How scientists study genes that control complete body regeneration

Original author: Peter Reuell
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Some animals are capable of amazing things when it comes to regeneration. If you cut off the paw of the salamander, it will grow again. Feeling threatened, the geckos drop their tails to distract the predator, and later grow them again.
In other animals, the regeneration process goes even further. Planaria, jellyfish and sea anemones can repair their bodies by being chopped into pieces.
A group of scientists led by Mansi Srivastava, a professor at the Department of Evolutionary Biology at Harvard University, sheds light on how animals do it, and along the way, studies a series of DNA switches that seem to control the genes for complete body regeneration.

Using the intestinal turbellariums of Hofstenia miamia , Srivastava and Andrew Gerke, a postdoc working in her laboratory, they found a piece of non-coding DNA that controls the activation of the early growth response (EGR) master gene. Being active, EGR controls many processes, “turning on” and “turning off” other genes.

“We found,” says Gercke, “that this master gene activates genes that are 'turned on' during regeneration." It turns out that non-coding regions of DNA “order” the coding regions to turn on or off, and thus, it would be right to call them “switches”. ”

For this process to work, the DNA in Hofstenia miamia cells , usually compactly and tightly folded, must change its structure, making new sites available for activation.

According to Gercke, many of these very tightly packed sections of the genome, due to the presence of regulatory switches that turn genes on or off, become physically more open. As indicated in the publication, the genome is very dynamic and changes during regeneration, as different parts of it open and close.

In order to understand the dynamic nature of the Hofstenia miamia genome , Gerka and Srivastava had to sequence it first, which in itself is not easy.
“A significant part of the work is dedicated to this,” says Srivastava. - We have decoded the genome of this species, and this is important, because it is the first genome decoded by this type of organisms. Until now, there was no complete sequence of the genome. ”

She also pointed out that Hofstenia miamia's intestinal turbellaria is a new model for studying regeneration.

“Previous work involving other species helped us learn a lot about regeneration,” says Srivastava, “but there are reasons to work with these new organisms.” One of them is that Hofstenia miamiaoccupy an important phylogenetic position. The way they relate to other animals allows scientists to make a series of statements regarding evolution. The second reason for interest in Hofstenia miamia, says Srivastava, is that they are great for laboratory rats. “I collected them several years ago during my post-doctoral studies in Bermuda in the field, and since we brought them to the laboratory, they have proven to be far more suitable for work than other organisms.”

Working with hofstenia miamia, scientists were able to demonstrate the dynamic nature of the genome during regeneration - Gerka was able to detect 18,000 sections of the genome that underwent changes. According to Srivastav, in the course of this work they obtained truly significant results. She showed that EGR acts as a “switch” for regeneration - when it is “turned on”, other processes are started, but nothing happens without it.

“We were able to reduce the activity of this gene and found that if you do not have EGR, nothing happens. Animals simply cannot regenerate. All downstream genes are not turned on, because of this, other “switches” do not work and, figuratively speaking, the whole house is plunged into darkness. ”

By discovering new data on how the process works in worms, work also helps to understand why it does not work in humans. “It seems that the EGR master gene and downstream genes that it“ turns on and off ”are also present in other species, including humans,” says Gercke.

“We had a reason to name this gene Hofstenia miamia - EGR. When you look at its sequence, it looks the same as that of a gene that was previously studied in humans and other animals, says Srivastava. “If you put human cells in a petri dish and stress them, no matter mechanical or toxic, they will begin to express EGR.”

The question, according to Srivastav, is: “If we humans are able to“ turn on ”EGR, and not just“ turn on ”, but“ turn on ”exactly when our cells are damaged, why don't we regenerate?” One possible answer: if EGR is a “switch”, then “wiring” may be something else. What EGR “binds” to in human cells may differ from what it “binds” to in Hofstenia miamia . Thanks to the work of Andrew Gercke, a way was discovered to get to this “wiring”. Scientists want to find out what these connections are, and then apply them to other animals, including vertebrates with their limited regeneration.

In the future, Srivastava and Gerke hope to find out whether the genetic “switches” that are activated during regeneration are the same that work during growth and development. Scientists also plan to continue work on a better understanding of the dynamic nature of the genome.

“Now we know that these“ switches ”are needed for regeneration purposes, we look at which“ switches ”are involved in the development process, and whether they are the same, says Srivastava. “Are these the same mechanisms that work in the development process, or some other?”

The group is also working to understand the exact ways in which EGR and other genes activate the regeneration process, as in Hofstenia miamia., and in other species. According to scientists, this study is important for understanding not only this particular site, but the entire genome as a whole - both non-coding and coding parts of DNA.
“Only 2% of the genome is made by proteins,” says Gercke. - We want to know what the other 98% of the genome are doing during the complete regeneration of the body? It is known that it is in the areas of non-coding DNA that many changes occur that provoke diseases ... but the importance of non-coding DNA in processes such as complete regeneration is underestimated. "
“I think this is just the tip of the iceberg. We studied some of the “switches”, but there are other questions regarding how the genome behaves on a wider scale, not only how its pieces “open” and “close”. All this is important in the process of “turning on” and “turning off” genes, I believe there are several levels of regulation here. ”

“When you look at the natural world, the natural question arises: if the gecko can do this, why can't I? - says Srivastava. - There are many species that can regenerate, and others that cannot, but if you compare the genomes of all animals - most of the genes that we have are in Hofstenia miamia. We believe that the likely answer to this question will not be related to whether we have found specific genes, but to how they are related to each other, and you can get the answer only by deciphering the genome. ”

Translated by Irina Abramidze , SENS Volunteers

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