Study uncovers genes that control process of whole-body regeneration
Harvard Gazette, March 2019 -- When it comes to
regeneration, some animals are capable of amazing feats. If you cut off a
salamander’s leg, it will grow back. When threatened, some geckos drop their
tails to distract their predator, only to regrow them later.
Other animals take the process even further.
Planarian worms, jellyfish, and sea anemones can actually regenerate their
bodies after being cut in half.
Led by Assistant Professor of Organismic and
Evolutionary Biology Mansi Srivastava, a team of researchers is shedding new
light on how animals pull off the feat, along the way uncovering a number of
DNA switches that appear to control genes for whole-body regeneration. The
study is described in a March 15 paper in Science.
Using three-banded panther worms to test the
process, Srivastava and Andrew Gehrke, a postdoctoral fellow working in her
lab, found that a section of noncoding 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 activates] genes that are turning on during regeneration,” Gehrke said.
“Basically, what’s going on is the noncoding 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, Gehrke said, the DNA in
the worms’ cells, which normally is 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,” he said, “because there are regulatory
switches in there that have to turn genes on or off. 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.”
Before Gehrke and Srivastava 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,” Srivastava said.
“We’re releasing the genome of this species, which is important because it’s
the first from this phylum. Until now there had been no full genome sequence
available.”
It’s also noteworthy, she added, because the
three-banded panther worm represents a new model system for studying
regeneration.
“Previous work on other species helped us learn many
things about regeneration,” she said. “But there are some reasons to work with
these new worms.” For one thing, they’re in an important phylogenetic position.
“So the way they’re related to other animals … allows us to make statements
about evolution.” The other reason, she said, is, “They’re really great lab
rats. I collected them in the field in Bermuda
a number of years ago during my postdoc, and since we’ve brought them into the
lab they’re amenable to a lot more tools than some other systems.”
While those tools can demonstrate the dynamic
nature of the genome during regeneration — Gehrke was able to identify as many
as 18,000 regions that change — what’s important, Srivastava said, is how much
meaning he was able to derive from studying them. She said 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,” Srivastava 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,” Gehrke 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,” Srivastava 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.”
The question is, Srivastava said, “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 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
Andrew has 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, Srivastava and Gehrke 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.
“Now that we know what the switches are for
regeneration, we are looking at the switches involved in development, and
whether they are the same,” Srivastava said. “Do you just do development over
again, or is a different process involved?”
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.
In the end, Srivastava and Gehrke said, the study
highlights the value of understanding not only the genome, but all of the
genome — the noncoding as well as the coding portions.
“Only about 2 percent of the genome makes things
like proteins,” Gehrke said. “We wanted to know: What is the other 98 percent
of the genome doing during whole-body regeneration? People have known for some
time that many DNA changes that cause disease are in noncoding regions … but it
has been underappreciated for a process like whole-body regeneration.
“I think we’ve only just scratched the surface,” he
continued. “We’ve looked at some of these switches, but there’s a whole other
aspect of how the genome is interacting on a larger scale, not just how pieces
open and close. And all of that is important for turning genes on and off, so I
think there are multiple layers of this regulatory nature.”
“It’s a very natural question to look at the
natural world and think, if a gecko can do this, why can’t I?” Srivastava said.
“There are many species that can regenerate, and others that can’t, but it
turns out if you compare genomes across all animals, most of the genes that we
have are also in the three-banded panther worm … so we think that some of these
answers are probably not going to come from whether or not certain genes are
present, but from how they are wired or networked together, and that answer can
only come from the noncoding portion of the genome.”
This research was supported with funding from
the Milton Fund of Harvard University, the Searle Scholars Program, the Smith
Family Foundation, the National Science Foundation, the Helen Hay Whitney
Foundation, the Human Frontier Science Program, the National Institutes of
Health, the Biomedical Big Training Program at UC Berkeley, the Marthella
Foskett Brown Chair in Biological Sciences, and the Howard Hughes Medical
Institute.
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