Study uncovers genetic switches that control process of whole-body regeneration — ScienceDaily

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When it comes to regeneration, some animals can achieve amazing feats – if you cut your legs from the scorpion, it will grow again. When threatened, some geckos will distract their tails and re-grow them later.

Other animals go further. Fly worms, jellyfish and anemones can actually regenerate the entire body after cutting in half.

Led by Mansi Srivastava, an assistant professor of organic and evolutionary biology, a research team is revealing how animals can achieve this feat and discovering many DNA transformations that seem to control the body's regenerative genes. The study is described in the March 15th paper Science .

Using the three-banded Panther worm to test this process, Srivastava and her laboratory work postdoctoral fellow Andrew Gehrke found that a piece of non-coding DNA controls an activated growth response, or EGR, that was previously called the "master control gene." Once activated, EGR controls many other processes by turning other genes on or off.

"We found that this major gene is happening… and this is activating genes that are turned on during regeneration," Gehrke said. "Basically, what is happening is that the non-encoded area tells the encoding area to open or close, so a good way to think about it is as if they were switches."

Gehrke said that in order for this process to work, the DNA in the worm's cells is usually tightly folded and compacted and must be changed to make the new area available for activation.

"Many very close parts of the genome actually become more open, because there are regulatory switches that must turn genes on or off," he said. “Therefore, an important finding in this paper is that the genome is very dynamic and does change during regeneration because different parts are turned on and off.”

But before Gehrke and Srivastava can understand the dynamic nature of the worm genome, they must assemble its sequence – this is not a simple feat in itself.

"This is an important part of this article – we are releasing the genome of this species, which is important because it is the first of this door," Srivastava said. "So far, there is no complete genomic sequence."

She said that this is also worth noting because the three banded panthers represent a new model system for studying regeneration.

"Previous research on other species helped us learn a lot about regeneration," she said. "But there are some reasons to use these new worms, one of which is that they are in an important phylogenetic position, so their relationship with other animals… allows us to make a statement about evolution.

"Another reason is that they are really great lab mice," she continued. “I collected them in Bermuda a few years ago during my postdoctoral period, and since we brought them into the lab, they can use more tools than other systems.”

While these tools can demonstrate the dynamic nature of the genome during regeneration – Gehrke is able to identify up to 18,000 areas of change – what is important is what she can say from studying them.

She said that the results show that EGR is like a power switch for regeneration – once it is turned on, other processes can happen, but without it, there is no reaction.

"We are able to reduce the activity of this gene, and we found that if you don't have Egr, nothing happens," Srivastava said. "Animals can't regenerate. All these downstream genes won't open, so the other switches don't work, and the whole house is basically darkened."

Although the study reveals new information on how this process works in worms, it may also help explain why it does not apply to humans.

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

"The reason we call this gene in worm Egr is because when you look at its sequence, it is similar to genes that have been studied in humans and other animals," Srivastava said. “If you put human cells in the plate and put pressure on them, whether mechanical or toxic, they will be expressed immediately.

"But the question is: If humans can open Egr, not just open it, but do so when our cells are injured, why can't we regenerate it?" Srivastava said. "The answer may be that if EGR is a power switch, we think the wiring is different. The EGR that people talk about in human cells may be different from what it says in the three-banded panther, and what Andrew is doing. A method was proposed to obtain this connection. So we wanted to figure out what these connections are and then apply them to other animals, including vertebrates that can only undergo more limited regeneration."

Moving on, Srivastava and Gehrke say they want to study whether the genetic switches activated during regeneration are identical to the genetic switches used in the development process and continue to work to better understand the dynamic nature of the genome.

"Now we know the switches used for regeneration, we are studying the switches involved in development and whether they are the same," Srivastava said. “Have you just redeveloped, or does it involve a different process?”

The team is also committed to understanding the precise ways in which EGR and other genes activate the regeneration process, including the three-banded panther and other species.

Finally, Srivastava and Gehrke say the study emphasizes not only the value of understanding the genome, but also the understanding of all genomes – non-coding and coding.

"Only about 2% of the genome produces something like protein," Gehrke said. “We want to know: What do the other 98% of the genomes in the whole body regenerate do? People have long known that many DNA changes that cause disease are in non-coding regions… but it has been underestimated like whole body regeneration. Process.

"I think we only touch the surface," he continued. "We have studied some of these switches, but there is another aspect to how the genome interacts on a larger scale, not just how to open and close the fragments, all of which are important for opening and closing genes, so I think this kind of regulatory nature has multiple layers."

"Looking at nature is a very natural question and thinks that if the gecko can do this, why can't I," Srivastava said. “There are many species that can be regenerated, some species cannot be regenerated, but it turns out that if you compare the genomes of all animals, most of the genes we have are also present in the three banded panthers… so we think some of them The answer may not come from the existence of certain genes, but from how they are connected or networked together, and the answer can only come from the non-coding part of the genome."

This study was awarded to the Harvard University Milton Foundation, the Searle Scholar Program, the Smith Family Foundation, the National Science Foundation, the Helen Allenni Foundation, the Human Frontier Science Program, the National Institutes of Health, and Biomedical Sciences. Major training program, University of California, Berkeley, Marthella Foskett Brown, Biological Science Chair, and Howard Hughes Medical Institute.


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