A new study shows that a swath of DNA left in the mouse genome by an ancient viral infection is crucial for early development in the womb.
The viral DNA turns on genes that give cells in early mouse embryos the potential to become almost any type of cell in the body, according to a study published in Science Advances in December. The viral DNA itself, known as MERVL, is activated by a protein called the “Dux transcription factor,” which binds to the sequence and essentially starts the development of the embryo.
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New research not only elucidates the role of MERVL and Dux in the womb, but also reveals their harmful effects that may appear later in life. This is “an important study,” said Sherif Cordia, a postdoctoral researcher focusing on stem cells and developmental biology at the University of Leuven, who was not involved in the study.
Researchers from the UK’s Medical Research Council Institute of Medicine used a gene editing tool called CRISPR activation (CRISPRa) to unravel the close relationship between Dux and MERVL. Unlike traditional CRISPR, which cuts DNA and changes its code, CRISPRa increases the activity of specific genes without changing the underlying DNA sequence.
The research team used CRISPRa to turn on either Dux or MERVL in mouse embryonic stem cells. This allowed the researchers to examine how each factor affected early embryonic development.
When the researchers turned on only MERVL, the stem cells showed “totipotency,” or the ability to become any cell type. This is an important feature of the earliest embryos. However, the researchers found that the cells lacked a key feature. This suggests that while MERVL plays an important role in early mouse embryonic development, Dux is also required.
On the other hand, turning on Dux alone produced cells that more closely resembled natural early embryonic cells. Therefore, the researchers believe that Dux activates genes required for embryonic development independently of MERVL.
Dux and MERVL are so closely related during early stages of embryonic development that scientists previously suspected that MERVL might also contribute to Dux’s harmful effects later in life. But new research suggests that’s not the case.
The researchers tested how Dux causes cell damage by examining its effects on stem cells with and without a gene called NOXA, which is known to be involved in cell death caused by various stressors. They discovered that Dux turns on this NOXA gene, producing a protein that causes cell death. When the team removed NOXA, Dux did much less damage. This indicated that NOXA and not MERVL was responsible for the toxicity.
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Potential therapeutic target
NOXA was already known to be elevated in FSHD, a muscle-wasting disease in humans. The study authors believe that developing drugs that inhibit NOXA could prevent cell death in this condition, thereby improving muscle cell survival.
“Facioscapulohumeral muscular dystrophy is a complex disease,” senior study author Michelle Perchard, head of the Chromatin and Development Group at the Medical Research Council Institute of Medicine, said in a statement.
“Only some cells activate DUX4, even though all cells in a patient have the genetic changes that cause it,” she explained. “Understanding what causes activation of DUX4 in muscle cells alone and how this compares to activation in early development is an important question we would like to explore in future studies.”
“It’s worth comparing” how mouse Dux and human DUX4 function, Cordia said, adding that future studies should investigate how MERVL controls nearby genes and exactly how and when MERVL is turned off during mouse embryonic development.
Importantly, Khodeer pointed out that MERVL is not present in the human genome. But scientists suspect that certain parts of the human genome may be equivalent to MERVL. As in mice, these stretches of DNA are remnants of ancient viral infections.
Caudill said the new results raise several questions. For example, do early human embryos develop by the same mechanisms seen in mice? And what fragments of human ancient viral DNA might play a role similar to MERVL in this early stage of development? “Answering these questions could reveal species-specific differences in early developmental control,” he told Live Science via email.
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