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"Epigenetic" Marks a Clue to Multiple Functions of the Brain - 12/04/2007

"Epigenetic" Marks a Clue to Multiple Functions of the Brain

Release Date: December 4, 2007

A team of Johns Hopkins scientists has catalogued chemical tags attached to more than 800 genes from 76 human brain samples and collected the first evidence of how these special, inherited epigenetic “marks” might account for different brain functions. The results appear in the December issue of The American Journal of Human Genetics.

“It’s quite remarkable how clear the differences are and a bit surprising, because the genes we looked at weren’t necessarily known to be brain function genes,” says Andrew Feinberg, M.D., professor of medicine, oncology and molecular biology and genetics and director of the Center for Epigenetics at Hopkins.

“It makes sense that different geographic regions of the brain, because they’re responsible for a range of operations from memory to motor control, would be using different genes,” he says, “but we think this is the first evidence that specific brain functions, carried out by specific genes, may be determined by their epigenetic signatures.”

The signatures at play are known as methyl groups (particular combinations of a carbon and three hydrogen molecules), which can attach directly to the basic component of all genes, DNA.

Proper DNA methylation is required for normal development, gene function and overall genome stability, and disruption of methylation has long been linked to cancer and brain diseases.

“Because disruption in DNA methylation causes Rett syndrome, which leads to severe mental retardation and motor dysfunction, we suspected that methylation itself might be important in normal brain development,” says James Potash, M.D., M.P.H, associate professor of psychiatry at Hopkins.

The group then began cataloging the methylation sites on or around genes taken from the cerebral cortex, integral to higher thought processes; the cerebellum, central to motor control; and the pons, which acts as a relay station in the brain stem. These brain regions are widely different in their location and makeup. They compared DNA from different parts of each brain sample using a gene chip that tested more than 1,500 sites in the genome to determine which were methylated.

“What we found were striking differences in DNA methylation depending on where we looked,” says Feinberg.

Specific patterns of methylation were related to brain region and were unrelated to age, gender or cause of death.

“What's really interesting about this work is that epigenetics probably helps control the development of one cell type from another,” says Potash. “This study raises the possibility that errors in development might underlie brain diseases such as bipolar disorder, autism, major depression and schizophrenia.”

The research was funded by the National Institutes of Health.

Authors on the paper are Christine Ladd-Acosta, Sarven Sabunciyan, Robert Yolken, Tiffany Dinkins, Pauline Callinan, Potash and Feinberg, all of Hopkins; Jonathan Pevsner of the Kennedy-Krieger Institute, Baltimore; Maree Webster of Uniformed Services University of the Health Sciences, Bethesda, Md.; and Jian-Bing Fan of Illumina, San Diego, Calif.

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