Neuronal activity modifies the DNA methylation landscape in the adult brain

Abstract

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.

Plasticity of DNA methylation in a nerve injury model of pain

“…22 An increasing number of reports have further proposed that the methylome-transcriptome relationship cannot be represented by a simple model when considering large, high quality datasets. 10,21,23,36,37 In these studies, positive and negative correlations between methylation alterations and transcriptome changes were found only for a minority of CpGs. It was also suggested that the relationship depends on the CpG-content of the promoter region.…”

“…To date, the only previous publication reporting genome-wide dynamic methylome alterations in the field of neurobiology is, to the best of our knowledge, the report by Guo et al 10 Guo et al studied CpGs in genic regions using mixed tissue from the mouse hippocampus after electrostimulation. Our study found, similarly to the observation by Guo et al, that methylome alteration in the adult nervous system can occur rapidly.…”

“…9 DNA methylation is seen in all regions of the genome and its different patterns demarcate the tissue specific "methylome." While organ differences-because they are stark and persistent-highlight the lifelong stability of the methylome, recent studies in the CNS have demonstrated dynamic modification of CpG sites in response to neural activity 10 akin to the remodeling of other chromatin marks, which can occur rapidly.…”

Epigenetic regulation of memory: implications in human cognitive disorders

“…Neuronal activation in mouse dentate granule neurons induces dynamic remodeling of genomic DNA methylation profiles, with methylation changes occurring largely outside of CpG islands in association with brain specific genes (27). Although the effect of these methylation changes on gene expression is not known, this work shows that DNA methylation is plastically regulated in response to neuronal activity.…”

“…DNA methylation has traditionally been viewed as a stable epigenetic mark, however, many recent studies have shown that DNA methylation is plastically regulated, especially in neurons (25)(26)(27). Neuronal activation in mouse dentate granule neurons induces dynamic remodeling of genomic DNA methylation profiles, with methylation changes occurring largely outside of CpG islands in association with brain specific genes (27).…”