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bioRxiv · 10.1101/059972

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

Xiang Li·Wei Wei·Quan Lin·Christophe Magnan·Michael Emami·Luis Eduardo Wearick-Silva·Thiago Viola·Paul Marshall·Rodrigo Grassi-Oliveira·Sarah Nainar·Cathrine Broberg Vagbo·Magnar Bjoras·Pierre Baldi·Robert Spitale·Timothy William Bredy
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Abstract

Here we report that the recently discovered mammalian DNA modification N6-methyl-2-deoxyadenosine (m6dA) is dynamically regulated in primary cortical neurons, and accumulates along promoters and coding sequences within the genome of activated prefrontal cortical neurons of adult C57/BI6 mice in response to fear extinction learning. The deposition of m6dA is generally associated with increased genome-wide occupancy of the mammalian m6dA methyltransferase, N6amt1, and this correlates with fear extinction learning-induced gene expression. Of particular relevance for fear extinction memory, the accumulation of m6dA is associated with an active chromatin state and the recruitment of transcriptional machinery to the brain-derived neurotrophic factor (Bdnf) P4 promoter, which is required for Bdnf exon IV mRNA expression and for the extinction of conditioned fear. These results expand the scope of DNA modifications in the adult brain and highlight changes in m6dA as a novel neuroepigenetic mechanism associated with activity-induced gene expression and the formation of fear extinction memory.

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Xiang Li, Wei Wei, Quan Lin, Christophe Magnan, Michael Emami, Luis Eduardo Wearick-Silva, Thiago Viola, Paul Marshall, Rodrigo Grassi-Oliveira, Sarah Nainar, Cathrine Broberg Vagbo, Magnar Bjoras, Pierre Baldi, Robert Spitale, Timothy William Bredy. 2016-06-21. The formation of extinction memory requires the accumulation of N6-methyl-2-deoxyadenosine in DNA. https://doi.org/10.1101/059972

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