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 weall know, his guardian angel Clarence Odbody shows him the kind of mark he'sreally made on Bedford Falls.
What George Bailey didn't know was the mark we all make inour lives from birth—the impact made by our DNA and its role in our traits.
There exists a mediator between nature and nurture known asepigenetics. A group of molecules that sit atop our DNA, the epigenome (whichmeans "above the genome") tells genes when to turn on and off.
"Epigenetics research refers to the study of heritablechanges in gene function that occur without a change in the sequence of theDNA, but rather involve alterations in DNA methylation and the histone code,"notes Duke University's Randy Jirtle. "Thus, if you think of the genome asbeing comparable to the hardware of a computer, the epigenome is the softwarethat tells the computer when, where, and how to work."
Jirtle points out that in the past only genetic mutationswere 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 geneinactivating mutations have been found that result in a number of humandiseases like sickle cell anemia, cystic fibrosis and breast cancer," he says.
Epigenetic changes can cause inappropriate gene function byresulting in either over or under expression.
"A number of developmental disorders are caused by epigeneticchanges such as Beckwith-Wiedemann, Angelman, Prader-Willi, and Silver-Russellsyndromes. Type I and Type II diabetes have been associated with imprintedgenes—a subset of genes in which one parental copy of the gene is normallysilenced epigenetically," notes Jirtle. "Autism has also been recentlyassociated with epigenetic deregulation of the oxytocin receptor gene (OXTR).Epigenetic dysregulation of genes is also intimately involved in cancerformation."
It has just been demonstrated that histone methylation playsa crucial role in the long-term actions of cocaine on neuronal morphology andbehavior that may underlie cocaine addiction.
"Although both genetic mutations and epigenetic changesresult in human diseases, I think that it will ultimately become clear thatepigenetic changes give rise to human diseases more frequently that geneticmutations," Jirtle adds.
Jirtle points out that epigenetic deregulation of geneexpression causes myriad human diseases and neurological disorders.
"Consequently, we finally appreciate that there are noveltargets for which drugs can be designed that focus on the epigenome rather thanthe genome," he says. "This is comparable to finding a completely new mine toextract gold."
Having made its impact, epigenetic therapy has a brightfuture.
"Epigenetic therapy is already being used to treatMyelodysplastic Syndrome (MDS). Valproic acid is used to treat epilepsy andbipolar disorder," Jirtle says. "Interestingly, it is a histone deacetylase(HDAC) inhibitor. Thus, it is possible that its efficacy in treatingneurological problems may result, in part, on its ability to alter theepigenome."
The focus of medicine in the past as been on therapy, andJirtle says there is a bright future for drugs that target the epigenome.
"I also believe, however, that there will be a substantialmarket for chemical agents and nutritional factors that prevent inappropriateepigenetic events from occurring during our life. For example, we demonstratedthat these nutritional supplements (e.g. methyl donors or genistein cancounteract 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 ismedicine."
Part of Jirtle's work includes research with mice. In oneproject one mouse weighs 20 grams and has brown fur. The other is a hefty 60grams with yellow fur and is prone to diabetes and cancer. They are identicaltwins, with identical DNA.
So what accounts for the differences?
Jirtle made one of the mice brown and one yellow by alteringtheir epigenetics in utero through diet.The mother of the brown, thin mouse was given a dietary supplement of folicacid, vitamin B12 and other nutrients while pregnant, and the mother of theobese mouse was not. (Though the mice had different mothers, they'regenetically 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, soit cannot be assumed that obesity in humans is preventable with prenatalvitamins. But his experiment is part of a growing body of research that hassome scientists rethinking humans' genetic destinies. Is our hereditaryfate—bipolar disorder or cancer at age 70, for example—sealed upon theformation 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 thatit would invest $190 million to accelerate epigenetic research. The list ofillnesses to be studied in the resulting grants reveals the scope of theemerging 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 thana 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; itattracted 470.
"It's the flavor of the month," Michael Meaney, a brainresearcher at McGill University in Montreal, tells the Washington Post.
When a gene is turned off epigenetically, the DNA hasusually been methylated. Biologists have known for decades that methylation isinvolved in cell differentiation in utero,making one cell a skin cell, another cell a liver cell, and so on. Celldifferentiation is also what happens when scientists prompt an embryonic stemcell to grow into a specific type of cell. But five years ago, when Meaneysubmitted a paper suggesting that DNA methylation happens throughout life inresponse to environmental changes, he was told, "This just can't happen."
"When a methyl group binds to cytosine in DNA, it canproject into the major grove of the double helix molecule, blocking the abilityof 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 chromatincondensation, and gene inactivation because the transcription factors requiredfor gene expression cannot access the DNA."
Epigenetic events are permanent, but reversible.
"Thus, even though epigenetic changes may be difficult toalter once established, it is possible to reverse them otherwise epigenetictherapy would not be effective in the treatment of some cancers," Jirtle adds.
Duke Department of Medicine researcher Simon Gregorydescribed the link between DNA methylation and autism in a paper published inOctober in the journal BMC Medicine.
Most genetic studies of autism focus on variations in theDNA sequence itself, especially on genes that are missing. Gregory and hiscolleagues looked at an oxytocin receptor gene, called OXTR, and found thatabout 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 toothers is common for those with autism spectrum disorders.
Because this was only a pilot study, more research isnecessary. 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 diagnoseautism.
"Methylation has been very hot in the cancer field for a numberof years," Gregory tells the Washington Post. "To find something like this associated with autism is veryexciting."
Epigenetic therapy is still very inexact—"a pretty broadbrush," adds Jirtle. But oncologists have seen some success in using it againstleukemia. Azacitidine, sold as Vidaza and used to treat bone-marrow cancer andblood disorders, became the first FDA-approved epigenetic drug in 2004. Whentumor-suppressing genes aren't doing their job, due to a genetic mutation orhypermethylation, cancer cells can replicate uncontrollably. But bymanipulating the epigenetic marks, doctors can get tumor-suppressing genes towork again. Toxicologists also have a big stake in epigenetics.
The potential human implications—do the chemicals we ingesttoday affect our great-grandchildren?—are tremendous. In addition topesticides, toxicologists are studying chemicals in plastics, such asphthalates and bisphenol A, to see if they could enhance our risk of disease byaltering the epigenome.
As a result of epigenomic research, we know the mark we makeour own lives starts at birth and extends beyond the impact George Bailey hadon Bedford Falls.
