DNA sequence behind muscle regeneration begins to unravel

The researchers say the newly discovered sequences could one day give a great boost to mammals' ability to regrow damaged tissue or body parts

Animals that regrow body parts like zebrafish and newts certainly function very differently to the way humans do, but we might one day be able to borrow some of these traits. A closer look at the mechanism driving these remarkable regenerative abilities has suggested that they could be recreated in mice, with the scientists involved hopeful it could ultimately improve our capacity to regrow damaged body parts.

Researchers have previously identified a long list of the genes that give certain animals the ability to regenerate damaged tissues. Some of these genes happen to have counterparts in humans, but unfortunately, when we have a limb severed it tends to stay that way. This key difference has lead researchers to suspect that it's not the genes themselves driving the regeneration, but rather the sequences of DNA that regulate their behavior in the event of an injury.

"We want to know how regeneration happens, with the ultimate goal of helping humans realize their full regenerative potential," says Kenneth Poss, professor of cell biology at Duke University School of Medicine. "Our study points to a way that we could potentially awaken the genes responsible for regeneration that we all carry within us."

By observing the regeneration of the fin and heart in zebrafish, the team has now identified one of these regulatory sequences. Called tissue regeneration enhancer elements (TREEs), these DNA chains not only switch genes on at injury sites, but can also be engineered to manipulate how effectively animals are able to regenerate.

The scientists reduced the TREE to the shortest necessary DNA sequence, finding that it could actually be separated into two parts, one to activate genes in an injured heart and another to activate genes in an injured fin. By fusing these sequences to a pair of regeneration genes, they wound up with a transgenic zebrafish possessing enhanced regenerative abilities in the aftermath of an injury.

The team then set its sights on replicating this in mammals. By attaching a TREE to a gene called lacZ, they found that the regulator sequence was able to activate gene expression in damaged paws and hearts of transgenic mice.

"We are just at the beginning of this work, but now we have an encouraging proof of concept that these elements possess all the sequences necessary to work with mammalian machinery after an injury," says Poss.

Poss says that there could be different kinds of TREEs, including some that turn on genes in all tissues and some that activate genes only in certain tissue, like the heart. He believes that by combining these sequences with genome-editing technologies, it could give a great boost to mammals' ability to regrow damaged tissue or body parts.

"We want to find more of these types of elements so we can understand what turns on and ultimately controls the program of regeneration," he says. "There may be strong elements that boost expression of the gene much higher than others, or elements that activate genes in a specific cell type that is injured. Having that level of specificity may one day enable us to change a poorly regenerative tissue to a better one with near-surgical precision."

The research was published in the journal Nature.

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