A master regulator of regeneration identified!

When it comes to regeneration, some animals are capable of amazing feats - if you cut the leg off a salamander, it will grow back. When threatened, some geckos drop their tails as a distraction, and regrow them later.

Other animals take the process even further. Planarian worms, jellyfish, and sea anemones can actually regenerate their entire bodies after being cut in half.

A team of researchers is shedding new light on how animals pull off the feat, and uncovered a number of DNA switches that appear to control genes for whole-body regeneration. The study is described in a paper in Science.

Using three-banded panther worms to test the process, researchers found that a section of non-coding DNA controls the activation of a "master control gene" called early growth response, or EGR. Once active, EGR controls a number of other processes by switching other genes on or off.

"What we found is that this one master gene comes on...and that's activating genes that are turning on during regeneration," the lead author said. "Basically, what's going on is the non-coding regions are telling the coding regions to turn on or off, so a good way to think of it is as though they are switches."

For that process to work, the lead said, the DNA in the worms' cells, which is normally tightly folded and compacted, has to change, making new areas available for activation.

"A lot of those very tightly packed portions of the genome actually physically become more open, because there are regulatory switches in there that have to turn genes on or off," the lead said. "So one of the big findings in this paper is that the genome is very dynamic and really changes during regeneration as different parts are opening and closing."

But before the researchers could understand the dynamic nature of the worm's genome, they had to assemble its sequence - no simple feat in itself.

"That's a big part of this paper - we're releasing the genome of this species, which is important because it's the first from this phylum," the senior author said. "Until now there had been no full genome sequence available."

And it's also noteworthy, the senior author said, because the three banded panther worm represents a new model system for studying regeneration.

The lead was able to identify as many as 18,000 regions that change. The results show that EGR acts like a power switch for regeneration - once it is turned on, other processes can take place, but without it, nothing happens.

"We were able to decrease the activity of this gene and we found that if you don't have Egr, nothing happens," another author said. "The animals just can't regenerate. All those downstream genes won't turn on, so the other switches don't work, and the whole house goes dark, basically."

While the study reveals new information about how the process works in worms, it also may help explain why it doesn't work in humans.

"It turns out that Egr, the master gene, and the other genes that are being turned on and off downstream are present in other species, including humans," another author said.

"The reason we called this gene in the worms Egr is because when you look at its sequence, it's similar to a gene that's already been studied in humans and other animals," the author said. "If you have human cells in a dish and stress them, whether it's mechanically or you put toxins on them, they'll express Egr right away.

"But the question is: If humans can turn on Egr, and not only turn it on, but do it when our cells are injured, why can't we regenerate?" the author said. "The answer may be that if EGR is the power switch, we think the wiring is different. What EGR is talking to in human cells may be different than what it is talking to in the three-banded panther worm, and what authors have done with this study is come up with a way to get at this wiring. So we want to figure out what those connections are, and then apply that to other animals, including vertebrates that can only do more limited regeneration."

Going forward, the authors said, they hope to investigate whether the genetic switches activated during regeneration are the same as those used during development and to continue working to better understand the dynamic nature of the genome.

The team is also working on understanding the precise ways that EGR and other genes activate the regeneration process, both for three-banded panther worms, and for other species as well.