Epigenetics Links Nature and Nurture

Researchers at the JHU Epigenetics Center developed a tool to scan the genome and measure DNA methylation in various genes using a microarray chip called CHARM, which stands for comprehensive high-throughput arrays for relative methylation. Each microarray chip can simultaneously study 40,000 regions in a genome to describe which genes are methylated and thus suppressed.

The CHARM microarrays scan the epigenome to find out which genes are expressed and which are not, Eirikur Briem, M.S., manager of the Epigenetics Center's microarray laboratory, explained.

Like the way DNA microarrays made genomewide scanning possible, the CHARM microarray chips allow researchers to map DNA methylation patterns quickly in millions of genes.

“Genomewide scans allow us to look at the whole genome rather than one gene at a time; this [CHARM microarray] is a platform for us to pick up things that we had no idea about,” said Potash. Thus, researchers need not confine their hunt for disease-related genes and proteins to the usual suspects: dopamine, serotonin, brain-derived neurotrophic factor, or norepinephrine. Unexpected pathways may be discovered.

The center has received funding to conduct a “gigantic schizophrenia study,” Potash said with a hint of pride. He and his colleagues will compare patients, their family members, and control subjects without schizophrenia for distinct epigenetic differences in hopes of identifying genetic expressions or suppressions involved in the disorder.

A big hurdle in studying epigenetic markers is choosing what tissue to study. Unlike genetic material, which is the same in nearly all cells throughout the body, the epigenetic pattern differs by tissue.

Potash pointed to a study he and his colleagues published in Nature Genetics in February 2009 in which they applied CHARM testing to brain, liver, and spleen tissue. “The study shows clearly that DNA methylation patterns differ a lot among the three types of tissues,” he said. “In fact, the DNA methylation patterns in the human brain are more like the patterns in mouse brain than the patterns in the human liver or human spleen.”

In the ongoing schizophrenia epigenetics study, Potash and colleagues decided to use white blood cells for analysis, because it is extremely difficult to obtain brain tissue from a living person, not to mention hundreds of people. “If we find clear differences [between patients and controls], that is going to be interesting anyway... [because] some of the epigenetic differences are also reflected in the brain,” said Potash. As insurance, they also plan to examine postmortem brain tissues of patients with schizophrenia to corroborate the findings from the blood analysis.

Furthermore, “Whatever differences show up in blood, if replicated, could be used as a marker for the disease,” Potash said.

Potash cautioned against unrealistic expectations that this type of research can revolutionize medicine overnight and find a cure for every illness. He does believe, however, that the discoveries will move psychiatry forward in long strides. For example, research will help psychiatrists predict, even quantify, a person's risk for developing a mental illness based on his or her genetic markers, according to Potash. With the help of further clinical evidence, individuals at high risk who do not meet diagnostic criteria can be targeted for prevention measures, thus staving off psychiatric disorders before they take shape.

Second, genetics can help clinicians predict who will respond to which drug and choose the best treatment for each patient. Lastly, understanding the pathophysiology of psychiatric disorders will help neurobiologists and pharmacologists design new drugs that work more effectively with fewer side effects.