Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2014 May 30.
Published in final edited form as: Child Dev. 2012 Aug 10;84(1):49–57. doi: 10.1111/j.1467-8624.2012.01793.x

DNA Methylation: A Mechanism for Embedding Early Life Experiences in the Genome

Moshe Szyf 1, Johanna Bick 2
PMCID: PMC4039199  NIHMSID: NIHMS373301  PMID: 22880724

Abstract

Although epidemiological data provide evidence that early life experience plays a critical role in human development, the mechanism of how this works remains in question. Recent data from human and animal literature suggest that epigenetic changes, such as DNA methylation, are not only involved in cellular differentiation, but also in the modulation of genome function in response to early life experience affecting gene function and the phenotype. Such modulations may serve as a mechanism for life-long genome adaptation. These changes seem to be widely distributed across the genome and to involve central and peripheral systems. Examining the environmental circumstances associated with the onset and reversal of DNA methylation will be critical for understanding risk and resiliency.

Keywords: DNA methylation, epigenetics, early experience

Epidemiological data point to the importance of early life experience in setting life-long health and mental health trajectories in humans (Power, Jefferis, Manor, & Hertzman, 2006). Recent evidence suggests that early life is an especially sensitive period in which environmental signals affect the structure and function of the genome. These epigenetic processes seem to be ideal mechanisms for how early life environments may influence lifelong trajectories of health and wellness. The current review provides an overview of a specific epigenetic process, DNA methylation, and presents evidence from human and animal research supporting links between early life stress, changes in DNA methylation, and phenotypic variation.

Epigenetics

The modern synthesis of Mendelian genetics and Darwinian evolution culminated with the discovery of the structure of DNA and eventually in the sequencing of the human genome. Until recently, the common belief has been that inter-individual differences in sequence (i.e., structural differences in the strings of A, C, G, and T nucleotides) would account for the differences in phenotype, susceptibility to disease, and behavioral differences between individuals. Genome-wide associations have indeed identified rare alleles that associate with differences in behavior and disease susceptibility (Manolio et al., 2009). However, the structural variations in sequence have accounted for only a small fraction of human phenotypic variation and human disease (Manolio et al., 2009). There is some evidence that these inter-individual differences in sequences (i.e., allelic variations) do not operate alone, but interact with environmental conditions to predict phenotypic outcomes (Caspi et al., 2003). Although the interaction between genotypes and environmental conditions has been an exciting possibility, there is significant controversy regarding the replicability of these original findings (Risch et al., 2009).

The function of DNA not only depends on the variation in sequence, but also on the manner by which it is stably programmed. The idea that DNA function could be stably diversified without changing the sequence comes from the study of cellular differentiation during embryonal development. The process that generates and organizes epigenetic patterns is both highly programmed and organized while also dynamic and responsive to the environment (Szyf, McGowan, & Meaney, 2008). This sensitivity of the epigenetic machinery to the environment can modify the transcriptome (i.e., what is transcribed from the genome) without modifying the genome itself; these transcriptome modifications, in turn, can have a long-term impact on somatic and mental health.

Whereas the transcriptional activity involving mRNA in response to environmental influences has been studied for decades (Schirmer, Fischer, Madureira, & Pillai, 2010), more recent research has examined the specific epigenetic mechanisms associated with genomic alterations resulting from environmental signals. These mechanisms involve chemical changes that affect the transcriptional (or functional) activity of the DNA, without altering the specific sequence of the DNA and include 1) chromatin structure and histone modification that gate the access of transcriptional machinery to genes (Jenuwein & Allis, 2001; Strahl & Allis, 2000), 2) non-coding RNA activities including microRNA that regulate gene expression through altering chromatin configuration, inhibition of translation, and degradation of RNA (Bergmann & Lane, 2003), and, 3) remarkably, the DNA molecule that itself bears epigenetic information encoded in the DNA methylation pattern (Fig. 1) (Razin & Riggs, 1980; Razin & Szyf, 1984). Recently, a specific modification of DNA methylation 5-hydroxymethylcytosine (involving an additional chemical change to the DNA methylation pattern) has been found to be particularly abundant in the brain early in embryogenesis (Jin, Wu, Li, & Pfeifer, 2011). This epigenetic process may also be important for further diversifying gene function (Williams et al., 2011). However, its specific role in controlling gene expression and its relationship with DNA methylation is still unknown. This review focuses on the third epigenetic process described above, in which information encoded in the DNA methylation patterns, whose accessibility profile changes in response to environmental signals, influences the transcriptional activity of DNA, and shapes phenotypic outcomes in the long term.

