Early life adversity is associated with long-tem impacts on behaviour and physical and mental health. The mechanisms mediating the impact of early life environment on the phenotype are proposed to involve a change in the state of deoxyribonucleic acid (DNA) methylation and, as a consequence, in the stable programming of gene expression. Recent studies suggest that the changes in DNA methylation affect broad genomic regions, as well as peripheral tissues in addition to brain regions. Although the data are still scarce, it points to the possibility that DNA methylation is a mechanism of genome adaptation to signals from early life social environment. This modulation of the DNA methylation pattern is proposed to result in long-term impact on the phenotype that could become maladaptive under certain contexts later in life. This model has implications on our understanding of behavioural and mental health pathologies, as well as their diagnosis and therapeutics.
Van SpeybroeckL.From epigenesis to epigenetics: The case of C H Waddington. Ann N Y Acad Sci. 2002;981:61–81.
2.
StrahlBDAllisCD. The language of covalent histone modifications. Nature. 2000;403:41–45.
3.
JenuweinTAllisCD. Translating the histone code. Science. 2001;293:1074–1080.
4.
BergmannALaneME. HIDden targets of microRNAs for growth control. Trends Biochem Sci. 2003;28:461–463.
5.
RazinARiggsAD. DNA methylation and gene function. Science. 1980;210:604–610.
6.
RazinASzyfM.DNA methylation patterns. Formation and function. Biochim Biophys Acta. 1984;782:331–342.
7.
JinSGWuXLiAX, Genomic mapping of 5-hydroxymethylcytosine in the human brain. Nucleic Acids Res. 2011;39:5015–5024.
8.
KriaucionisSHeintzN.The nuclear DNA base 5-hydroxymethylcytosine is present in Purkinje neurons and the brain. Science. 2009;324:929–930.
9.
ItoSD'AlessioACTaranovaOV, Role of TET proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification. Nature. 2010;466:1129–1133.
10.
WilliamsKChristensenJPedersenMT, TET1 and hydroxymethylcytosine in transcription and DNA methylation fidelity. Nature. 2011;473:343–348.
11.
IqbalKJinSGPfeiferGP, Reprogramming of the paternal genome upon fertilization involves genome-wide oxidation of 5-methylcytosine. Proc Natl Acad Sci U S A. 2011;108:3642–3647.
12.
SuraniMAHajkovaP.Epigenetic reprogramming of mouse germ cells toward totipotency. Cold Spring Harb Symp Quant Biol. 2010;75:211–218.
13.
AdamsRL. Eukaryotic DNA methyltransferases—structure and function. Bioessays. 1995;17:139–145.
14.
AdamsRLBurdonRH. DNA methylation in eukaryotes. CRC Crit Rev Biochem. 1982;13:349–384.
15.
AdamsRLDavisTFultonJ, Eukaryotic DNA methylase—properties and action on native DNA and chromatin. Curr Top Microbiol Immunol. 1984;108:142–156.
16.
ListerRPelizzolaMDowenRH, Human DNA methylomes at base resolution show widespread epigenomic differences. Nature. 2009;462:315–322.
17.
CombMGoodmanHM. CpG methylation inhibits proenkephalin gene expression and binding of the transcription factor AP-2. Nucleic Acids Res. 1990;18:3975–3982.
18.
InamdarNMEhrlichKCEhrlichM.CpG methylation inhibits binding of several sequence-specific DNA- binding proteins from pea, wheat, soybean and cauliflower. Plant Mol Biol. 1991;17:111–123.
19.
NanXCampoyFJBirdA.MeCP2 is a transcriptional repressor with abundant binding sites in genomic chromatin. Cell. 1997;88:471–481.
20.
PowerCAthertonKStrachanDP, Life-course influences on health in British adults: Effects of socio-economic position in childhood and adulthood. Int J Epidemiol. 2007;36:532–539.
21.
PowerCJeffriesBJManorO, The influence of birth weight and socioeconomic position on cognitive development: Does the early home and learning environment modify their effects?J Pediatr. 2006;148:54–61.
22.
