May 13, 2008— -- Epigenetics is among the hottest topics in medical science today. It is the subject of papers in many of the leading journals and it is a top priority for funding at the National Institutes of Health. And it could turn out to be a big part of the story in depression and bipolar disorder.
So what is epigenetics?
The term has been around since developmental biologist Conrad Waddington used it in the 1940s to refer to factors that influence how a genetic predisposition will ultimately play out in a biological or clinical outcome.
Now, in the molecular era, the term refers more narrowly to heritable information within cells that is not the DNA sequence itself.
While genetic transmission of information can be thought of as constituted by the chemical letters of the DNA sequence, epigenetic transmission can be considered to reside in the fonts of those letters, and in the punctuation.
The fonts matter. For example, take the sentences, "I hate being depressed," and "I hate being depressed." While the words are the same, the second one is a stronger statement. Or take "I hate being depressed!!!" Stronger still. Analogously, epigenetic modification of genes plays a major role in how strongly a gene is turned on.
These modifications take two forms: DNA methylation and histone marks.
DNA methylation refers to the addition of a chemical group called a methyl group to places in the DNA sequence. To use another metaphor, these act like locks on the factory door, determining whether chemical workers can come in and turn genes on.
Histones form balls of protein around which DNA wraps. They act like magnets that, when oriented plus to minus, lock the DNA into a closed position, but when oriented plus to plus, repel, and cause the DNA to open up. Various chemical modifications or marks influence the plus vs. minus state and thus help determine whether the doors to the gene are open.
Many cancer genes are known to be regulated by epigenetic machinery, including the colon cancer gene, APC, and the breast cancer gene, BRCA1.
But epigenetics has recently been found to play a role in the brain as well.
Our group at Johns Hopkins recently measured DNA methylation levels in hundreds of genes, comparing patterns across three different brain regions. We found that levels differed between regions for many of the genes, suggesting that DNA methylation signatures distinguish brain regions and may help account for the unique roles played by each of the three.
A dramatic example of the role of DNA methylation in brain disease is Rett syndrome, in which a hereditary defect in the DNA methylation machinery leads to a failure to turn off appropriate genes in the brain and a subsequent decline in neurodevelopment for the unfortunate children afflicted with this illness.
However, epigenetic marks can also be altered by the environment. For example, one study showed much greater DNA methylation differences between middle-aged identical twins than between very young ones, suggesting these changes accumulated during the lifetime of the twins.
Might stress be one of the life experiences that influence epigenetic marks?
A fascinating study from McGill University in Montreal suggests the answer could be yes. Researchers showed that in rats, differential maternal behavior towards pups influences their stress sensitivity in adulthood. Pups of better rat mothers showed differences in DNA methylation and histone marks compared to those of less attentive moms at the site of a key stress system gene. Treatment with a drug that changed the epigenetic marks abolished the maternal effect on stress sensitivity, supporting a causal role for epigenetics.
Another study, from the University of Texas Southwestern Medical Center, provides evidence that epigenetic changes can be induced by stress in adulthood. Adult mice exposed to highly aggressive neighbors become socially avoidant, defeated, and subordinate, in some ways mimicking human depression. Researchers showed that these mice developed histone changes in a depression-related gene, and that these changes were reversed by the antidepressant imipramine.
There is evidence that other antidepressants — Parnate and Prozac — can also alter histone marks. And giving mice a histone-altering chemical produces an antidepressant-like effect. One of the leading bipolar disorder medications, valproic acid, influences histones as well.
At the Johns Hopkins Epigenetics Center, we are investigating epigenetic variations that might play a role in stress, depression, and bipolar disorder. One of our tools is a microarray, sometimes called a chip, which is about the size of your hand, and has 2.1 million microscopic pieces of DNA on it.
When DNA from a person or a mouse is placed on it, the chip can detect methylation across nearly every gene in the mix, all at the same time. The lead developer of this tool, center director Andrew Feinberg, named it CHARM, an acronym, because Baltimore, where Johns Hopkins is located, has been optimistically dubbed "Charm City."
There is ample reason to be optimistic that advances in our understanding of the epigenetics of mood disorders will ultimately lead to better treatments. As Winston Churchill, who suffered from depression himself, said: "For myself I am an optimist — it does not seem to be much use being anything else."
Dr. James Potash is an associate professor of psychiatry and co-director of the Mood Disorders Program at the Johns Hopkins School of Medicine in Baltimore, Maryland. If you have questions or comments, please email at firstname.lastname@example.org. To participate in our genetic and clinical studies, call 1-877-MOODS-JH.