Turning back the cellular clock

It is widely accepted that an enzyme called Tet plays an important role, but something else seems to be at play, according to results published in Nature Cell Biology.

One of the key steps in giving a cell its identity is the addition of biological "dimmer switches," called methyl groups, which sit on the surface of its DNA and turn genes "up" or "down." Together, these methyl group markers tell each cell what its specific role is -- be that as a heart, skin or brain cell.

One of the few cell types that can add and remove their methyl groups naturally is a fertilized egg, formed when a sperm and egg fuse together. By removing methyl groups from the sperm and egg, the fertilized cell becomes a blank canvas. As it grows into an embryo, new methyl groups are added onto the DNA of these embryonic cells. By adding them in different places in different cells, the individual cells acquire new identities and specialized functions.

Scientists had thought that fertilized eggs use the enzyme Tet to remove methyl groups from DNA. But today's results show that this is only half of the story. When the research team, from the MRC Clinical Sciences Centre (CSC) based at Imperial College London, genetically engineered mice so that their fertilized eggs lacked Tet3 (one of the Tet enzymes specifically present in the egg) they saw that the eggs could still remove the methyl groups. The same happened when they chemically blocked Tet's action. According to the scientists, this shows that Tet is not the only way in which fertilized eggs remove this modification on the DNA.

"What we've shown is that the Tet explanation is partly true, but it's not the complete story. We tried to dig a little deeper," says Rachel Amouroux who is the first author of the research. The study suggests that another, unknown mechanism is involved.

Understanding how these methyl group switches are removed could help scientists to produce immature cells, known as stem cells, in the laboratory. These cells are important because their ability to develop into any cell in the body means they can be used to repair or replace damaged and diseased tissue. Scientists make stem cells by 'reprogramming' mature cells, which turns back the clock so that the cells shift back into their immature state.

Scientists don't fully understand how this process happens naturally. If they can find out what's really happening here, they may be able to generate stem cells more efficiently.

Current techniques successfully reprogramme only a small proportion of cells. Even in those that are successfully reprogrammed there can be subtle but important variations that make them unsuitable for medical treatments.

The CSC scientists developed a new technique in order to follow the activity of Tet enzyme in the egg in greater detail than had been possible before. "This cutting edge technology uses mass spectroscopy, a method that breaks the DNA into single 'letters' then precisely analyses each of them and any chemical modifications of them," says Petra Hajkova, who leads the CSC's Reprogramming and Chromatin group, where the research was carried out.

"We found that the reprogramming process is much more complicated than previously thought," says Hajkova. "There is a constant race between the mechanisms removing the chemical modifications, and the mechanisms trying to put them back into place. When we want to reprogramme a cell, we have to think about both -- how to remove the modifications and, equally importantly, how to protect the newly unmodified DNA from becoming modified again."