FengJZhouYCampbellSL, DNMT1 and DNMT3a maintain DNA methylation and regulate synaptic function in adult forebrain neurons. Nat Neurosci. 2010;13:423–430.
23.
FengJChangHLiE, Dynamic expression of de novo DNA methyltransferases DNMT3a and DNMT3b in the central nervous system. J Neurosci Res. 2005;79:734–746.
24.
BhattacharyaSKRamchandaniSCervoniN, A mammalian protein with specific demethylase activity for mCpG DNA. Nature. 1999;397:579–583.
25.
RamchandaniSBhattacharyaSKCervoniN, DNA methylation is a reversible biological signal. Proc Natl Acad Sci U S A. 1999;96:6107–6112.
26.
HammSJustGLacosteN, On the mechanism of demethylation of 5-methylcytosine in DNA. Bioorg Med Chem Lett. 2008;18:1046–1049.
27.
OswaldJEngemannSLaneN, Active demethylation of the paternal genome in the mouse zygote. Curr Biol. 2000;10:475–478.
28.
LucarelliMFusoAStromR, The dynamics of myogenin site-specific demethylation is strongly correlated with its expression and with muscle differentiation. J Biol Chem. 2001;276:7500–7506.
29.
BruniquelDSchwartzRH. Selective, stable demethylation of the interleukin-2 gene enhances transcription by an active process. Nat Immunol. 2003;4:235–240.
30.
WilksASeldranMJostJP. An estrogen-dependent demethylation at the 5′ end of the chicken vitellogenin gene is independent of DNA synthesis. Nucleic Acids Res. 1984;12:1163–1177.
31.
SzyfMThebergeJBozovicV.Ras induces a general DNA demethylation activity in mouse embryonal P19 cells. J Biol Chem. 1995;270:12690–12696.
32.
MastronardiFGNoorAWoodDD, Peptidyl argininedeiminase 2 CpG island in multiple sclerosis white matter is hypomethylated. J Neurosci Res. 2007;85:2006–2016.
33.
DongENelsonMGraysonDR, Clozapine and sulpiride but not haloperidol or olanzapine activate brain DNA demethylation. Proc Natl Acad Sci U S A. 2008;105:13614–13619.
34.
FusoANicoliaVCavallaroRA, DNA methylase and demethylase activities are modulated by one-carbon metabolism in Alzheimer's disease models. J Nutr Biochem. 2011;22:242–251.
35.
WeaverICCervoniNChampagneFA, Epigenetic programming by maternal behavior. Nat Neurosci. 2004;7:847–854.
36.
LevensonJMRothTLLubinFD, Evidence that DNA (cytosine-5) methyltransferase regulates synaptic plasticity in the hippocampus. J Biol Chem. 2006;281:15763–15773.
37.
MillerCASweattJD. Covalent modification of DNA regulates memory formation. Neuron. 2007;53:857–869.
38.
FengJFanG.The role of DNA methylation in the central nervous system and neuropsychiatric disorders. Int Rev Neurobiol. 2009;89:67–84.
39.
JostJP. Nuclear extracts of chicken embryos promote an active demethylation of DNA by excision repair of 5-methyldeoxycytidine. Proc Natl Acad Sci U S A. 1993;90:4684–4688.
40.
RazinASzyfMKafriT, Replacement of 5-methylcytosine by cytosine: A possible mechanism for transient DNA demethylation during differentiation. Proc Natl Acad Sci U S A. 1986;83:2827–2831.
41.
KangaspeskaSStrideBMetivierR, Transient cyclical methylation of promoter DNA. Nature. 2008;452:112–115.
42.
ShenJCRideoutWMDJonesPA. High frequency mutagenesis by a DNA methyltransferase. Cell. 1992;71:1073–1080.
43.
ZinggJMShenJCJonesPA. Enzyme-mediated cytosine deamination by the bacterial methyltransferase MMspI. Biochem J. 1998;332:223–230.
44.
BarretoGSchaferAMarholdJ, GADD45A promotes epigenetic gene activation by repair-mediated DNA demethylation. Nature. 2007;445:671–675.
45.
JinSGGuoCPfeiferGP. GADD45A does not promote DNA demethylation. PLoS Genet. 2008;4:e1000013.