Figure 1.

Figure 1

Open in a new tab

The pattern of DNA methylation is sculpted during gestation. The DNA methylation pattern is sculpted during embryogenesis by enzymes that add methyl groups (de novo methyltransferases) such as DNMT3a or DNMT3b, enzyme that copies the DNA methylation pattern (maintenance DNMT1) and demethylases. Different patterns of methylation are generated in distinctive cell types creating a cell type identity.

The Process of DNA Methylation

DNA methylation refers to the process by which the DNA molecule is chemically altered through an addition of methyl groups to a specific nucleotide (cytosine) on the chain of the millions of base pairs of nucleotides that comprise DNA (Adams, 1995; Adams & Burdon, 1982; Adams et al., 1984). By adding information to the DNA molecule without changing the specific sequence of the gene, DNA methylation alters the transcriptional state of DNA, leading to changes in gene expression (Comb & Goodman, 1990; Inamdar, Ehrlich, & Ehrlich, 1991). Additionally, DNA methylation can lead to a recruitment of enzymes that modify the chromatin, or protein structure surrounding the DNA molecule, rendering it into an “inactive” state thereby silencing the gene; Fig. 2).

Figure 2.

Figure 2

Open in a new tab

DNA methylation in promoters silences gene expression by different mechanisms. The first mechanism involves interference with binding of transcription factors (top right). The second mechanism involves recruitment of chromatin modifying enzymes and formation of inactive chromatin (bottom right). (AC-histone acetylation; horizontal arrow-transcription; MeCP2 a methylCpG binding protein; HDAC histone deacetylase; SUV39 a histone methyltransferase; Sin3A a co-repressor; HPI a methylated histone binding protein).

Almost three decades ago, it was shown that patterns of DNA methylation vary across cell types (Fig. 1) (Razin & Szyf, 1984). DNA methylation is involved in the diversification of genome function during embryogenesis and cellular differentiation. For some time, it has been believed that once the DNA methylation patterns are generated during embryogenesis, they remain “fixed” throughout life. The biological properties related to the nucleotide sites and enzymes involved in DNA methylation seemed to imply a rigidity in DNA methylation patterns following birth (See Szyf et al., 2008, for a review of this topic). However, it has recently been considered that environmental signals might influence DNA methylation patterns outside of embryogenesis and cellular differentiation, by occurring after birth, especially during the early stages of the development (Szyf et al., 2008).

DNA Methylation as a Mechanism for Diversification of Genome Function in Response to Experience

Given that development related to emotional and behavioral maturation occurs largely after birth, the possibility that DNA methylation could potentially serve as a mechanism for the diversification of genome's functioning in response to external experiential environmental signals following birth has been examined. In recent years, new data point to models in which DNA methylation are dynamic and reflective of altered extra and intra-cellular signaling (Figure 3), constituting pathological or adaptive mechanisms that are responsive to environmental stimuli, and leading to changes in either gene silencing or activation (see Szyf et al., for a review of this topic). The literature refers to the emergence of new DNA methylation sites (i.e., de novo methylation) and the removal of DNA methylation (by demethylation) (Bhattacharya, Ramchandani, Cervoni, & Szyf, 1999; Detich, Bovenzi, & Szyf, 2003; Detich, Hamm, Just, Knox, & Szyf, 2003; Detich, Theberge, & Szyf, 2002; Ramchandani, Bhattacharya, Cervoni, & Szyf, 1999) (see Figure 3 for proposed biochemical mechanisms of DNA demethylation). However, it is important to note that the process by which DNA is demethylated is highly controversial (Ng, et al., 1999) and there is reluctance to accept the idea that DNA methylation is reversible (Wolffe, Jones, & Wade, 1999).

Figure 3.

Figure 3

Open in a new tab

The DNA methylation pattern is an equilibrium between DNA methylation and demethylation reactions. Several demethylase enzymatic activities were proposed; bona fide demethylation that releases the methyl moiety (MBD2) as well as a repair reaction that involves modification of the methyl group to 5-hydroxymethyl cytosine by TET1, deamination by AID, glycosylation by MBD4 or other glycosylases that is followed by excision and repair with base excision repair enzymes (BER) and insertion of an unmethylated cytosine.

DNA Methylation as a Genome Adaptation Mechanism

Recent efforts have examined the dynamics of DNA methylation patterns following birth. It has been proposed that these DNA methylation adaptations early in life are system-wide and that they involve multiple gene-circuitries (McGowan et al., 2011) (Fig. 4). The idea that the adaptations to early life adversity are system-wide has important implications for studying the DNA methylation changes that respond to adversity in living human populations. If indeed the response to social adversity is not limited to the brain then it should be possible to study, follow, and assess interventions in peripheral cells such as T cells.

