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Epigenomic Map of the Developing Brain

Summary

New research reveals details of changing DNA methylation patterns as the brain matures.

 

Highlights

  • Methylation is the addition of methyl chemical groups to nucleotide bases in a strand of DNA. The marks influence which genes are expressed or at what levels they’re expressed.
  • Researchers have found a unique type of methylation, previously found in humans only in embryonic stem cells, before the new survey of neurons. Now, Howard Hughes Medical Institute scientists and their collaborators have found that they appear in brain cells during the first years of life, when key learning processes are being established.

A previously underappreciated type of chemical mark on DNA may be key to how neurons in the brain develop and mature. In humans, the marks—a unique type of methylation—were known only to exist in embryonic stem cells before the new survey of neurons. Now, Howard Hughes Medical Institute scientists and their collaborators have found that they appear in brain cells during the first years of life, when key learning processes are being established. The discovery was reported July 4, 2013 in the journal Science.

“There is this entire, potentially very important regulatory system that we didn’t know about,” says HHMI- Gordon and Betty Moore Foundation Investigator Joseph R. Ecker of the Salk Institute for Biological Studies, who led the new work. “And we certainly didn’t know there was a drastic change in these marks in neurons during a critical time in the development of the brain.”

Methylation is the addition of methyl chemical groups to nucleotide bases in a strand of DNA. The marks influence which genes are expressed or what levels they’re expressed at. Most methylation occurs at specific locations in the DNA, typically on a cytosine (C) that sits next to a guanine (G)—and is called CG methylation. More than 80 percent of all CG sequences in the genome have a methyl group added. But sometimes, a cytosine that’s followed by a different DNA base (A, T, or C) can have a methyl group added, in a process dubbed non-CG methylation. Most human cells don’t have any non-CG methylation, but the same group of scientists have previously shown that embryonic stem cells, which have the potential to differentiate into any adult cell type, have extensive non-CG methylation that disappears once the cells differentiate. They had never been shown to exist in adult human cells before, so scientists assumed non-CG methylation marks were key only to the genetic patterning involved in cell differentiation.

Now that we have these epigenomic maps, we can start to study whether methylation is altered in disease states or in different regions of the brain.

Joseph Ecker

Ecker first developed methods to study methylation, including the non-CG type, in plants, and recently began applying his techniques to humans, teaming up with neurobiologists including HHMI investigator Terrence J. Sejnowski, also at the Salk Institute, to focus on the role of methylation in the brain.

To pinpoint the location of methyl groups, Ecker and his colleagues process DNA in a way that converts every unmethylated cytosine to a different nucleic acid, uracil. Then, they sequence the DNA in question; any cytosine left in the sequence must have been marked with a methyl to prevent its conversion to uracil. When the team began using the method on the brain cells from mice, they discovered that fetal brains have no non-CG methylation. But after birth, as a mouse develops, the amount of non-CG methylation in the neurons rapidly increases.

“When we saw this in mice, we immediately began looking at it in human samples, and what we found was a very similar story,” says Ecker. “The increase in non-CG methylation happens during a time in development when there is a lot going on with the brain and also during a time when there are things that are known to go wrong. It provides a whole new avenue to pursue.”

In human neurons, Ecker and his collaborators found that levels of non-CG methylation increased in neurons between birth and adolescence, and then remained relatively steady, accounting for more than half of all methylation, for the rest of life. In non-neuronal cells in the brain, non-CG methylation was present, but at much lower levels.

“The accumulation of non-CG methylation in neurons is really striking,” Ecker says.

The researchers don’t yet know the function of the non-CG methylation, but they found that it most often was present in genes that were turned off, and that its positions were largely the same between organisms—even between mice and human brain cells—suggesting that it controls vital functions in neurons. Ecker’s lab plans to further investigate the role of non-CG methylation at a cellular level, and also to determine how much the methylation patterns vary between different people or types of neurons. Altered patterns of methylation could, for example, lead to developmental learning disorders or cognitive declines in old age.

“Now that we have these epigenomic maps, we can start to study whether methylation is altered in disease states or in different regions of the brain,” he says.

Scientist Profile

Investigator
Salk Institute for Biological Studies
Molecular Biology, Plant Biology
Investigator
Salk Institute for Biological Studies
Biophysics, Neuroscience

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