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Learning a new language of Life
By Susan A. Steeves
Adding a group of molecules to a gene can change plants’ and animals’ characteristics much as an author can change
literary meaning by adding or subtracting punctuation.
Like a comma makes a reader pause or a period makes a reader stop, certain sets of molecules can attach to a gene and
modulate the gene’s activity level. These molecules create biochemical changes that act as on/off switches to activate or
silence particular genes. A gene’s status dictates the orders sent to a cell that control its function and ultimately contributes
to disease risk and physical traits in people, animals, plants and other living organisms. It can even affect personality tra its.
Researchers, including an interdisciplinary group at Purdue University, increasingly are investigating the how, why and
what that flips genetic switches. This science realm is called “epigenetics,” from the Greek and Latin meaning “on top of
genes.”
Even some expected physical and psychological similarities, or phenotypes, between brothers and sisters may not hold
true because a gene has been turned on or off abnormally due to epigenetic changes.
“Epigenetic alteration can lead to differences in appearance or physical condition between so-called identical siblings,”
says Perry Kirkham, program coordinator in the Purdue Office of the Vice President of Research and one of the driving
forces of the university’s epigenetic group. “There are no differences in the gene sequence between the siblings, but
changes in the regulation of gene expression lead to very obvious differences in the phenotype of the siblings.”
Seeking cures for kids
For Amy Lossie, epigenetics is a fascinating way to learn more about how genes function and a basis to develop new
disease treatments. “Our ultimate goal is to determine how genes are turned on and off,” says Lossie, a Department of
Animal Sciences geneticist. “It’s intriguing to me that the difference between mice and people is probably not that the two
species have different proteins, but that the genes that encode the proteins are turned on or off at different times and/or
different places during embryo development.”
Eventually, Lossie and other scientists want to be able to control genetic on/off switches that activate or silence genes so
they can develop more effective treatment and maybe cures for a host of diseases, including cancer and two that ignited
Lossie’s investigation into epigenetics—Angelman syndrome and Prader-Willi syndrome.
Prader-Willi youngsters are morbidly obese by age 2 and keep gaining weight, even on very low-calorie diets. Angelman
patients lead tough lives, too; most have recurrent seizures and complete lack of verbal skills. Often, these youngsters are
wheelchair-bound by about age 5 because of their progressively poor neuromuscular control.
Scientists have found that the same chromosome area is malfunctioning in both Prader-Willi and Angelman children. The
difference is that in Prader-Willi syndrome some genes inherited from the father are silenced; in Angelman syndrome it’s
some of the mother’s genes that are turned off.
Currently, Lossie’s research is focused on determining how epigenetic events occur and are regulated during embryonic
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development. Learning this might lead to ways to help people with diseases, such as Prader-Willi or Angelman syndromes.
“What we’re trying to do is put the punctuation in so that we can read the DNA and figure out how the genes are turned on
and off during mammalian fetal development,” she says.
Switching it on or off
The makeup of a gene isn’t changed when epigenetic modifications occur. It’s the architecture that is altered by addition
or subtraction of a group of molecules that activate or silence the gene. “Basically it’s just the addition of four atoms, a
carbon and three hydrogens, that determine whether a gene is turned on or turned off,” says Lossie.
Methyl groups are the most common of the molecules that can act as switches to activate or silence a gene. Addition of
methyl groups is called “methylation”; removal is called “demethylation.” During growth and development, the timing of a
methyl group change can determine the epigenetic effect on plants and animals.
“There are certain genes that you don’t want turned on at certain stages in the life cycle,” says Scott Briggs, a Purdue
biochemist who studies enzymes that affect methyl groups.
Briggs specifically looks at histone methyltransferases, a type of enzyme that has been implicated in cancers. Histones
are proteins around which DNA is wrapped like thread on a spool so that an entire genome fits into cells’ nucleosomes.
Some forms of cancer develop because a methyl group shuts off a gene that normally would stop cancer. When
functioning normally, one of these suppressor genes will prevent cell over-proliferation that characterizes cancers.
“If you can modulate these enzymes in cancer or other diseases, you could possibly change the outcome,” Briggs says.
“That’s a nice thing about epigenetic modifications: They alter gene expression without changing the DNA sequence. Since
the genetic code is maintained, we may be able to develop drugs that would alter or reverse the gene expression, or
epigenetic profile, of a cancer cell.”
