The establishment of synaptic plasticity and long-term memory requires lasting cellular and molecular modifications that, as a whole, must endure despite the rapid turnover of their constituent parts. Such a molecular feat must be mediated by a stable, self-perpetuating, cellular information storage mechanism. DNA methylation, being the archetypal cellular information storage mechanism, has been heavily implicated as being necessary for stable activity-dependent transcriptional alterations within the CNS. This review details the foundational discoveries from both gene-targeted and whole-genome sequencing studies that have brought DNA methylation to our attention as a chief regulator of activity- and experience-dependent transcriptional alterations within the CNS. We present a hypothetical framework to resolve disparate experimental findings regarding distinct manipulations of DNA methylation and their effect on memory, taking into account the unique impact activity-dependent alterations in DNA methylation potentially have on both memory-promoting and memory-suppressing gene expression. And last, we discuss potential avenues for future inquiry into the role of DNA methylation during remote memory formation.
AbelTKandelE. 1998. Positive and negative regulatory mechanisms that mediate long-term memory storage. Brain Res Brain Res Rev26:360–78.
2.
AdamsJPSweattJD. 2002. Molecular psychology: roles for the ERK MAP kinase cascade in memory. Annu Rev Pharmacol. Toxicol42:135–63.
3.
BarretoGSchäferAMarholdJStachDSwaminathanSKHandaV, and others. 2007. Gadd45a promotes epigenetic gene activation by repair-mediated DNA demethylation. Nature445:671–5.
4.
BaubecTColomboDFWirbelauerCSchmidtJBurgerLKrebsAR, and others. 2015. Genomic profiling of DNA methyltransferases reveals a role for DNMT3B in genic methylation. Nature. Epub Jan21. doi:10.1038/nature14176.
5.
BhutaniNBradyJJDamianMSaccoACorbelSYBlauHM. 2010. Reprogramming towards pluripotency requires AID-dependent DNA demethylation. Nature463:1042–7.
6.
BirdA. 2002. DNA methylation patterns and epigenetic memory. Genes Dev. 16:6–21.
7.
BlissTVCollingridgeGL. 1993. A synaptic model of memory: long-term potentiation in the hippocampus. Nature361:31–9.
8.
CrickF. 1984. Memory and molecular turnover. Nature312:101.
9.
DashPKHebertAERunyanJD. 2004. A unified theory for systems and cellular memory consolidation. Brain Res. Brain Res. Rev. 45:30–7.
10.
DayJJKennedyAJSweattJD. 2015. DNA methylation and its implications and accessibility for neuropsychiatric therapeutics. Annu Rev Pharmacol Toxicol55:591–611.
11.
DayJJSweattJD. 2010. DNA methylation and memory formation. Nat Neurosci13:1319–23.
12.
DeatonAMBirdA. 2011. CpG islands and the regulation of transcription. Genes Dev25:1010–22.
13.
FengJZhouYCampbellSLLeTLiESweattJD, and others. 2010. Dnmt1 and Dnmt3a maintain DNA methylation and regulate synaptic function in adult forebrain neurons. Nat Neurosci13:423–30.
14.
FranklandPWBontempiBTaltonLEKaczmarekLSilvaAJ. 2004. The involvement of the anterior cingulate cortex in remote contextual fear memory. Science304:881–3.
15.
GenouxDHaditschUKnoblochMMichalonAStormDMansuyIM. 2002. Protein phosphatase 1 is a molecular constraint on learning and memory. Nature418:970–5.
16.
GuoJUMaDKMoHBallMPJangM-HBonaguidiMA, and others. 2011a. Neuronal activity modifies the DNA methylation landscape in the adult brain. Nat Neurosci14:1345–51.
17.
GuoJUSuYShinJHShinJLiHXieB, and others. 2014. Distribution, recognition and regulation of non-CpG methylation in the adult mammalian brain. Nat Neurosci17:215–22.
18.
GuoJUSuYZhongCMingG-LSongH. 2011b. Hydroxylation of 5-methylcytosine by TET1 promotes active DNA demethylation in the adult brain. Cell145:423–34.
19.
HeY-FLiB-ZLiZLiuPWangYTangQ, and others. 2011. Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA. Science333:1303–7.
20.
HermannAGoyalRJeltschA. 2004. The Dnmt1 DNA-(cytosine-C5)-methyltransferase methylates DNA processively with high preference for hemimethylated target sites. J Biol Chem279:48350–9.
21.
HollidayR. 1999. Is there an epigenetic component in long-term memory?J Theor Biol200:339–41.
22.
ItoSD’AlessioACTaranovaOVHongKSowersLCZhangY. 2010. Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification. Nature466:1129–33.
23.
JinS-GGuoCPfeiferGP. 2008. GADD45A does not promote DNA demethylation. PLoS Genet4:e1000013.
24.
KaasGAZhongCEasonDERossDLVachhaniRVMingG-L, and others. 2013. TET1 controls CNS 5-methylcytosine hydroxylation, active DNA demethylation, gene transcription, and memory formation. Neuron79:1086–93.
25.
KandelER. 2001. The molecular biology of memory storage: a dialogue between genes and synapses. Science294:1030–8.
26.
KriaucionisSHeintzN. 2009. The nuclear DNA base 5-hydroxymethylcytosine is present in Purkinje neurons and the brain. Science324:929–30.
27.
LeachPTPoplawskiSGKenneyJWHoffmanBLiebermannDAAbelT, and others. 2012. Gadd45b knockout mice exhibit selective deficits in hippocampus-dependent long-term memory. Learn. Mem. 19:319–24.
28.