Figure 4.

Figure 4

Open in a new tab

The dynamic relationship between DNA methylation pattern and the early environments. Chemical biosphere and social environments activate signaling pathways that target DNA methylation/demethylation enzymes to multiple targets in the genome in several tissues modulating the DNA methylation pattern. The modulation of the DNA methylation pattern in different tissues alters the phenotype. There is a bilateral relationship between the DNA methylation pattern and the environment. The DNA methylation matrix defines the relationship with the environment which in turn continues to modulate the DNA methylation pattern.

DNA Methylation Embedding Early Life Experiences in the Genome

Models of natural variation in maternal care in rodents have been used to demonstrate the profound impact of maternal care and “nurture” on a panel of phenotypes in the offspring that last into adulthood (Ruppenthal, Arling, Harlow, Sackett, & Suomi, 1976; Suomi, Collins, Harlow, & Ruppenthal, 1976). In the rat, the adult offspring of mothers that exhibit increased levels of pup licking and grooming over the first week of life show increased hippocampal glucocorticoid receptor (GR) expression, enhanced GR feedback sensitivity, decreased hypothalamic corticotrophin releasing factor (CRF) expression and more modest hypothalamus-pituitary-adrenal (HPA) stress responses compared to animals reared by mothers that exhibited lower levels of increased licking and grooming toward their offspring (Francis, Diorio, Liu, & Meaney, 1999; Liu et al., 1997). The GR/NR3C1 gene encoding the glucocorticoid receptor (GR exon 17 promoter) exhibits differences in DNA methylation and histone acetylation (involved in chromatin remodeling) in the hippocampus of the offspring of high and low licking and grooming mothers. Differences in DNA methylation in response to variations in maternal licking and grooming emerged early in life and remained stable into adulthood illustrating that epigenetic programming early in life could set up life-long behavioral trajectories (Weaver et al., 2004).

The basic concepts of this study were repeated more recently in several other models of early life social adversity. Exposure of infant rats to stressed caretakers that displayed abusive behavior produced persisting changes in methylation of brain-derived neurotropic factor (BDNF) gene promoter in the adult prefrontal cortex (Roth, Lubin, Funk, & Sweatt, 2009). Furthermore, early life stress in mice caused sustained DNA hypomethylation of an important regulatory region of the arginine vasopressin (AVP) gene (Murgatroyd et al., 2009).

There have been several attempts to examine whether the results from animal studies could be translated to humans. Methylation patterns of GR genes were examined among a cohort of suicide victims in Quebec who had experienced abuse in early childhood (McGowan et al., 2009). Individuals with treatment-resistant forms of major depression showed decreased GR expression and increased HPA activity. Site-specific differences in DNA methylation in the GR exon 1f promoter and its expression were detected between suicide completers who had reported social adversity early in life and suicide completers who did not experience social adversity early in life (McGowan et al., 2009). Epigenetic modulation of other candidate genes has been implicated in suicide; the Gamma-aminobutyric acid A receptor alpha 1 subunit (GABRA1) promoter (Linthorst, Flachskamm, Muller-Preuss, Holsboer, & Reul, 1995) within the frontopolar cortex (Poulter et al., 2008) and Tropomyosin-related kinase B (TRKB) in the frontal cortex of suicide completers (Ernst et al., 2009). It is unknown yet whether these changes in DNA are also associated with early life adversity.

In addition, the state of methylation of ribosomal RNA (rRNA) gene promoters has also been examined. Ribosomal RNA forms the skeleton of the ribosome, which is the protein synthesis machinery essential for building new memories and creating new synapses in the brain. One possible way to control the protein synthesis capacity of a cell is through changing the fraction of active rRNA alleles in a cell (Brown & Szyf, 2007). It has previously been shown that the fraction of rRNA genes that is active and associated with relevant transcription machinery is unmethylated while the fraction that is inactive (and therefore not associated with transcriptional activity) is methylated (Brown & Szyf, 2007). In the cohort of suicide victims in Quebec who were abused as children and their control group, results showed that only the suicide victims who had also experienced childhood abuse had higher overall methylation in their rRNA genes and expressed less rRNA. This difference in methylation was brain-region specific: it was present in the hippocampus and was not observed in the cerebellum. Based on the retrospective design of this study, it is not possible to determine whether early life abuse was directly responsible for DNA methylation profiles. However, ongoing longitudinal work may address this issue (see for example, (Naumova et al., 2011).