In a genetic mutation, DNA actually is damaged, so the gene’s sequence is disrupted, and this often is inherited. But
epigenetic changes also can be inherited. So, in some cases, cancers, obesity, diabetes, behavior and even hair color could
be affected in progeny and future generations, depending on when and where methyl groups or other small molecules work
their magic on a gene.
Being able to reverse the effect of something your mother ate or maybe your diet is the important difference between an
epigenetic change and a genetic mutation. Laboratory research already has shown that a diet change for a mother at risk for
some diseases can change gene activity so that her offspring are disease free.
Passing it on
In a landmark epigenetic study, Duke University scientists fed a diet high in methyl to some obese, gold-colored mother
mice that also were prone to cancer and diabetes. In these mice, methyl groups attached to a mistakenly turned-on gene in
the mother and caused the obesity, odd color and disease risk. The methyl-high diet turned off the gene in the mother mice.
The “fixed” gene transferred into the embryos’ chromosomes as the cells duplicated to form the offspring, which were born a
normal color and size, and without the predisposition to diabetes.
Epigenetics shows that a gene being turned on or off can change the hereditary phenotype of both plants and animals for
generations without harming their DNA. If the DNA isn’t harmed, then future generations may be able to adapt to changing
situations.
“A plant wants as much potential success for its progeny as possible,” says Joe Ogas, biochemistry professor, who works
with a mustard-cousin research plant, Arabidopsis. “Imagine that over the course of evolution a plant has come to realize
that it’s experienced a certain environment and that its offspring are likely to experience that environment as well.
Epigenetics regulation offers the potential to turn off or turn on certain sets of genes in anticipation of the offspring bei ng
successful in that environment.
“Similarly with animals—epigenetics can lock in a particular pattern of gene expression. Selection is a powerful driving
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force in evolution, and it’s had millennia to identify best-case strategies for an organism to successfully pass genes on to the
next generation.“
Ogas studies a gene called “PKL“ involved in rearranging histones so that the enzymes similar to those Briggs works with
can modify the histones. Methyl groups aren’t the only biochemical mechanisms that cause epigenetic changes. Acetylation
and ubiquitylation are also biochemical mechanisms that can add or subtract small molecules to turn genes on or off.
Interest by national and international research groups and funding sources is gaining momentum in the quest to determine
how these processes work.
The National Institutes of Health and the National Science Foundation (NSF) have earmarked federal funding specifically
for studying the epigenome. Purdue biochemist Ann Kirchmaier recently received a nearly $500,000 NSF grant to probe the
mystery of how deacetylation silences—permanently turns off—genes in cells and how epigenetic change is inherited.
“The heritable feature of epigenetic gene regulation necessitates that cells tightly control if, when and where silencing wil l
occur,” Kirchmaier says. “If the wrong genes are permanently turned on or off, it can lead to developmental defects, cancer
and other catastrophic disorders.”
Finding ways to stop improper flicking of genetic switches is spawning a new class of drugs, and scientists are striving for
even more. Researchers now are experimenting with epigenetics to program cell function for use in repairing specific
injuries and diseases.
Stopping the mistakes
University of Wisconsin and Kyoto University scientists last year made a skin cell regress so that it was no longer a skin
cell. The cell didn’t know where it belonged yet; it had been transformed into an undifferentiated cell, or stem cell, the same
type of cell that causes controversy if it comes from an embryo.
Understanding how to trigger the on/off genetic switch may allow scientists to remove some of the genetic programming
that tells a cell to change from an undifferentiated embryo cell to a cell designed for a specific function, such as bone or
muscle.
“If we can understand epigenetics, then we can understand how to reverse gene expression from on to off o r vice versa.
We already know that as a cell progresses from a stem cell to a differentiated state there are a large number of epigenetic
changes,” Ogas says. “The more we understand the changes, the more we’ll be able to direct cells to particular outcome s.”
Understanding how to use epigenetics-based genetic reprogramming could help treat people with many disorders,
including children like those Lossie hugged at Prader-Willi conferences and Angelman syndrome clinics.
“These kids are just really special,” says Lossie, whose graduate school advisors were involved with patients with the
disorders. “Being able to see the kids, and talk with the kids and the parents, and knowing that someday we might be
making a difference kept me going in graduate school. It’s at the forefront for me today: How can we make a difference?”
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