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 Epigenetics research takes aim at cancer, Alzheimer’s, autism and other illnesses
01-10-2010
SHARING OPTIONS:
“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.”
“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.
Jirtle points out that epigenetic deregulation of gene
expression causes myriad human diseases and neurological disorders.
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.”
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.
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?
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.
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.”
“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.
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.
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