Summary: A new Emory University study reports that adenine methylation in DNA increases up to fourfold in the brain during stress.
Source: Emory University.
As genome science advances, researchers are uncovering additional chemical marks on DNA beyond the four canonical bases. Are these modifications meaningful signals that regulate gene activity, or are they accidental byproducts of molecular processes?
Researchers at Emory University School of Medicine, led by Peng Jin, PhD, investigated an uncommon DNA modification in animals: methylation of the DNA base adenine (N6-methyladenine, or 6mA). Their work indicates that 6mA becomes more abundant in the brain after stress and may be linked to gene regulation and neuropsychiatric conditions.
The study is published in Nature Communications.
DNA methylation on cytosine (5-methylcytosine) is well known to reduce gene expression and serve as a key mechanism of epigenetic regulation — changing how genes are read without altering the underlying sequence. Methylation adds a small chemical group (–CH3) to a base. In bacteria, methylation of adenine plays roles in defense against invading viruses. More recently, 6mA has been detected in insects and mammals, but its function in animal tissues, especially the brain, remained unclear.
Adding a methyl group to adenine could affect how DNA-binding proteins interact with the genome, altering gene activity. While enzymes that write, read and erase cytosine methylation are well characterized, the molecules that handle adenine methylation in animal DNA are still largely unknown.
“We found that 6mA is dynamic, which suggests it may have a regulatory role,” says Peng Jin. “However, the proteins that recognize, add, or remove this mark in DNA remain to be identified.” The team also noted that enzymes known to methylate adenine in RNA do not appear to contribute to DNA 6mA in this context.
First author Bing Yao, PhD, who recently established his own lab at Emory to study noncanonical DNA modifications, worked with Jin and colleagues to examine how 6mA responds to stress. They analyzed the prefrontal cortex of mice exposed to established behavioral stress paradigms commonly used to model depressive-like responses (forced swim and tail suspension tests).
Using two sensitive detection methods — liquid chromatography coupled to mass spectrometry and antibody-based binding assays for N6-methyladenine — the researchers observed an approximately fourfold increase in 6mA levels in brain DNA following stress. Although the overall abundance remained low (about 25 parts per million), the modification was not evenly distributed across the genome.
Genome-wide mapping revealed that 6mA was enriched in intergenic regions and largely excluded from protein-coding exons. Regions that lost 6mA tended to correspond with genes that were upregulated after stress, implying that removal of 6mA may accompany transcriptional activation. The data also point to potential interactions between adenine and cytosine methylation pathways.
Notably, genes with stress-induced changes in 6mA overlapped significantly with loci previously associated with neuropsychiatric disorders. While this correlation does not establish causation, the authors propose that abnormal regulation of 6mA in response to stress could misdirect DNA-binding proteins and contribute to disease-related changes in gene expression. Further research is needed to identify the enzymes that control 6mA, determine how this mark is targeted to specific genomic locations, and clarify its role in brain function and psychiatric illness.
Funding: This research was supported in part by the National Institute of Neurological Disorders and Stroke (NS051630, NS097206) and the National Institute of Mental Health (MH102690).
Source: Quinn Eastman, Emory University.
Publisher: Organized by NeuroscienceNews.com.
Image credit: NeuroscienceNews.com (public domain).
Original research: Full open-access article “DNA N6-methyladenine is dynamically regulated in the mouse brain following environmental stress” by Bing Yao, Ying Cheng, Zhiqin Wang, Yujing Li, Li Chen, Luoxiu Huang, Wenxin Zhang, Dahua Chen, Hao Wu, Beisha Tang & Peng Jin in Nature Communications. Published online October 24, 2017. doi:10.1038/s41467-017-01195-y
Emory. “Mysterious DNA Modification Seen in Stress Response.” NeuroscienceNews, 24 October 2017.
Abstract
DNA N6-methyladenine is dynamically regulated in the mouse brain following environmental stress
Chemical modifications on DNA, such as 5-methylcytosine and 5-hydroxymethylcytosine, have important roles in the mammalian brain. A novel adenine modification, N6-methyladenine (6mA), has been reported in mammalian cells, but its presence and function in the brain were unclear. This study demonstrates dynamic regulation of 6mA in the mouse brain following environmental stress. Overall 6mA levels increase significantly after stress. Genome-wide 6mA profiling combined with transcriptome analysis reveals an inverse relationship between dynamic 6mA changes and a subset of upregulated neuronal genes and downregulated LINE transposon expression. Genes with stress-induced 6mA alterations significantly overlap with loci implicated in neuropsychiatric disorders. These results support an epigenetic role for 6mA in the mammalian brain and suggest its potential involvement in neuropsychiatric disease.
Study citation: “DNA N6-methyladenine is dynamically regulated in the mouse brain following environmental stress” by Bing Yao et al., Nature Communications, published online October 24, 2017. doi:10.1038/s41467-017-01195-y