Stress has a way of getting under our skin, where it can sink in so deep that it modifies our brain’s DNA. While it can alter DNA cytosine modifications, such as 5-methylcytosine (5mC), a new role for the N6-methyladenine (6mA) modification in stress response has now emerged. DNA 6mA has recently made the grade as a eukaryotic epigenetic mark, although its functions remain a mystery, particularly in the brain, which is well known for repurposing epigenetic modifications to suit its need for dynamic post-mitotic responses.
To gain a deeper understanding of 6mA in the mammalian brain, the lab of Peng Jin at Emory University (Georgia) exposed young adult male mice to chronic restraint stress. First, the team quantified 6mA in several brains regions involved in stress response via ultra-performance liquid chromatography-tandem mass spectrometer (UHPLC-MS/MS). Their analysis revealed that while 6mA is present the brain, only the prefrontal cortex (PFC) exhibits a considerable increase in global 6mA levels in response to chronic stress.
Then the team turned to 6mA immunoprecipitation followed by high-throughput sequencing, where they found that:
- Regions of differential 6mA are primarily intergenic
- The differentially methylated intragenic regions are enriched for in introns and depleted in exons
- From the genic perspective, regions that lose 6mA tend to occur around the transcription start site, while regions with a gain tend to be in the gene body
- Integration with RNA-seq uncovered an inverse association with down-regulated LINE transposon expression and up-regulated brain-related genes
- A comparison of 6mA and 5mC distributions suggests epigenetic cross-talk
- The differentially methylated regions significantly overlap with regions associated with depression, schizophrenia, and autism spectrum disorders
Jin concludes, “We found that 6-methyl A is dynamic, which could suggest a functional role. That said, the enzymes that recognize, add and erase this type of DNA methylation are still mysterious.” Overall, 6mA is a promising new player in the brain’s epigenome, where its role in stress response could deepen our understanding of psychiatric disorders.
Go explore this new neuroepigenomic frontier over at Nature Communications, October 2017