Importantly, although significant methylation differences were observed between the controls and suicide victims, the participants did not vary in their DNA sequence. The fact that the difference in methylation was brain-region specific and that no sequence differences were observed further strengthens the conclusion that this difference in methylation was driven by environmental rather than genetic variation (McGowan et al., 2008).

The impact of early life adversity is not limited to the brain or to candidate genes; the effect is system and genome-wide

Early studies examining epigenetic changes associated with early life adversity have focused on select candidate genes. However, the large number of phenotypes that are associated with early life adversity both in animals and humans suggest that the impact of early adversity on the DNA methylation pattern is broad and should affect peripheral tissues in addition to specific brain regions. Moreover, it is by now almost self evident that genes do not act independently but participate in functional gene circuitries (van Weerd, Koshiba-Takeuchi, Kwon, & Takeuchi, 2011). A candidate gene approach biases us to reiterate what is already well established and could be tedious and frustrating when the “wrong” candidate gene is investigated. The advent of genome-wide association studies (GWAS) to DNA methylation and genome function mapping enable us probe the entire system rather than a limited set of genes. However, given that methylation levels are examined in up to several millions of CPG sites (locations of DNA where methylation activity is high), there is also great risk for type I errors with the genome wide approach. Moreover, the differentially methylated sites can be located anywhere in the genome, not necessarily within a gene or its specific parts, thus making interpretations difficult.

In several studies involving both humans and animals, McGowan et al. (2011) have tested whether the epigenetic responses to early life adversity was genome-wide. First, in a study involving adult rats, they examined the state of DNA methylation, histone acetylation (an epigenetic process related to changes in chromatin, the protein structure surrounding the DNA molecule) and gene expression in a 7 million base pair region of chromosome 18, which contains the GR gene, in the hippocampus. Natural variations in maternal care in the rat were associated with coordinate changes in DNA methylation, alterations in the chromatin, and variation in gene expression spanning over a hundred kilobase pairs. Interestingly, a chromosomal region containing a cluster of gene families implicated in synaptogenesis (known as protocadherinα, -β, and -γ (Pcdh)) showed the highest differential response to maternal care. The entire cluster revealed changes in DNA methylation, chromatin, and gene expression in response to variations in maternal care. This finding suggests that the DNA methylation response to early life maternal care is coordinated across gene clusters that cover broad areas in the genome. Furthermore, epigenetic response to early life maternal care involves not only single candidate gene promoters, such as that of the GR gene, but involves regions surrounding the gene, including transcriptional and intragenic sequences, as well as sequences residing distantly from transcription start sites and regions containing non-coding RNAs (McGowan et al., 2011).

The finding from the animal work has also been replicated in humans. Suderman and colleagues (2001) showed that a similar pattern of response to childhood abuse is associated with DNA methylation differences throughout the genomic region spanning the six and a half million base-pair region centered at the GR (NR3C1) gene in the hippocampus of adult humans. The DNA methylation differences associated with child abuse bear a striking resemblance to DNA methylation differences between adult offspring of high and low maternal care rats. This provides evidence for an analogous cross-species epigenetic and transcriptional response to early life environment (Suderman, McGowan, Turecki & Szyf, unpublished manuscript).

Epigenetic changes due to early life stress are system wide

Primate studies have been important for examining whether the epigenetic response to early life adversity is system-wide, involving parallel central and peripheral systems (involving the brain as well as T cells). For example, Provencal and colleagues (2012) (Provencal, Suderman, Suomi & Szyf, unpublished manuscript) showed that similar to the rat and human findings, the changes associated with differences in rearing are not limited to the brain, but occur in T cells as well. Although the vast majority of DNA methylation changes that associate with rearing are different in T cells than the prefrontal cortex, some similarities were detected. These data are consistent with the hypothesis that the response to early life adversity is genome-wide and system-wide.

