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Epigenetics research takes aim at cancer, Alzheimer’s, autism and other illnesses
01-10-2010
EDIT CONNECT
SHARING OPTIONS:
DURHAM, N.C.—In the classic movie "It's a Wonderful Life,"
George Bailey
wonders what life would be like if he'd never been born. As we
all know, his guardian angel Clarence Odbody shows him the kind of mark he's
really
made on Bedford Falls.
What George Bailey didn't know was the mark we all make in
our lives from birth—the impact made by our
DNA and its role in our traits.
There exists a mediator between nature and nurture known as
epigenetics. A group of molecules that sit atop our DNA, the epigenome (which
means "above the genome") tells genes when to turn on and off.
"Epigenetics research refers to the study of heritable
changes in gene function that occur without a
change in the sequence of the
DNA, but rather involve alterations in DNA methylation and the histone code,"
notes Duke University's Randy Jirtle. "Thus, if you think of the genome as
being
comparable to the hardware of a computer, the epigenome is the software
that tells the computer when, where, and how to work."
Jirtle points out that in the past only genetic mutations
were thought to cause diseases and
neurological disorders. Thus, much time,
money and effort has gone into defining mutations involved in human diseases.
"This approach has been quite successful since gene
inactivating mutations have been found that result in a number of human
diseases like sickle cell anemia, cystic fibrosis and breast cancer," he says.
Epigenetic
changes can cause inappropriate gene function by
resulting in either over or under expression.
"A number of developmental disorders are caused by epigenetic
changes such as Beckwith-Wiedemann, Angelman, Prader-Willi, and Silver-Russell
syndromes. Type I and Type II diabetes have been associated with imprinted
genes—a subset of genes in which one parental copy of the gene is normally
silenced epigenetically," notes Jirtle. "Autism has also been recently
associated with epigenetic deregulation of the oxytocin receptor gene (OXTR).
Epigenetic dysregulation of genes is also intimately involved in cancer
formation."
It has
just been demonstrated that histone methylation plays
a crucial role in the long-term actions of cocaine on neuronal morphology and
behavior that may
underlie cocaine addiction.
"Although both genetic mutations and epigenetic changes
result in human
diseases, I think that it will ultimately become clear that
epigenetic changes give rise to human diseases more frequently that genetic
mutations,"
Jirtle adds.
Jirtle points out that epigenetic deregulation of gene
expression causes myriad
human diseases and neurological disorders.
"Consequently, we finally appreciate that there are novel
targets for which drugs can be designed that focus on the epigenome rather than
the genome," he says. "This is comparable to finding a completely new
mine to
extract gold."
Having made its impact, epigenetic therapy has a bright
future.
"Epigenetic therapy is already being used to treat
Myelodysplastic Syndrome (MDS). Valproic acid
is used to treat epilepsy and
bipolar disorder," Jirtle says. "Interestingly, it is a histone deacetylase
(HDAC) inhibitor. Thus, it is possible that
its efficacy in treating
neurological problems may result, in part, on its ability to alter the
epigenome."
The focus of medicine in the past as been on therapy, and
Jirtle says there is a bright future for drugs that target the epigenome.
"I also believe, however, that there will be a substantial
market for chemical agents and nutritional factors
that prevent inappropriate
epigenetic events from occurring during our life. For example, we demonstrated
that these nutritional supplements (e.g.
methyl donors or genistein can
counteract the reduction in DNA methylation caused by the endocrine disruptor,
bisphenol A, used in manufacturing hard
clear plastic and sealants," he says.
"To paraphrase what Hippocrates stated over two millennium ago, food is
medicine."
Part of Jirtle's work includes research with mice. In one
project one mouse weighs 20 grams and has brown fur. The other
is a hefty 60
grams with yellow fur and is prone to diabetes and cancer. They are identical
twins, with identical DNA.
So
what accounts for the differences?
Jirtle made one of the mice brown and one yellow by altering
their epigenetics in utero through diet.
The mother of the brown, thin mouse was given a dietary supplement of folic
acid, vitamin B12 and
other nutrients while pregnant, and the mother of the
obese mouse was not. (Though the mice had different mothers, they're
genetically identical as a
result of inbreeding.) The supplement "turned off"
the agouti gene, which gives mice yellow coats and insatiable appetites.
