Transposable elements, once thought to be "junk" DNA, have been found to play a significant role in gene regulation during early embryonic development. These DNA sequences, which originated from ancient viral infections in our ancestors, now make up 8-10% of the mammalian genome.
A research team led by Dr. Michelle Percharde, Head of the Chromatin and Development group at the LMS, along with former postdoctoral researcher Dr. Paul Chammas, has focused on a specific viral transposable element known as MERVL. This element becomes highly active during a brief period when a mouse embryo reaches the two-cell stage—the moment when the fertilized egg divides into two cells and activates its own genome for the first time. At this stage, cells are considered totipotent, meaning they can give rise to all cell types of both the embryo and extraembryonic tissues such as the placenta.
MERVL functions as a central switch that activates many genes specific to this early developmental stage. However, its exact role had not been fully understood.
To investigate MERVL’s function, researchers used CRISPR activation technology to turn on MERVL elements in mouse embryonic stem cells. This approach aimed to mimic what occurs naturally in two-cell embryos. The study found that activating only MERVL produced cells that resembled those at the two-cell stage but retained some features of totipotency. The team described these as having an "intermediate phenotype." Their findings indicate that turning on MERVL alone is enough to induce certain totipotent characteristics during early development.
The activation of MERVL is controlled by a transcription factor called Dux—a protein that helps regulate gene activity. While Dux is necessary for initiating the two-cell developmental program, prolonged activity becomes toxic and leads to cell death.
Researchers also used CRISPR technology to activate Dux itself. They observed that Dux not only activated MERVL but also triggered other genes, including one responsible for producing Noxa—a protein that induces cell death. This confirmed that it is Dux, rather than MERVL, responsible for negative effects on cells under these conditions.
"By being able to compare what's happening in these different contexts, we can see that transposable elements in this case aren't the bad guys," said Paul Chammas. "And we've successfully started to unpick some of the different roles different parts of the network play in early development."
In humans, the equivalent transcription factor is called DUX4. It appears crucial for early development but must be permanently deactivated afterward. Certain genetic mutations cause abnormal activation of DUX4 in adults and lead to facioscapulohumeral muscular dystrophy (FSHD), a disease marked by progressive muscle weakness and wasting due to increased cell death in muscle tissue.
The research showed that DUX4 also raises levels of human NOXA protein in human cells. Analysis of patient samples revealed those with more severe forms of FSHD had higher NOXA levels.
These findings suggest NOXA could serve as a therapeutic target for FSHD; drugs designed to inhibit NOXA might help prevent muscle cell death and improve outcomes for patients with this condition.
Dr. Michelle Percharde holds positions as Head of Chromatin and Development Group at LMS and Honorary Senior Lecturer at Imperial College London.
This study received funding from UK Research and Innovation (UKRI) and the Medical Research Council (MRC).
