Almost 60 years after James Watson and Francis Crick revolutionized biology by describing the molecular structure of DNA and showing how genetic information is stored, replicated, and passed down from one generation to the next, the field is undergoing another sea change.
“Epigenetics will not be as revolutionary as the discovery of the structure of DNA, but it does represent an exciting, major advance in our understanding,” says Eric Nestler, a professor of psychiatry and neuroscience at the Mount Sinai Medical Center in New York and a member of the Dana Alliance for Brain Initiatives.
Epigenetics is defined as the study of heritable changes in gene activity that are not due to changes in DNA sequence. Instead, they may be caused by “silencing” a gene, for example, rather than mutating it.
The nucleus of every cell in the body contains 1 meter of DNA, tightly coiled and wrapped around barrel-shaped histone protein molecules. Epigenetic mechanisms involve chemical modifications to the histones or to the DNA itself. These changes remodel the architecture of the chromosomes, opening up a particular gene to the machinery that synthesizes protein, or closing it down, so that the gene is switched off.
We are only beginning to understand how environment shapes our DNA, but we do know these processes are involved in almost every aspect of normal and abnormal brain function. Life experiences can leave long-lasting epigenetic “marks” on the chromosomes in neurons. These marks can have profound effects on our behavior in later life.
A landmark 2004 study by Michael Meaney of McGill University and colleagues showed that the quality of maternal care significantly affects the behavior of offspring in adulthood. Rat pups repeatedly licked and groomed by their mother during the first week of life were better able to cope with stress and fearful situations as adults, compared with those who received little or contact with the mother.
These effects were linked to epigenetic changes in the gene encoding the glucocorticoid receptor, a protein that controls many aspects of the body’s response to stress. Licking and grooming led to higher levels of the receptor in part of the brain called the hippocampus, and an improved stress response, in the “high care” group offspring. By contrast, levels of the receptor protein were reduced, and the stress response diminished, in the “low care” group. The hippocampus is essential for memory formation, which also involves epigenetic mechnanisms. It may be that as the brain forms memories of traumatic events, it also triggers these epigenetic changes.
The researchers also found these effects are reversible. Fostering low care pups to mothers that maintained high levels of contact removed the epigenetic mark associated with reduced licking and grooming, and their stress response was comparable to that of high care pups. The scientists also could reverse the effects by giving the pups a chemical that inhibits the epigenetic modification of the glucocorticoid receptor induced by lack of licking and grooming.
Early life events can have long-lasting effects on human behavior, too. In a follow-up study published in 2009, Meaney's group reported that there are epigenetic differences between the brains of suicide victims with a history of childhood abuse and those of suicide victims with no abuse or people who died suddenly of other causes.
So could the epigenetic marks caused by stressful events be reversed in humans? Investigating this is difficult, as it would require studies in which groups of children are subjected to different (and not always positive) environmental conditions. Researchers continue to build a case using animal models, though.
“In the rat, we have completed a study examining the degree to which environmental enrichment in the juvenile period can reverse effects of variations in maternal care,” says Meaney. He also is involved in a large study of human infants, “focusing more on differential susceptibility [to epigenetic changes] rather than reversibility.”
Epigenetics of addiction
Other researchers have shown that drug addiction is also likely to involve epigenetic mechanisms. Giving mice repeated doses of cocaine is known to cause long-lasting changes in gene expression and in the strength of connections between cells in the nucleus accumbens (or “reward center”), and these changes are believed to underlie various aspects of addiction.
Earlier this year, Nestler and his colleagues found that these changes are caused by epigenetic mechanisms. They showed that blocking the enzyme that performs the changes not only blocks the changes in gene expression and connectivity associated with repeated cocaine use, but also significantly reduces the animals' preference for the drug. This suggests that chemicals that block the enzyme might be effective in treating addiction in humans.
“The inhibitors available today do not penetrate the brain adequately,” says Nestler; many labs are working to develop compounds that would. Another problem is specificity – inhibitors that block a range of epigenetic mechanisms, rather than only the ones associated with drug use, would likely have unwanted side effects.
Blocking cognitive decline?
In May, researchers at the Laboratory for Aging and Cognitive Diseases in Göttingen reported that the memory problems that occur in aged mice are linked to removal of small groups of atoms called acetyl groups from histones in the hippocampus, leading to widespread changes of gene expression. They also found that chemicals called histone deactylation inhibitors can re-instate memory function in the older animals. These chemicals could potentially be used to slow down or prevent memory loss in people, and perhaps even to treat Alzheimer's. But again, getting the drugs into the brain poses a major problem, as does ensuring they affect only their specific targets.
“Our hypothesis is that genetic and environmental risk factors lead to a distinct epigenetic signature,” says senior author André Fischer. This signature may be a “biomarker” for Alzheimer's, and the ability to detect it could help doctors to identify people who are at risk of the disease. Samples of brain tissue cannot be taken from living patients, so Fischer and his colleagues are investigating whether the epigenetic changes can be measured in other types of cells, such as immune system cells, which can be obtained in blood samples.
“I am optimistic that epigenetic strategies will have clinical applications,” says Fischer, “but we have to appreciate that neuroscientists only started investigating these mechanisms 3-4 years ago.”
Moheb Costandi is a molecular and developmental neurobiologist turned freelance science writer based in London. He is the author of the Neurophilosophy weblog.