How scientists study the genes that control the complete regeneration of the body

Some animals are capable of amazing things when it comes to regeneration. If you cut off a salamander's paw, it will grow back. Feeling threatened, geckos reject their tails to distract the predator, and later grow them again.

In other animals, the regeneration process goes even further. Planaria, jellyfish and anemone can restore their bodies, being chopped into pieces.

A group of scientists, led by Mensi Srivastava, a professor at the Department of Evolutionary Biology at Harvard University, sheds light on how animals do it, and at the same time studies a series of DNA switches that seem to control the genes for complete regeneration of the body.



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



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



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

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According to Gerk, many of these very tightly packed sections of the genome become physically more open due to the presence of control switches that “turn on” or “turn off” genes. As indicated in the publication, the genome is very dynamic and changes during regeneration, since its different parts open and close.



To understand the dynamic nature of the genome of Hofstenia miamia , Gerke and Srivastava had to sequence it first, which in itself is not easy.

“Much of the work is dedicated to this,” says Srivastava. - We have deciphered the genome of this species, and this is important, because it is the first decoded genome of this type of organism. Until now, there was no complete sequence of the genome. ”

She also pointed out that Hofstenia miamia's bowel-free turbellarians 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 miamia occupy an important phylogenetic position. The way they relate to other animals allows scientists to make a number of statements regarding evolution. The second reason for the interest in Hofstenia miamia, as Srivastava says, is that they are great for the role of lab rats. “I collected them several years ago during my post-doctoral studies in Bermuda in the field, and since we brought them to the lab, they have shown themselves to be much more suitable for work than other organisms.”



Working with Hofstenia miamia , scientists were able to demonstrate the dynamic nature of the genome during regeneration — Gerke was able to detect 18,000 genome regions that had undergone changes. According to Shrivastava, in the course of this work, they obtained truly meaningful results. She showed that EGR acts as a “switch” for regeneration - when it is “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 can not 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, the work also helps to understand why it does not work in humans. “It seems that the EGR master gene and the downstream genes that it“ turns on ”and“ turns off ”are also present in other species, including humans,” Gerke says.



“We had a reason to call this gene Hofstenia miamia - EGR. When you look at its sequence, it also looks like a gene that was previously studied in humans and other animals, says Srivastava. “If you put human cells in a Petri dish and put them under stress, no matter mechanical or toxic, they will start expressing the EGR.”



The question, according to Shrivastava, is: “If we humans can“ turn on ”EGR, and not just“ turn on ”, but“ turn on ”exactly when our cells are damaged, why don't we regenerate?”. One of the likely answers: if the EGR is a “switch”, then something else may be “wired”. What the EGR binds to in human cells may differ from what it binds to in Hofstenia miamia . Thanks to the work of Andrew Gerke, 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 as those that work during growth and development. Scientists also plan to continue working on a better understanding of the dynamic nature of the genome.







“Now we know that these“ switches ”are needed for regeneration, we look at which“ switches ”are involved in the development process, and whether they are not the same, says Srivastava. “Are these the same mechanisms that work in the development process, or some other?”



The group is also working on understanding the exact ways in which EGR and other genes activate the regeneration process, both in Hofstenia miamia and in other species. According to scientists, this study is important for understanding not only this particular region, but also the entire genome as a whole - both non-coding and coding parts of DNA.

“Only 2% of the genome produces proteins,” Gerke says. - We want to know what the other 98% of the genome do during the complete regeneration of the body? It is known that many changes occur in areas of non-coding DNA that provoke diseases ... but the value 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 about how the genome behaves on a larger scale, not only how its pieces open and close. All this is important in the process of “turning on” and “turning off” genes, I suppose there are several levels of regulation. ”



“When you look at the natural world, a natural question arises: if a gecko can do this, why can't I? - Srivastava says. - There are many species that can regenerate, and others that can not, but if you compare the genomes of all animals - most of the genes that we have, Hofstenia miamia also has . 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 the answer can be obtained only by deciphering a section of the genome. ”



Translated by Irina Abramidze , SENS Volunteers Group