Transposable Elements Not So Selfish After All
Commonly believed to be genetic parasites, recent work suggests that at least some transposable elements might be critical for the organism.
Only about 1 per cent of the human genome encodes proteins. The value and purpose of the rest of the 99 per cent isn’t entirely clear yet. We know that much of these ‘non-coding’ regions are responsible for the regulatory elements that control the expression of that 1 per cent. In addition to these regulatory genes, there are also transposable elements.
Transposable elements make up a huge part of our genomes. As far as anyone can tell, they exist purely to get passed on to future generations. They jump around the genome inserting themselves in new locations, with some leaving thousands of copies imprinted on the genome. This jumping around can potentially disrupt the normal workings of the cell if they land in a regulatory or expression region. Otherwise, these transposons are thought to be relatively inert.
That is, until now…
Miguel Ramalho-Santos, PhD, an associate professor of obstetrics/gynecology and reproductive sciences and a member of the Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research at UCSF, has been interested in transposons since he first set up his lab as an independent UCSF Fellow in 2003.
He and his colleagues decided to take a closer look at LINE1, a transposon that accounts for around 20 per cent of the human genome. They noticed that embryonic stem cells, and early embryos, express high levels of LINE1. “Given the standard view of transposons, these early embryos were really playing with fire,” he remembers thinking. “It just didn’t make any sense, and I wondered if something else was going on.”
It wasn’t until 2013, when Michelle Percharde joined the lab as a postdoc, that the project really took off. “When I saw all the LINE1 RNA that’s present in the nucleus of developing cells, I agreed there must be some role it’s playing,” Percharde said. “Why let your cells make so much of this RNA if it’s either dangerous or doing nothing?”
The next step was to figure out a way to study transposons. This resulted in eliminating LINE1 RNA from mouse embryonic stem cells. Astonishingly, she saw the gene expression pattern in these cells revert back to what is seen in two-cell embryos. The team went one step back further, eliminating LINE1 from fertilised eggs. The same pattern was observed, which meant the embryos never progressed past the first cell division.
Ramalho-Santos suggests that transposons like LINE1 might be responsible for making early stage development more robust. As risky as have jumping genes around, it does mean that they will always be there during a very delicate phase of development.
“These genes have been with us for billions of years and have been the majority of our genomes for hundreds of millions of years,” Ramalho-Santos said. “I think it’s fair to ask if the 1.5 per cent of protein-coding genes are the free-riders, and not the other way around. We now think these early embryos are playing with fire but in a very calculated way. This could be a very robust mechanism for regulating development.”
“Scientists have done so much work on protein-coding genes, and they’re less than 2 per cent of the genome, whereas transposons make up nearly 50 per cent,” Percharde added. “I’m personally excited to continue exploring novel functions of these elements in development and disease.”
Take a look in Cell for this most excellent paper.