Abstract
Chemical modifications on DNA molecules, such as 5-methylcytosine and 5-hydroxymethylcytosine, play important roles in the mammalian brain. A novel DNA adenine modification, N(6)-methyladenine (6mA), has recently been found in mammalian cells. However, the presence and function(s) of 6mA in the mammalian brain remain unclear. Here we demonstrate 6mA dynamics in the mouse brain in response to environmental stress. We find that overall 6mA levels are significantly elevated upon 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 transposon expression. Genes bearing stress-induced 6mA changes significantly overlap with loci associated with neuropsychiatric disorders. These results suggest an epigenetic role for 6mA in the mammalian brain as well as its potential involvement in neuropsychiatric disorders.
Highlights
Chemical modifications on DNA molecules, such as 5-methylcytosine and 5-hydroxymethylcytosine, play important roles in the mammalian brain
In order to test 6mA changes in response to stress, we applied the highly sensitive ultra-performance liquid chromatography tandem mass spectrometer (UHPLC-MS/MS) to precisely quantify 6mA dynamic changes upon stress in several brain regions involved in stress response, including the prefrontal cortex (PFC), hippocampus (HIP), amygdala (AMY), and hypothalamus (HYP)
We explored the correlation between cytosine methylation and adenine methylation in the context of neurons and non-neurons using a genome-wide methylated DNA immunoprecipitation (MeDIP) data set in mouse cortex[33]
Summary
Chemical modifications on DNA molecules, such as 5-methylcytosine and 5-hydroxymethylcytosine, play important roles in the mammalian brain. A novel DNA adenine modification, N6methyladenine (6mA), which is prevalent in prokaryotes[3], was recently found in the genome of high eukaryotes, including green algae, worms, fruit flies, frogs, zebrafish, pigs, and mice[4,5,6,7,8,9] Evidence from these studies suggests potential epigenetic roles for 6mA, its precise biological function(s) remain elusive[10]. Genes bearing stress-induced 6mA changes significantly overlap with loci associated with neuropsychiatric disorders These results together suggest a potential epigenetic role for 6mA in the mammalian brain as well as its possible involvement in mental illness
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