These findings have had important implications for examining epigenetic changes among humans. Given that changes in DNA methylation associated with maternal rearing are detectable in T cells, researchers have become interested in performing population DNA methylation studies examining either whole blood or T cells among humans. Evidence from several studies indicates that it is indeed possible to detect differences in DNA methylation in peripheral system. Borghol and colleagues examined the impact of socioeconomic positioning on blood DNA methylation from the British birth cohort of 1958 (Borghol et al., 2011). This study detected a signature of DNA methylation that was associated with early life adversity (Borghol et al., 2011). Furthermore, the pituitary adenylate cyclase-activating polypeptide (PACAP) gene (ADCTAP1), a protein known to be involved in stress response in the pituitary, was found to be differentially methylated in peripheral blood cells in humans with post traumatic stress syndrome (Ressler et al., 2011). Differences in DNA methylation of the GR promoter were also observed in peripheral blood cells among newborns exposed prenatally to maternal depression than a comparison group (Oberlander et al., 2008). Infants who were prenatally exposed to maternal depression showed increased methylation in the GR promoter in lymphocytes in comparison to control newborns (Oberlander et al., 2008). Finally, telomere length differences, measured from buccal swabs, were identified between orphans in the Bucharest Early Intervention Project who were placed under high quality foster care when compared with those subjected to continued care in institutions (Drury et al., 2011). These few studies are encouraging in that they point to the possibility that a DNA methylation response to early life adversity could be molecularly detected in peripheral systems.

How is experience translated into DNA methylation changes?

One of the most appealing aspects of the hypothesis that DNA methylation embeds experience “under the skin” is that it allows us to start to chart a molecular bridge between the world and the DNA that might be responding to predicted rules and mechanisms. Although there is not much that can be done to prevent the sequence changes that randomly occur during the course of human evolution, giving rise to certain risky phenotypes, there may be potential avenues of intervention that leads to changes in the activity of genes. Understanding the “rules” governing DNA methylation changes in response to experience might make it possible in the future to design both prevention and intervention strategies that change the expression of genes to promote healthy outcomes.

If indeed the change in DNA methylation is not stochastic, it could be linked to experience through triggering of signaling pathways. Cervoni and Szyf (2001) showed a decade ago that the histone deacetylase inhibitor TSA (an enzyme associated with re-modeling of the chromatin) could induce a DNA demethylation event, beyond that which is found to occur during DNA replication. Since histone acetylation could be affected by triggering of signaling pathways by extracellular signals (Magnaghi-Jaulin, Ait-Si-Ali, & Harel-Bellan, 1999) such as cAMP signaling mediated pathways (Yuan & Gambee, 2001), induction of histone acetylation in response to activation of signaling cascades could serve as a conduit that could lead to demethylation of DNA. These early data were further supported by animal experiments that showed that it was possible to reverse epigenetic programming by maternal care by treating adult offspring of low licking and grooming mothers with TSA (Weaver et al., 2004).

Although the signaling pathways mediating the relationship between external triggers and DNA methylation are as yet unclear, examples that could provide a plausible working hypothesis have been previously reported. Maternal behavior triggers a signaling pathway that involves the serotonin receptor, increase in cAMP, recruitment of the transcription factor nerve growth factor-induced protein A (NGFI-A), which in turn recruits the histone acetyltransferase CBP, and the methylated DNA binding protein and candidate DNA demethylase MBD2 to the GR promoter (Weaver et al., 2007). It has been hypothesized that that the increased histone acetylation triggered by CREB binding protein (CBP) or by other recruited histone acetyltransferases (HATs) facilitates the demethylation of the gene by MBD2 or other DNA demethylases (Weaver, Brown, Hellstrom, Meaney, & Szyf, unpublished manuscript).

A different signaling cascade linking social exposure to DNA demethylation provides a mechanism for how early life stress results in persistent life-long hypomethylation of the arginine vasopressin (AVP) gene. The AVP promoter is methylated and bound by MeCp2. Depolarization of hypothalamic neurons triggers phosphorylation of MeCp2 at Ser438 by calcium dependent CamKII (calmodulin kinase II) (Murgatroyd et al., 2009). This phosphorylation converts MeCp2 from a transcriptional silencer with high affinity to methylated DNA into a transcriptional activator with low affinity to methylated DNA (Zhou et al., 2006). This facilitates demethylation of the AVP gene. Phosphorylation of MeCP2 in response to neuronal activation has been shown to facilitate demethylation of the BDNF promoter (Chen et al., 2003). This signaling pathway delineates a direct link between neuronal activation and the phosphorylation state of a protein interacting with methylated genes in the brain. Neuronal activation resulting in signaling through phosphorylation of proteins interacting with methylated DNA might be a general pathway that links social exposure and the activation of neurons. Future studies are required to map the signaling pathways that link early life adversity to the DNA methylation/demethylation of gene circuitries in brain and T cells.

Therefore, scientific knowledge concerning the process by which environmental signals affect DNA methylation or demethylation patterns is progressing. Despite the exciting progress in the field, many questions regarding the process of methylation remain unanswered. For example, given that DNA methylation appears to be dynamic after birth, how is the pattern of methylation that is critical for maintaining the terminal differentiation phenotype maintained? Also, what is protecting the cell-type specific DNA methylation pattern from drifting? Continued efforts involving human and animal models will be critical for answering these important questions in the future.