LeeH-KTakamiyaKHanJ-SManHKimC-HRumbaughG, and others. 2003. Phosphorylation of the AMPA receptor GluR1 subunit is required for synaptic plasticity and retention of spatial memory. Cell112:631–43.
29.
LevensonJM. 2006. Evidence that DNA (cytosine-5) methyltransferase regulates synaptic plasticity in the hippocampus. J Biol Chem281:15763–73.
30.
LevensonJMO’RiordanKJBrownKDTrinhMAMolfeseDLSweattJD. 2004. Regulation of histone acetylation during memory formation in the hippocampus. J Biol Chem279:40545–59.
31.
LevensonJMQiuSWeeberEJ. 2008. The role of reelin in adult synaptic function and the genetic and epigenetic regulation of the reelin gene. Biochim Biophys Acta1779:422–31.
32.
LismanJE. 1985. A mechanism for memory storage insensitive to molecular turnover: a bistable autophosphorylating kinase. Proc Natl Acad Sci U S A82:3055–7.
33.
ListerRMukamelEANeryJRUrichMPuddifootCAJohnsonND, and others. 2013. Global epigenomic reconfiguration during mammalian brain development. Science341:1237905.
34.
LubinFDRothTLSweattJD. 2008. Epigenetic regulation of BDNF gene transcription in the consolidation of fear memory. J Neurosci28:10576–86.
35.
MaDKJangMHGuoJUKitabatakeYChangMLPow-anpongkulN, and others. 2009. Neuronal activity-induced Gadd45b promotes epigenetic DNA demethylation and adult neurogenesis. Science323:1074–7.
36.
MartinowichKHattoriDWuHFouseSHeFHuY, and others. 2003. DNA methylation–related chromatin remodeling in activity-dependent BDNF gene regulation. Science302:890–3.
37.
MillerCAGavinCFWhiteJAParrishRRHonasogeAYanceyCR, and others. 2010. Cortical DNA methylation maintains remote memory. Nat Neurosci13:664–6.
38.
MillerCASweattJD. 2007. Covalent modification of DNA regulates memory formation. Neuron53:857–69.
39.
MirandaTBJonesPA. 2007. DNA methylation: the nuts and bolts of repression. J Cell Physiol213:384–90.
40.
NanXNgHHJohnsonCALahertyCDTurnerBMEisenmanRN, and others. 1998. Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature393:386–9.
41.
NgHHBirdA. 1999. DNA methylation and chromatin modification. Curr Opin Genet Dev9:158–63.
42.
OkanoMBellDWHaberDALiE. 1999. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell99:247–57.
43.
OkanoMXieSLiE. 1998. Cloning and characterization of a family of novel mammalian DNA (cytosine-5) methyltransferases. Nat Genet19:219–20.
44.
PennerMRRothTLChawlaMKHoangLTRothEDLubinFD, and others. 2011. Age-related changes in Arc transcription and DNA methylation within the hippocampus. Neurobiol Aging32:2198–210.
45.
PittengerCKandelE. 1998. A genetic switch for long-term memory. C R Acad Sci II321:91–6.
46.
PoppCDeanWFengSCokusSJAndrewsSPellegriniM, and others. 2010. Genome-wide erasure of DNA methylation in mouse primordial germ cells is affected by AID deficiency. Nature463:1101–5.
47.
RobersonEDSweattJD. 2001. Memory-forming chemical reactions. Rev Neurosci12:41–50.
48.
RudenkoADawlatyMMSeoJChengAWMengJLeT, and others. 2013. Tet1 is critical for neuronal activity-regulated gene expression and memory extinction. Neuron79:1109–22.
49.
SmithZDMeissnerA. 2013. DNA methylation: roles in mammalian development. Nat Rev Genet14:204–20.
50.
SultanFADayJJ. 2011. Epigenetic mechanisms in memory and synaptic function. Epigenomics3:157–81.
51.
SultanFAWangJTrontJLiebermannDASweattJD. 2012. Genetic deletion of Gadd45b, a regulator of active DNA demethylation, enhances long-term memory and synaptic plasticity. J Neurosci32:17059–66.
52.
SuzukiMMBirdA. 2008. DNA methylation landscapes: provocative insights from epigenomics. Nat Rev Genet9:465–76.
53.
SweattJD. 2013. The emerging field of neuroepigenetics. Neuron80:624–32.
54.
TahilianiMKohKPShenYPastorWABandukwalaHBrudnoY, and others. 2009. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science324:930–5.
55.
VarleyKEGertzJBowlingKMParkerSLReddyTEPauli-BehnF, and others. 2013. Dynamic DNA methylation across diverse human cell lines and tissues. Genome Res. 23:555–67.
56.
WeeberEJBeffertUJonesCChristianJMForsterESweattJD, and others. 2002. Reelin and ApoE receptors cooperate to enhance hippocampal synaptic plasticity and learning. J Biol Chem277:39944–52.
57.
WestAEChenWGDalvaMBDolmetschREKornhauserJMShaywitzAJ, and others. 2001. Calcium regulation of neuronal gene expression. Proc Natl Acad Sci U S A98:11024–31.
58.
WiltgenBJBrownRAMTaltonLESilvaAJ. 2004. New circuits for old memories: the role of the neocortex in consolidation. Neuron44:101–8.
59.
WuHZhangY. 2014. Reversing DNA methylation: mechanisms, genomics, and biological functions. Cell156:45–68.
60.
WuSCZhangY. 2010. Active DNA demethylation: many roads lead to Rome. Nat Rev Mol Cell Biol11:607–20.
61.
XieWBarrCLKimAYueFLeeAYEubanksJ, and others. 2012. Base-resolution analyses of sequence and parent-of-origin dependent DNA methylation in the mouse genome. Cell148:816–31.