46.
MaDKJangMHGuoJU, Neuronal activity-induced GADD45B promotes epigenetic DNA demethylation and adult neurogenesis. Science. 2009;323:1074–1077.
47.
RaiKHugginsIJJamesSR, DNA demethylation in zebrafish involves the coupling of a deaminase, a glycosylase, and GADD45. Cell. 2008;135:1201–1212.
48.
PoppCDeanWFengS, Genome-wide erasure of DNA methylation in mouse primordial germ cells is affected by AID deficiency. Nature. 2010;463;1101–1105.
49.
GuoJUSuYZhongC, Hydroxylation of 5-methylcytosine by TET1 promotes active DNA demethylation in the adult brain. Cell. 2011;145:423–434.
50.
RuppenthalGCArlingGLHarlowHF, A 10-year perspective of motherless-mother monkey behavior. J Abnorm Psychol. 1976;85:341–349.
51.
SuomiSJCollinsMLHarlowHF, Effects of maternal and peer separations on young monkeys. J Child Psychol Psychiatry. 1976;17:101–112.
52.
LiuDDiorioJTannenbaumB, Maternal care, hippocampal glucocorticoid receptors, and hypothalamic–pituitary–adrenal responses to stress. Science. 1997;277:1659–1662.
53.
FrancisDDiorioJLiuD, Nongenomic transmission across generations of maternal behavior and stress responses in the rat. Science. 1999;286:1155–1158.
54.
RothTLLubinFDFunkAJ, Lasting epigenetic influence of early-life adversity on the BDNF gene. Biol Psychiatry. 2009;65:760–769.
55.
MurgatroydCPatchevAVWuY, Dynamic DNA methylation programs persistent adverse effects of early-life stress. Nat Neurosci. 2009;12:1559–1566.
56.
McGowanPOSasakiAHuangTC, Promoter-wide hypermethylation of the ribosomal RNA gene promoter in the suicide brain. PLoS ONE. 2008;3:e2085.
57.
McGowanPOSasakiAD'AlessioAC, Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nat Neurosci. 2009;12:342–348.
58.
OberlanderTFWeinbergJPapsdorfM, Prenatal exposure to maternal depression, neonatal methylation of human glucocorticoid receptor gene (NR3C1) and infant cortisol stress responses. Epigenetics. 2008;3:97–106.
59.
BergmanASiegalML. Evolutionary capacitance as a general feature of complex gene networks. Nature. 2003;424:549–552.
60.
ColvisCMPollockJDGoodmanRH, Epigenetic mechanisms and gene networks in the nervous system. J Neurosci. 2005;25:10379–10389.
61.
FrankMEbertMShanW, Differential expression of individual gamma-protocadherins during mouse brain development. Mol Cell Neurosci. 2005;29:603–616.
62.
GarrettAMWeinerJA. Control of CNS synapse development by {gamma}-protocadherin-mediated astrocyte-neuron contact. J Neurosci. 2009;29:11723–11731.
63.
McGowanPOSudermanMSasakiA, Broad epigenetic signature of maternal care in the brain of adult rats. PLoS One. 2011;6:e14739.
64.
SudermanMMcGowanPOSasakiA, Conserved epigenetic sensitivity to early life experience in the rat and human hippocampus. Proc Natl Acad Sci U S A. 2012;109(Suppl 2):17266–17272.
65.
ProvencalNSudermanMJGuilleminC, The signature of maternal rearing in the methylome in rhesus macaque prefrontal cortex and T cells. J Neurosci. 2012;32:15626–15642.
66.
BorgholNSudermanMMcArdleW, Associations with early-life socio-economic position in adult DNA methylation. Int J Epidemiol. 2012;41:62–74.
MehtaDKlengelTConneelyKN, Childhood maltreatment is associated with distinct genomic and epigenetic profiles in posttraumatic stress disorder. Proc Natl Acad Sci U S A. 2013;110:8302–8307.
69.
WeaverICChampagneFABrownSE, Reversal of maternal programming of stress responses in adult offspring through methyl supplementation: Altering epigenetic marking later in life. J Neurosci. 2005;25:11045–11054.
