It has been called the “other” methylated base of DNA. Well studied in bacteria and plants, but relatively mysterious in insects and mammals, this form of epigenetic modification appears to have a role in the brain. It may even be involved in neuropsychiatric disorders.

This other methylated base of DNA is N(6)-methyladenine (6mA). According to geneticists at Emory University School of Medicine, overall 6mA levels are “significantly elevated upon stress.” This finding, which came from studies of environmentally stressed mice, prompted the geneticists to scrutinize the epigenetic marks—where they occurred, and where they didn’t—more closely. The geneticists found epigenetic patterns that suggested at least some of the 6mA activity was dynamic and that aberrant 6mA in response to stress could contribute to neuropsychiatric disease.

Details of the work appeared October 24 in the journal Nature Communications, in an article entitled  “DNA N6-Methyladenine Is Dynamically Regulated in the Mouse Brain following Environmental Stress.” The article notes that while epigenetic changes, such as 5-methylcytosine and 5-hydroxymethylcytosine, are known to play important roles in the mammalian brain, the presence and function(s) of 6mA in the mammalian brain remain unclear. Shifting the focus from cytosine to adenine, the scientists sought to demonstrate 6mA dynamics in the mouse brain in response to environmental stress.

“Genome-wide 6mA and transcriptome profiling reveal an inverse association between 6mA dynamic changes and a set of upregulated neuronal genes or downregulated LINE [long interspersed nuclear element] transposon expression,” wrote the article’s authors. “Genes bearing stress-induced 6mA changes significantly overlap with loci associated with neuropsychiatric disorders.”

For C-methylation, scientists know a lot about the enzymes that grab it, add it, or erase it. For A-methylation, less is known.

“We found that 6-methyl A is dynamic, which could suggest a functional role,” said Emory’s Peng Jin, Ph.D., who led the current study. “That said, the enzymes that recognize, add, and erase this type of DNA methylation are still mysterious.” Dr. Jin added that it does appear that the enzymes that add methyl groups to A when it is part of RNA are not involved.

In the Nature Communications paper, Dr. Jin and colleagues looked at the prefrontal cortex region of the brain in mice that were subjected to stress in standard models for the study of depression (forced swim test and tail suspension test). Under these conditions, the abundance of 6mA in the brain cells' DNA rose four-fold, the scientists found.

The DNA modification was detected with two sensitive techniques: liquid chromatography/mass spectrometry and binding to an antibody against 6mA. The peak abundance is about 25 parts per million, which isn't that high—but it appears to be confined to certain regions of the genome.

The methyl-A modification tended to appear more in regions that were between genes and was mostly excluded from the parts of the genome that encode proteins. The loss of methyl-A correlates with genes that are upregulated with stress, suggesting that something removes it around active genes. There does seem to be some “cross talk” between A- and C-methylation, noted Dr. Jin.

Genes bearing stress-induced 6mA changes overlapped with those associated with neuropsychiatric disorders, a relationship that needs more investigation. The scientists speculate that aberrant 6mA in response to stress could contribute to neuropsychiatric diseases by ectopically recruiting DNA-binding proteins.

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