New Study Finds Permanent Changes in Brain Genes May Not be So Permanent After All

In a new study published in the January 28 issue of Nature Neuroscience, a team of researchers at Johns Hopkins a new gene control mechanism and how it may contribute to Rett Syndrome, a nervous system disorder affecting mostly girls that causes problems with movement and communication.

Normally cells turnoff genes they don't need by attaching a chemical methyl group to the DNA. This process is called methylation. Scientists for a long time believed that methyl groups could only stick to a particular DNA sequence - a cytosine followed by a guanine - called CpG. In recent years, however, it has been found that they can follow other sequences. The non-CpG methylation has been found in stem cells as well as in neurons in the brain. 

Johns Hopkins research team has discovered that non-CpG methylation occurs later and more dynamically in neurons than previously appreciated, and that it acts as a system of gene regulation, which can be independent of traditional CpG methylation.

The team, led by Hongjun Song, Ph.D., professor of neurology and director of Johns Hopkins Medicine's Institute for Cell Engineering's Stem Cell Program, had found non-CpG methylation prevalent in neurons. The finding is surprising because this wasn't found in any other cells besides stem cells.

The scientists examined the genes that were being transcribed in neurons and found that non-CpG methylation stops genes from being expressed  like the form of methylation scientists had seen in stem cells. On the basis of genome mapping, the scientists also identified the location of non-CpG methylation. It was also found that it carves out its own niche, and are distributed in regions without CpG methlyation. "That was the first hint that maybe it can function independently of CpG methylation," Song said.

The new kind of methylation also seems to operate under different rules. Scientists have long thought methylation was final. Once a cytosine gets a methyl stuck to it, so the story went, that gene is shut off forever. "This became dogma," Song said. "Once cells become the right type, they don't change their identity or DNA methylation."

However, non-CpG methylation was found to happen later, when the neuron is mature. The conventional wisdom said it was irreversible. The researchers learned this from an experiment in which they knocked out in adult mice the enzymes that attach methyl groups to DNA. They found the neurons still had just as much CpG methylation, but the non-CpG methylation dropped off. This suggests that non-CpG methylation is an active process, according to Song, with methyl groups continually being taken off and put back on, adding to evidence that non-CpG methylation may play more of a role in managing operations in mature cells.

The researchers also found a way that non-CpG methylation is similar to CpG methylation in one important way: it's read by MeCP2, an enzyme long identified as a player in methylation.

That's significant because a mutation in MeCP2 causes Rett Syndrome, and understanding DNA methylation is key to understanding this syndrome. The disorder occurs, Song says, when working copies of the gene for MeCP2 are silenced during development.