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Cited by 71Epigenetics and DNA MethylationMemory and Neural MechanismsRNA modifications and cancer

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

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Li, Xiang, Zhao, Qiongyi, Wei, Wei, Lin, Quan, Magnan, Christophe, Emami, Michael R., Wearick-Silva, Luis E., Viola, Thiago W. +14 more·2019·Nature Neuroscience
DOI 10.1038/s41593-019-0339-xPMC PMC6462436
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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.

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  • Alterations in m6dA deposition are necessary for the formation of threat extinction memories within IL.

    “These findings suggest that alterations in m6dA deposition are necessary for the formation of threat extinction memories within IL [63].”

    From Prefrontal cortex, amygdala, and threat processing: implications for PTSD (2022) · cites this paper as [63]

  • Knockdown of N6amt1 within IL blocks changes to the m6dA mark at the Bdnf promoter in vivo and impairs threat extinction retention.

    “Recently, Li et al. [63], have shown that knockdown of N6amt1, the gene responsible for m6dA deposition, within IL, blocks changes to the m6dA mark at the Bdnf promoter in vivo and impairs threat extinction retention.”

    From Prefrontal cortex, amygdala, and threat processing: implications for PTSD (2022) · cites this paper as [63]

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Authors
Li, X., Zhao, Q., Wei, W., Lin, Q., Magnan, C., Emami, M. R., Wearick-Silva, L. E., Viola, T. W., Marshall, P. R., Yin, J., Madugalle, S. U., Wang, Z., Nainar, S., Vågbø, C. B., Leighton, L. J., Zajaczkowski, E. L., Ke, K., Grassi-Oliveira, R., Bjørås, M., Baldi, P. F., Spitale, R. C., & Bredy, T. W.
Affiliations
  • The University of Queensland (AU)
  • University of California, Los Angeles (US)
  • University of California, Irvine (US)
  • Instituto do Cérebro (BR)
  • Norwegian University of Science and Technology (NO)
Corresponding author
  • Li, Xiang
  • Bredy, Timothy W.
ORCID
Venue
Nature Neuroscience
Publisher
Springer Science and Business Media LLC
Published
2019-02-18
Volume
22
Issue
4
Pages
534-544
ISSN
  • 1097-6256 (ISSN-L)
  • 1546-1726
DOI
10.1038/s41593-019-0339-x
PMC
PMC6462436
OpenAlex
W2915235506
Cited by
71
References
1
Citations by year
2026: 3 · 2025: 12 · 2024: 4 · 2023: 11 · 2022: 9 · 2021: 16 · 2020: 10 · 2019: 5
FWCI
3.31
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Neuroscience (publishedVersion)
  • PubMed (publishedVersion)
  • LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (publishedVersion, other-oa)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
  • PUCRS Repository (Pontifical Catholic University of Rio Grande do Sul) (submittedVersion, cc-by-nc-sa)
Funders
  • National Institute of Mental Health (R01MH109588, R01MH105398)
  • National Institute of General Medical Sciences (R01GM123558)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA modifications and cancer
Keywords
DNA modification, fear extinction, activity-dependent gene expression, prefrontal cortex, epigenetic regulation, conditioned fear memory, brain-derived neurotrophic factor, promoter binding
MeSH terms
Animals, Deoxyadenosines, Extinction, Psychological, Fear, Gene Expression Regulation, Male, Mice, Inbred C57BL, Neurons, RNA, Messenger, Prefrontal Cortex, DNA Methylation, Brain-Derived Neurotrophic Factor, Epigenesis, Genetic

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