The formation of fear extinction memory requires the accumulation of N6-methyl-2’-deoxyadenosine in DNA

We have discovered that the DNA modification N6-methyl-2’-deoxyadenosine (m6dA) is dynamically regulated in post-mitotic neurons and accumulates genome-wide in the adult brain of C57BL6/J mice in response to fear extinction learning. The deposition of m6dA drives activity-induced gene expression and is necessary for the formation of fear extinction memory. In stimulated primary cortical neurons in vitro, m6dA accumulates within the P4 promoter of the gene encoding brain-derived neurotrophic factor (bdnf) and creates an active chromatin state resulting in the recruitment of the activating transcription factor Yin-Yang 1 and RNA polymerase II, which lead to increase bdnf exon IV mRNA expression. The effects are mediated by the activity of a putative adenine methyltransferase (N6amt1), the knockdown of which prevents m6dA deposition and related recruitment of chromatin and transcriptional machinery at the GATC site within bdnf exon IV promoter region. In the adult infralimbic prefrontal cortex, N6amt1-mediated accumulation of m6dA promotes the expression of bdnf exon IV, which is required for the formation of fear extinction memory. We propose a model in which the experience-dependent accumulation of m6dA creates an epigenetic state that is permissive for gene activation, and which plays a key role in the expression of genes associated with the formation of extinction memory. These findings dramatically expand the scope of DNA modification and its adaptive role in the regulation of experience-dependent gene expression in the adult brain.