Prospective and summary

DNA methylation is a mechanism for genome diversification; identical genomes could have different phenotypic expression resulting from differences in DNA methylation. The process of cellular differentiation illustrates how identical genomes could have different chemical identities defined by covalent chemical modifications. This review suggests that the same mechanism that provides genomes with different identities during cellular differentiation is involved in conferring differential identities to individuals in response to experience and particularly early life experience. Furthermore, these changes in DNA methylation in response to experience may constitute an adaptive response, which could turn maladaptive if there is a misfit between the DNA methylation pattern and the environment, resulting in human disease. One of the challenges is to understand the mechanisms that direct genome wide and system-wide DNA methylation adjustments and to delineate how these changes in DNA methylation could lead to changes in genome function and physiology. Delineating the signaling pathways leading from early life experience to DNA methylation changes is critical.

The hypothesis that DNA methylation changes are driving human disease and health problems bears an optimistic message; it might be possible to reverse either with pharmacological or behavioral interventions maladaptive DNA methylation marks. As several epigenetic drugs are now at different stages in clinical trials for the treatment of cancer (Kramer, Gottlicher, & Heinzel, 2001; Weidle & Grossman, 2000) and various psychiatric disorders (Simonini et al., 2001) there is hope for a possible rerouting of deleterious epigenetic effects. Understanding the pathways that lead from specific experiences to phenotypic DNA methylation changes should allow us to design prevention and intervention strategies to decrease disease and increase health and wellness.

Acknowledgments

Research in M.S.'s laboratory is supported by grants from the National Cancer Institute of Canada, the Canadian Institute of Health Research, the NICHD, the ERAnet NEURON, the Human Science Frontiers Program and the Sackler program for epigenetics and psychobiology at McGill University.

Contributor Information

Moshe Szyf, Department of Pharmacology and Therapeutics, McGill University.

Johanna Bick, Child Study Center, Yale University.

