The Curious Case of DNA Methylation

By Rahul Lodhavia | SQ Staff Writer | SQ Online (2013-14)

The human genome, or genetic information, is like a well organized assembly line. In it, there are millions of chemical tags that modify or mark the genome and regulate genes by telling it what to do, where to do it, and when to do it.

One such modifying tag is called DNA methylation. Researchers at the Salk Institute studied DNA methylation changes in postmortem mice and human brain tissue and found correlational data suggesting DNA methylation may play a significant role in the development of humans. Understanding the process of DNA methylation in the brain can provide insight into how diseases and events such as schizophrenia and traumatic brain injury arise in developing humans.

DNA methylation trend

Green stars indicates CG methylation and purple stars indicate non-CG methylation. The graph shows an increase in non-CG methylation during the early stages of human development. Image provided by Dr. Eran Mukamel.

DNA methylation is the addition of a methyl group, a carbon attached to three hydrogens, to the backbone of DNA in specific areas, particularly to a cytosine base followed by a guanine base. This type of methylation is commonly known as CG methylation. Despite our knowledge of DNA methylation in other types of cells in the body, we know relatively little about this chemical tag in the brain.

These researchers at the Salk Institute studied the pattern of DNA methylation changes in the frontal cortex. The frontal cortex is a region of the brain that is commonly associated with learning and memory and is constantly changing during development, making it the ideal area to study DNA methylation in developing humans.

Through their experiments, the researchers successfully mapped the locations of the millions of cytosine DNA methylation tags in neuronal and glial genomes using mice and human brain tissue. This mapping provided a reference for DNA methylation patterns which corresponded to different mice and human developmental stages.

In order to map these areas of CG DNA methylation, these researchers utilized a technique pioneered by Dr. Joe Ecker and Dr. Ryan Lister of the Salk Institute called Whole Genome Bisulfite Sequencing (WGBS) followed by high throughput sequencing.

Dr. Eran Mukamel, one of the co-authors on this research, said, “Before sequencing, we treat the DNA with sodium bisulfite which converts cytosine into uracil. The uracil gets read as a thymine during sequencing. However methylated cytosines do not get converted into uracil,  telling us which were methylated and unmethylated.”

One of the breakthroughs in their research came when Dr. Mukamel and his colleagues discovered that there was also non-CG methylation in addition to CG methylation. Non-CG methylation was occurring at cytosines that were not followed by a guanine. Upon discovering this non-CG methylation in brain cells, Dr. Mukamel and his colleagues analyzed its pattern in the development of the cortex and found that the rate of non-CG methylation was increasing rapidly during the first 20 years of human life.

“Our analysis of the data showed that there very well may be a correlation between brain development and non-CG methylation. The fact that something so uncommon in other cells is a major occurrence in brain cells means that evolutionarily it has been selected for and has a functionally important role,” Dr. Mukamel said.

Such a correlation suggests that both CG and non-CG DNA methylation plays a critical role in regulating the formation and destruction of synaptic connections that occur during early development.

In the future, Dr. Mukamel and his colleagues hope to explain this correlation through a causal link and prove even further that DNA methylation plays a critical role in early human development. He also hopes to compare DNA methylation in the brain with the DNA methylation that occurs in other tissues, such as the liver, heart, and lungs.

Dr. Mukamel and his fellow researchers at the Salk Institute have explored a very important facet of the brain. DNA methylation serves an important role in regulating the development of the brain and errors in its regulation can lead to diseases and conditions such as schizophrenia and traumatic brain injury. Fortunately, DNA methylation tags are not permanent, and as more research is done to understand its patterns, more strategies can be developed to potentially fix related neurological problems. As Dr. Mukamel said, “There is still plenty of exploration to be done.”