Neuronal activity modifies DNA methylation landscape in the adult brain

DNA methylation has been traditionally viewed as a highly stable epigenetic mark in post-mitotic cells, however, postnatal brains appear to exhibit stimulus-induced methylation changes, at least in a few identified CpG dinucleotides. How extensively the neuronal DNA methylome is regulated by neuronal activity is unknown. Using a next-generation sequencing-based method for genome-wide analysis at a single-nucleotide resolution, we quantitatively compared the CpG methylation landscape of adult mouse dentate granule neurons in vivo before and after synchronous neuronal activation. About 1.4% of 219,991 CpGs measured show rapid active demethylation or de novo methylation. Some modifications remain stable for at least 24 hours. These activity-modified CpGs exhibit a broad genomic distribution with significant enrichment in low-CpG density regions, and are associated with brain-specific genes related to neuronal plasticity. Our study implicates modification of the neuronal DNA methylome as a previously under-appreciated mechanism for activity-dependent epigenetic regulation in the adult nervous system.