Epigenomes vary greatly among species, Jirtle explains, so
it cannot be assumed that obesity in humans is preventable with
prenatal
vitamins. But his experiment is part of a growing body of research that has
some scientists rethinking humans' genetic destinies. Is our
hereditary
fate—bipolar disorder or cancer at age 70, for example—sealed upon the
formation of our double helices, or are there things we can do to
change it?
Are we recipients of our DNA, or caretakers of it?
Last year, the National Institutes of Health announced that
it would invest $190 million to
accelerate epigenetic research. The list of
illnesses to be studied in the resulting grants reveals the scope of the
emerging field: cancer, Alzheimer
's disease, autism, bipolar disorder,
schizophrenia, asthma, kidney disease, glaucoma, muscular dystrophy and more.
Epigenetics have been a focal point for Jirtle for more than
a decade. When he held is first epigenetics conference in 1998 in
Raleigh,
N.C., epigenetics was such a small field that he worried nobody would come.
About 160 people attended. Jirtle hosted another conference in
2005; it
attracted 470.
"It's the flavor of the month," Michael Meaney, a brain
researcher at McGill University in Montreal, tells the Washington Post.
When a gene is turned off epigenetically, the DNA has
usually been methylated. Biologists have
known for decades that methylation is
involved in cell differentiation in utero,
making one cell a skin cell, another cell a liver cell, and
so on. Cell
differentiation is also what happens when scientists prompt an embryonic stem
cell to grow into a specific type of cell. But five years
ago, when Meaney
submitted a paper suggesting that DNA methylation happens throughout life in
response to environmental changes, he was told, "This
just can't happen."
"When a methyl group binds to cytosine in DNA, it can
project into the
major grove of the double helix molecule, blocking the ability
of some transcription factors from binding to the promoter region of a gene,"
Jirtle
says. "DNA methylation coupled with molecular changes in the histones
(e.g. acetylation), which DNA is wrapped around, can result in chromatin
condensation, and gene inactivation because the transcription factors required
for gene expression cannot access the DNA."
Epigenetic events are permanent, but reversible.
"Thus, even
though epigenetic changes may be difficult to
alter once established, it is possible to reverse them otherwise epigenetic
therapy would not be
effective in the treatment of some cancers," Jirtle adds.
Duke Department of Medicine researcher Simon
Gregory
described the link between DNA methylation and autism in a paper published in
October in the journal BMC Medicine.
Most genetic
studies of autism focus on variations in the
DNA sequence itself, especially on genes that are missing. Gregory and his
colleagues looked at an
oxytocin receptor gene, called OXTR, and found that
about 70 percent of the 119 autistic people in his study had a methylated OXTR;
in a control group
of people without autism, the rate was about 40 percent.
Oxytocin is a hormone that affects social interaction; difficulty relating to
others is common
for those with autism spectrum disorders.
Because this was only a pilot study, more research is
necessary. But Gregory tells the Washington Post that methylation-modifying drugs may be a new avenue for treatments.
He also hopes that his
findings will provide a new tool for doctors to diagnose
autism.
"Methylation has been very hot
in the cancer field for a number
of years," Gregory tells the Washington Post. "To find something like this associated with autism is very
exciting."
Epigenetic therapy is still very inexact—"a pretty broad
brush," adds Jirtle. But
oncologists have seen some success in using it against
leukemia. Azacitidine, sold as Vidaza and used to treat bone-marrow cancer and
blood disorders,
became the first FDA-approved epigenetic drug in 2004. When
tumor-suppressing genes aren't doing their job, due to a genetic mutation or
hypermethylation, cancer cells can replicate uncontrollably. But by
manipulating the epigenetic marks, doctors can get tumor-suppressing genes to
work again. Toxicologists also have a big stake in epigenetics.
The potential human implications—
do the chemicals we ingest
today affect our great-grandchildren?—are tremendous. In addition to
pesticides, toxicologists are studying chemicals in
plastics, such as
phthalates and bisphenol A, to see if they could enhance our risk of disease by
altering the epigenome.
As a result of epigenomic research, we know the mark we make
our own lives starts at birth and extends beyond the
impact George Bailey had
on Bedford Falls.
Code: E01131005 Back |
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