer layer of cells, which will give rise to the placenta. LINE-1 is active in these cells, but unlike suckers, these do not die.

The research team suspects that because the placenta only lasts nine months, these cells are not damaged enough to cause damage at the DNA level.

This discovery is “remarkable”, says Ware. However, drawing these conclusions about embryonic development in utero can be risky.

Despite the fact that LINE-1 and HERV expression are mutually exclusive—rejects express LINE-1 and not HERV and vice versa—investigators have found no direct evidence that HERVH control LINE-1explain Cedric Feschottespecialist in molecular biology and professor of genetics at Cornell University.

Ware adds that it is unclear whether the REjects are simply “waste” or if they play a functional, albeit brief, role in the development of the embryo.

Embryonic stem cell research is hampered by the ethical aspect it involves. Several countries do not authorize it, and in those where it is possible, they use the “leftovers” of frozen embryos, five days old, donated by the parents after fertilization. in vitro succeeded.

As these embryos are analyzed outside the mother’s body, the researchers “cannot exclude the possibility that the evidence comes from a culture in vitroadds Feschotte.

Singh also states that the ability to select pluripotent cells from REject cells in an early embryo will be essential for researchers to advance their studies on regenerative medicinea field where it is necessary to cultivate different types of body tissues and recreate laboratory models of disease.

Identifying potential causes of damage to embryonic cells also allows us to expand our knowledge of early pregnancy.

Maybe one day, Feschotte says, it will be possible to monitor LINE-1 expression levels in growing embryos in a fertility clinic. And maybe that helps us explain early pregnancy loss during deployment.

However, it is important to emphasize that this discovery shows that the human genome is not a simple instruction manual, but an ecosystem.

“There are interactions between prey and predators”, explains Feschotte. “All of these seemingly complicated biological interactions occur at the level of the genome.”