References

  1. Adams RL. Eukaryotic DNA methyltransferases--structure and function. Bioessays. 1995;17:139–145. doi: 10.1002/bies.950170209. [DOI] [PubMed] [Google Scholar]
  2. Adams RL, Burdon RH. DNA methylation in eukaryotes. CRC Critical Reviews in Biochemistry. 1982;13:349–384. doi: 10.3109/10409238209108714. [DOI] [PubMed] [Google Scholar]
  3. Adams RL, Davis T, Fulton J, Kirk D, Qureshi M, Burdon RH. Eukaryotic DNA methylase--properties and action on native DNA and chromatin. Current Topics in Microbiology and Immunology. 1984;108:142–156. [PubMed] [Google Scholar]
  4. Bhattacharya SK, Ramchandani S, Cervoni N, Szyf M. A mammalian protein with specific demethylase activity for mCpG DNA. Nature. 1999;397:579–583. doi: 10.1038/17533. see comments. [DOI] [PubMed] [Google Scholar]
  5. Bergmann A, Lane ME. HIDden targets of microRNAs for growth control. Trends in Biochemical Sciences. 2003;28:461–463. doi: 10.1016/S0968-0004(03)00175-0. [DOI] [PubMed] [Google Scholar]
  6. Borghol N, Suderman M, McArdle W, Racine A, Hallett M, Pembrey M, Szyf M. Associations with early-life socio-economic position in adult DNA methylation. International Journal of Epidemiology. 2011:1–13. doi: 10.1093/ije/dyr147. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Brown SE, Szyf M. Epigenetic Programming of the rRNA Promoter by MBD3. Molecular and Cellular Biology. 2007;27:4938–4952. doi: 10.1128/MCB.01880-06. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H, Braithwaite A. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science. 2003;301:386–389. doi: 10.1126/science.1083968. [DOI] [PubMed] [Google Scholar]
  9. Cervoni N, Szyf M. Demethylase activity is directed by histone acetylation. Journal of Biological Chemistry. 2001;276:40778–40787. doi: 10.1074/jbc.M103921200. [DOI] [PubMed] [Google Scholar]
  10. Chen WG, Chang Q, Lin Y, Meissner A, West AE, Griffith EC, Greenberg ME. Derepression of BDNF transcription involves calcium-dependent phosphorylation of MeCP2. Science. 2003;302:885–889. doi: 10.1126/science.1086446. [DOI] [PubMed] [Google Scholar]
  11. Comb M, Goodman HM. CpG methylation inhibits proenkephalin gene expression and binding of the transcription factor AP-2. Nucleic Acids Research. 1990;18:3975–3982. doi: 10.1093/nar/18.13.3975. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Detich N, Bovenzi V, Szyf M. Valproate induces replication-independent active DNA demethylation. Journal of Biological Chemistry. 2003a;278:27586–27592. doi: 10.1074/jbc.M303740200. [DOI] [PubMed] [Google Scholar]
  13. Detich N, Hamm S, Just G, Knox JD, Szyf M. The methyl donor S adenosylmethionine inhibits active demethylation of DNA: A candidate novel mechanism for the pharmacological effects of Sadenosylmethionine. Journal of Biological Chemistry. 2003b;278:20812–20820. doi: 10.1074/jbc.M211813200. [DOI] [PubMed] [Google Scholar]
  14. Detich N, Theberge J, Szyf M. Promoter-specific activation and demethylation by MBD2/demethylase. Journal of Biological Chemistry. 2002;277:35791–35794. doi: 10.1074/jbc.C200408200. [DOI] [PubMed] [Google Scholar]
  15. Drury SS, Theall K, Gleason MM, Smyke AT, De Vivo I, Wong JY, Nelson CA. Telomere length and early severe social deprivation: linking early adversity and cellular aging. Molecular Psychiatry, Advance online publication. 2011 doi: 10.1038/mp.2011.53. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Ernst C, Deleva V, Deng X, Sequeira A, Pomarenski A, Klempan T, Szyf M. Alternative splicing, methylation state, and expression profile of tropomyosin-related kinase B in the frontal cortex of suicide completers. Archives of General Psychiatry. 2009;66:22–32. doi: 10.1001/archpsyc.66.1.22. [DOI] [PubMed] [Google Scholar]
  17. Francis D, Diorio J, Liu D, Meaney MJ. Nongenomic transmission across generations of maternal behavior and stress responses in the rat. Science. 1999;286:1155–1158. doi: 10.1126/science.286.5442.1155. [DOI] [PubMed] [Google Scholar]
  18. Inamdar NM, Ehrlich KC, Ehrlich M. CpG methylation inhibits binding of several sequence-specific DNA- binding proteins from pea, wheat, soybean and cauliflower. Plant Molecular Biology. 1991;17:111–123. doi: 10.1007/BF00036811. [DOI] [PubMed] [Google Scholar]
  19. Jenuwein T, Allis CD. Translating the histone code. Science. 2001;293:1074–1080. doi: 10.1126/science.1063127. [DOI] [PubMed] [Google Scholar]
  20. Jin SG, Wu X, Li AX, Pfeifer GP. Genomic mapping of 5 hydroxy-methylcytosine in the human brain. Nucleic Acids Research. 2011;39:5015–5024. doi: 10.1093/nar/gkr120. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Kramer OH, Gottlicher M, Heinzel T. Histone deacetylase as a therapeutic target. Trends in Endocrinology and Metabolism. 2001;12:294–300. doi: 10.1016/s1043-2760(01)00438-6. [DOI] [PubMed] [Google Scholar]
