2. Academic Validation
  3. The DNA modification N6-methyl-2'-deoxyadenosine (m6dA) drives activity-induced gene expression and is required for fear extinction

The DNA modification N6-methyl-2'-deoxyadenosine (m6dA) drives activity-induced gene expression and is required for fear extinction

  • Nat Neurosci. 2019 Apr;22(4):534-544. doi: 10.1038/s41593-019-0339-x.
Xiang Li # 1,  Qiongyi Zhao # 2,  Wei Wei 2,  Quan Lin 3,  Christophe Magnan 4,  Michael R Emami 5 6,  Luis E Wearick-Silva 7,  Thiago W Viola 7,  Paul R Marshall 2,  Jiayu Yin 2,  Sachithrani U Madugalle 2,  Ziqi Wang 2,  Sarah Nainar 8,  Cathrine Broberg Vågbø 9,  Laura J Leighton 2,  Esmi L Zajaczkowski 2,  Ke Ke 8,  Rodrigo Grassi-Oliveira 7,  Magnar Bjørås 9,  Pierre F Baldi 4,  Robert C Spitale 8,  Timothy W Bredy 10
Affiliations

Affiliations

  • 1 Cognitive Neuroepigenetics Laboratory, Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia. [email protected].
  • 2 Cognitive Neuroepigenetics Laboratory, Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia.
  • 3 Intellectual Development and Disabilities Research Center, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA.
  • 4 Department of Computer Science and Institute for Genomics and Bioinformatics, University of California Irvine, Irvine, CA, USA.
  • 5 Department of Neurobiology and Behavior and Center for the Neurobiology of Learning and Memory, University of California Irvine, Irvine, CA, USA.
  • 6 Molecular Biology Institute, University of California Los Angeles, Los Angeles, CA, USA.
  • 7 Brain Institute, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, Brazil.
  • 8 Department of Pharmaceutical Sciences, University of California Irvine, Irvine, CA, USA.
  • 9 Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
  • 10 Cognitive Neuroepigenetics Laboratory, Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia. [email protected].
  • # Contributed equally.
PMID: 30778148 DOI: 10.1038/s41593-019-0339-x
Abstract

DNA modification is known to regulate experience-dependent gene expression. However, beyond cytosine methylation and its oxidated derivatives, very little is known about the functional importance of chemical modifications on Other nucleobases in the brain. Here we report that in adult mice trained in fear extinction, the DNA modification N6-methyl-2'-deoxyadenosine (m6dA) accumulates along promoters and coding sequences in activated prefrontal cortical neurons. The deposition of m6dA is associated with increased genome-wide occupancy of the mammalian m6dA methyltransferase, N6amt1, and this correlates with extinction-induced gene expression. The accumulation of m6dA is associated with transcriptional activation at the brain-derived neurotrophic factor (Bdnf) P4 promoter, which is required for Bdnf exon IV messenger RNA 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 an epigenetic mechanism associated with activity-induced gene expression and the formation of fear extinction memory.

Figures
Products