PMID- 30778148 OWN - NLM STAT- MEDLINE DCOM- 20190521 LR - 20220416 IS - 1546-1726 (Electronic) IS - 1097-6256 (Print) IS - 1097-6256 (Linking) VI - 22 IP - 4 DP - 2019 Apr TI - The DNA modification N6-methyl-2'-deoxyadenosine (m6dA) drives activity-induced gene expression and is required for fear extinction. PG - 534-544 LID - 10.1038/s41593-019-0339-x [doi] AB - 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. FAU - Li, Xiang AU - Li X AUID- ORCID: 0000-0001-9646-670X AD - Cognitive Neuroepigenetics Laboratory, Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia. x.li12@uq.edu.au. FAU - Zhao, Qiongyi AU - Zhao Q AUID- ORCID: 0000-0002-6341-0416 AD - Cognitive Neuroepigenetics Laboratory, Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia. FAU - Wei, Wei AU - Wei W AUID- ORCID: 0000-0001-5768-7729 AD - Cognitive Neuroepigenetics Laboratory, Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia. FAU - Lin, Quan AU - Lin Q AD - Intellectual Development and Disabilities Research Center, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA. FAU - Magnan, Christophe AU - Magnan C AD - Department of Computer Science and Institute for Genomics and Bioinformatics, University of California Irvine, Irvine, CA, USA. FAU - Emami, Michael R AU - Emami MR AD - Department of Neurobiology and Behavior and Center for the Neurobiology of Learning and Memory, University of California Irvine, Irvine, CA, USA. AD - Molecular Biology Institute, University of California Los Angeles, Los Angeles, CA, USA. FAU - Wearick-Silva, Luis E AU - Wearick-Silva LE AD - Brain Institute, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, Brazil. FAU - Viola, Thiago W AU - Viola TW AD - Brain Institute, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, Brazil. FAU - Marshall, Paul R AU - Marshall PR AD - Cognitive Neuroepigenetics Laboratory, Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia. FAU - Yin, Jiayu AU - Yin J AD - Cognitive Neuroepigenetics Laboratory, Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia. FAU - Madugalle, Sachithrani U AU - Madugalle SU AD - Cognitive Neuroepigenetics Laboratory, Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia. FAU - Wang, Ziqi AU - Wang Z AD - Cognitive Neuroepigenetics Laboratory, Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia. FAU - Nainar, Sarah AU - Nainar S AD - Department of Pharmaceutical Sciences, University of California Irvine, Irvine, CA, USA. FAU - Vagbo, Cathrine Broberg AU - Vagbo CB AD - Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway. FAU - Leighton, Laura J AU - Leighton LJ AD - Cognitive Neuroepigenetics Laboratory, Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia. FAU - Zajaczkowski, Esmi L AU - Zajaczkowski EL AD - Cognitive Neuroepigenetics Laboratory, Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia. FAU - Ke, Ke AU - Ke K AD - Department of Pharmaceutical Sciences, University of California Irvine, Irvine, CA, USA. FAU - Grassi-Oliveira, Rodrigo AU - Grassi-Oliveira R AUID- ORCID: 0000-0001-9911-5921 AD - Brain Institute, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, Brazil. FAU - Bjoras, Magnar AU - Bjoras M AD - Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway. FAU - Baldi, Pierre F AU - Baldi PF AD - Department of Computer Science and Institute for Genomics and Bioinformatics, University of California Irvine, Irvine, CA, USA. FAU - Spitale, Robert C AU - Spitale RC AD - Department of Pharmaceutical Sciences, University of California Irvine, Irvine, CA, USA. FAU - Bredy, Timothy W AU - Bredy TW AUID- ORCID: 0000-0003-3280-126X AD - Cognitive Neuroepigenetics Laboratory, Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia. t.bredy@uq.edu.au. LA - eng GR - R01 GM123558/GM/NIGMS NIH HHS/United States GR - R01 MH105398/MH/NIMH NIH HHS/United States GR - R01 MH109588/MH/NIMH NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20190218 PL - United States TA - Nat Neurosci JT - Nature neuroscience JID - 9809671 RN - 0 (Bdnf protein, mouse) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Deoxyadenosines) RN - 0 (RNA, Messenger) RN - P582C98ULC (2'-deoxyadenosine) SB - IM MH - Animals MH - Brain-Derived Neurotrophic Factor/metabolism MH - *DNA Methylation MH - Deoxyadenosines/*metabolism MH - Epigenesis, Genetic MH - Extinction, Psychological/*physiology MH - *Fear MH - *Gene Expression Regulation MH - Male MH - Mice, Inbred C57BL MH - Neurons/*metabolism MH - Prefrontal Cortex/*metabolism MH - RNA, Messenger/metabolism PMC - PMC6462436 MID - NIHMS1518486 COIS- Competing Interests: The authors declare no competing financial interests. EDAT- 2019/02/20 06:00 MHDA- 2019/05/22 06:00 PMCR- 2019/08/18 CRDT- 2019/02/20 06:00 PHST- 2018/07/24 00:00 [received] PHST- 2019/01/10 00:00 [accepted] PHST- 2019/02/20 06:00 [pubmed] PHST- 2019/05/22 06:00 [medline] PHST- 2019/02/20 06:00 [entrez] PHST- 2019/08/18 00:00 [pmc-release] AID - 10.1038/s41593-019-0339-x [pii] AID - 10.1038/s41593-019-0339-x [doi] PST - ppublish SO - Nat Neurosci. 2019 Apr;22(4):534-544. doi: 10.1038/s41593-019-0339-x. Epub 2019 Feb 18.