DNA methylation, or addition of -CH3 groups, onto cytosine bases is an epigenetic method of turning off certain genes. A number of very recent studies have shown that this type of methylation is possible on another nucleotide base—adenine. However, the presence and function of these methyladenines remain unclear. In a recent study, Emory University School of Medicine researchers and collaborators in China have linked these modifications to brain regulation to environmental stress.
The team specifically looks at N6-methyladenine (6mA) dynamics within the mouse brain in response to stress. The mice are subjected to standard models for stress and depression (such as the forced swim test and tail suspension test) and the abundance of 6mA is detected using UHPLC-MS/MS and immunodetection.
In their findings published in Nature Communications, the team reports that overall 6mA levels are significantly elevated upon stress, up to a four-fold increase. Moreover, 6mA-immunoprecipitation coupled with high throughput sequencing shows that during stress, 6mA accumulates in certain genomic regions, but decreases in others. These regions tend to be in intronic, non-coding areas, but also around transcription start sites, hereby influencing gene expression.
The team reports that a decrease in 6mA is associated with a set of upregulated neuronal genes or downregulated LINE transposon expression. Genes affected by stress-induced 6mA changes also significantly overlap with genomic regions associated with neuropsychiatric disorders, such as depression. There also seems to be some “cross talk” between A and C types of DNA methylation.
"We found that 6-methyl A is dynamic, which could suggest a functional role," said senior author, Peng Jin, Ph.D. "That said, the enzymes that recognize, add and erase this type of DNA methylation are still mysterious."
The authors conclude that changes in levels of methyladenine in response to stress can influence the recruitment of transcription factors that drive gene expression. Further, these changes specifically affect the maintenance of normal brain function, and may have direct implications in the development of neuropsychiatric disorders. Thus, it will be important to further investigate the functional mechanisms of methylated adenine in future studies.
Image: Structure N6-Methyladenine (6mA) that includes the ribose sugar. First identified in bacteria, this nucleotide modification has been recently found in genomes of worms, fruit flies, frogs, zebrafish, pigs, and mice.