Charting the Chemical Choreography of Brain Development

Posted on August 27, 2013 by Dr. Francis Collins

Drawing of baby, adolescent, and adult with decorative brains

Credit: Image courtesy of Scot Nicholls

Once in a while a research publication reveals an entirely new perspective on a fundamental issue in biology or medicine. Today’s blog is about such a paper. The story, though complex, is very significant.

The choreography of human brain development is amazing, but quite mysterious. Today’s post highlights a study [1] that reveals the locations of some of the chemical choreographers that collaborate with DNA to orchestrate these fancy moves in the brain.

This complex developmental dance starts in the womb as our brain cells arise, migrate to their proper locations, and mature. By the time we’re born, each of us has close to 100 billion of these cells, called neurons. But that’s not all. The brain also contains lots of other cell types—especially glia. Glial cells were previously thought to act primarily as servants to the neurons, but they’re actually more like partners. Our birth inventory is just the first act. Over the course of our lives, our experiences and environment continue to shape and re-shape the brain’s connections, albeit in varying paces and patterns.

The millions of chemical tags that modify or mark the genome tell it what to do, and when and where to do it. Taken together, we call this diverse collection of chemical cues the “epigenome.”

One common type of tag, called DNA methylation, directly alters the genome. In this process, methyl groups—tags made up of one carbon and three hydrogen atoms—attach to the backbone of the DNA molecule in specific places, particularly to the DNA base called cytosine. These tags regulate the activity of genes, turning them on or off depending on the type of cell and phase of development.

We’ve learned from previous studies that medication, diet, aging, stress, disease, and exposure to various chemicals can alter the pattern of DNA methylation in the brain. Sometimes, these alterations compromise the brain’s health. But we haven’t been able to compare these changes with a healthy pattern of DNA methylation in brain cells. Now we can, thanks to this new map created through NIH-funded research.

In work published in the journal Science [1], researchers at the Salk Institute for Biological Studies, La Jolla, CA, charted the pattern of DNA methylation changes in the frontal cortex, a region of the brain associated with behavior and decision-making. Using post-mortem samples of mouse and human brain tissue, they precisely mapped the locations of the >100 million cytosine DNA methylation tags within the genomes of neurons and glia. This map [2] provides the research community with a wonderful reference of DNA methylation patterns corresponding to various stages of normal brain development in mice and humans.

Most researchers assume that methylation of cytosine happens almost exclusively in a specific DNA context—namely, when C (cytosine) is followed by G (guanine). That is certainly true in other tissues. But in the brain, the mappers found that non-CG methylation, an unconventional form of DNA methylation that’s almost non-existent in humans at birth, ramps up in neurons during the first two years of life. It then increases through adolescence until it finally plateaus in early adulthood, when the development of the frontal cortex is essentially complete. This period of escalating non-CG methylation overlaps with the time when connections between neurons are rapidly forming—suggesting that DNA methylation might be regulating which connections are formed or deleted.

Just as genetic mutations can lead to disease, glitches in DNA methylation may also trigger or increase the severity of brain disorders. Several studies have already linked abnormal methylation with disorders like schizophrenia, and conditions like Traumatic Brain Injury. This research is particularly exciting because these DNA methylation tags are not permanent. So, if we discover patterns of methylation that cause particular brain diseases, we can develop strategies to restore the healthy epigenetic profile—in effect, to bring those errant brain cells back in step with the dance of normal brain development.

Sketched image of a brain, neuron, glia, DNA, methylation sites, and a graph of methylation decreasing over time

Caption: Researchers mapped methylation sites in genomes of neurons and glia in the frontal cortex. mCH methyl tags, or non-CG methylation (purple stars), were absent at birth, but were added rapidly during the first few years of life and then more slowly until about age 30. After age 50, the number of mCH tags declined.
Credit: Eran Mukamel, Salk Institute

This study is a powerful example of how recent technological advances are revealing the secrets and complexities of the human brain—a process we hope to accelerate with the start of the BRAIN initiative!

References:

[1] Global epigenomic reconfiguration during mammalian brain development. Lister R, Mukamel EA, Nery JR, Urich M, Puddifoot CA, Johnson ND, Lucero J, Huang Y, Dwork AJ, Schultz MD, Yu M, Tonti-Filippini J, Heyn H, Hu S, Wu JC, Rao A, Esteller M, He C, Haghighi FG, Sejnowski TJ, Behrens MM, Ecker JR. Science. 2013 Aug 9;341(6146):1237905.

[2] Sequence data can be downloaded from National Center for Biotechnology Information GEO (GSE47966). The analyzed data is also available for browsing.

Link:

NHGRI Fact Sheet: Epigenomics

NIH support: National Institute of Mental Health; National Human Genome Research Institute; National Institute of Allergy and Infectious Diseases; National Institute of Child Health and Human Development; National Cancer Institute; National Institute of Neurological Diseases and Stroke