TY - JOUR T1 - The formation of extinction memory requires the accumulation of N6-methyl-2’-deoxyadenosine in DNA JF - bioRxiv DO - 10.1101/059972 SP - 059972 AU - Xiang Li AU - Wei Wei AU - Quan Li AU - Christophe Magnan AU - Michael Emami AU - Luis Wearick da Silva AU - Thiago W. Viola AU - Paul Marshall AU - Rodrigo Grassi-Oliveira AU - Sarah Nainar AU - Cathrine Broberg Vågbø AU - Magnar Bjørås AU - Pierre F. Baldi AU - Robert C. Spitale AU - Timothy William Bredy Y1 - 2016/01/01 UR - http://biorxiv.org/content/early/2016/06/20/059972.abstract N2 - We have discovered that the recently identified mammalian DNA modification N6-methyl-2-deoxyadenosine (m6dA) drives activity-induced gene expression in the adult brain and is associated with the formation of fear extinction memory in C57/Bl6 mice. In activated primary cortical neurons, m6dA accumulates within the P4 promoter of the gene encoding brain-derived neurotrophic factor (bdnf), which is associated with an active chromatin state, as well as the recruitment of the activating transcription factor Yin-Yang 1 and RNA polymerase II, thereby promoting bdnf exon IV mRNA expression. Lentiviral-mediated knockdown of a potential adenine methyltransferase, N6amt1, blocks the effect of neuronal activation on m6dA and its related chromatin and transcriptional machinery in vitro. These effects are recapitulated in the adult brain, where the extinction learning-induced N6amt1-mediated accumulation of m6dA in the infralimbic prefrontal cortex also enhances the expression of bdnf exon IV and is necessary for the formation of fear extinction memory. ER -