  22. Linthorst AC, Flachskamm C, Muller-Preuss P, Holsboer F, Reul JM. Effect of bacterial endotoxin and interleukin-1 beta on hippocampal serotonergic neurotransmission, behavioral activity, and free corticosterone levels: an in vivo microdialysis study. Journal of Neuroscience. 1995;15:2920–2934. doi: 10.1523/JNEUROSCI.15-04-02920.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Liu D, Diorio J, Tannenbaum B, Caldji C, Francis D, Freedman A, Meaney MJ. Maternal care, hippocampal glucocorticoid receptors, and hypothalamic-pituitary-adrenal responses to stress. Science. 1997;277:1659–1662. doi: 10.1126/science.277.5332.1659. [DOI] [PubMed] [Google Scholar]
  24. Magnaghi-Jaulin L, Ait-Si-Ali S, Harel-Bellan A. Histone acetylation in signal transduction by growth regulatory signals. Seminars in Cell and Developmental Biology. 1999;10:197–203. doi: 10.1006/scdb.1999.0301. [DOI] [PubMed] [Google Scholar]
  25. Manolio TA, Collins FS, Cox NJ, Goldstein DB, Hindorff LA, Hunter DJ, Visscher PM. Finding the missing heritability of complex diseases. Nature. 2009;461:747–753. doi: 10.1038/nature08494. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. McGowan PO, Sasaki A, D'Alessio AC, Dymov S, Labonte B, Szyf M, Meaney MJ. Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nature Neuroscience. 2009;12:342–348. doi: 10.1038/nn.2270. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. McGowan PO, Sasaki A, Huang TC, Unterberger A, Suderman M, Ernst C, Szyf M. Promoter-wide hypermethylation of the ribosomal RNA gene promoter in the suicide brain. PLoS ONE. 2008;3:e2085. doi: 10.1371/journal.pone.0002085. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. McGowan PO, Suderman M, Sasaki A, Huang TC, Hallett M, Meaney MJ, Szyf M. Broad epigenetic signature of maternal care in the brain of adult rats. PLoS One. 2011;6:e14739. doi: 10.1371/journal.pone.0014739. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Murgatroyd C, Patchev AV, Wu Y, Micale V, Bockmuhl Y, Fischer D, Spengler D. Dynamic DNA methylation programs persistent adverse effects of early-life stress. Nature Neuroscience. 2009;12:1559–1566. doi: 10.1038/nn.2436. [DOI] [PubMed] [Google Scholar]
  30. Naumova O, Lee M, Koposov R, Szyf M, Dozier M, Grigorenko E. Differential pattersn of whole-genome DNA methylation in orphans and children raised by their biological parents. Development and Psychopathology. doi: 10.1017/S0954579411000605. in press. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Ng HH, Zhang Y, Hendrich B, Johnson CA, Turner BM, Erdjument-Bromage H, Bird A. MBD2 is a transcriptional repressor belonging to the MeCP1 histone deacetylase complex. Nature Genetics. 1999;23:58–61. doi: 10.1038/12659. see comments. [DOI] [PubMed] [Google Scholar]
  32. Oberlander TF, Weinberg J, Papsdorf M, Grunau R, Misri S, Devlin AM. Prenatal exposure to maternal depression, neonatal methylation of human glucocorticoid receptor gene (NR3C1) and infant cortisol stress responses. Epigenetics. 2008;3:97–106. doi: 10.4161/epi.3.2.6034. [DOI] [PubMed] [Google Scholar]
  33. Poulter MO, Du L, Weaver IC, Palkovits M, Faludi G, Merali Z, Anisman H. GABAA receptor promoter hypermethylation in suicide brain: implications for the involvement of epigenetic processes. Biological Psychiatry. 2008;64:645–652. doi: 10.1016/j.biopsych.2008.05.028. [DOI] [PubMed] [Google Scholar]
  34. Power C, Jefferis BJ, Manor O, Hertzman C. The influence of birth weight and socioeconomic position on cognitive development: Does the early home and learning environment modify their effects? Journal of Pediatrics. 2006;148:54–61. doi: 10.1016/j.jpeds.2005.07.028. [DOI] [PubMed] [Google Scholar]
  35. Provencal N, Suderman M, Suomi S, Szyf M. The signature of maternal rearing in the methylome in rhesus macaque prefrontal cortex and T cells. 2012 doi: 10.1523/JNEUROSCI.1470-12.2012. Unpublished manuscript. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Ramchandani S, Bhattacharya SK, Cervoni N, Szyf M. DNA methylation is a reversible biological signal. Proceeding of the National Academy of Science. 1999;96:6107–6112. doi: 10.1073/pnas.96.11.6107. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Razin A, Riggs AD. DNA methylation and gene function. Science. 1980;210:604–610. doi: 10.1126/science.6254144. [DOI] [PubMed] [Google Scholar]
  38. Razin A, Szyf M. DNA methylation patterns. Formation and function. Biochimica et Biophysica Acta. 1984;782:331–342. doi: 10.1016/0167-4781(84)90043-5. [DOI] [PubMed] [Google Scholar]
  39. Ressler KJ, Mercer KB, Bradley B, Jovanovic T, Mahan A, Kerley K, Myers AJ. Post-traumatic stress disorder is associated with PACAP and the PAC1 receptor. Nature. 2011;470:492–497. doi: 10.1038/nature09856. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Risch N, Herrell R, Lehner T, Liang KL, Eaves L, Hoh J, Merikangas KR. Interaction between the seratonin transporter gene (5-HTTLPR), stressful life events, and risk of depression. Journal of American Medical Association. 2009;23:2462–2471. doi: 10.1001/jama.2009.878. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Roth TL, Lubin FD, Funk AJ, Sweatt JD. Lasting epigenetic influence of early-life adversity on the BDNF gene. Biological Psychiatry. 2009;65:760–769. doi: 10.1016/j.biopsych.2008.11.028. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Ruppenthal GC, Arling GL, Harlow HF, Sackett GP, Suomi SJ. A 10-year perspective of motherless-mother monkey behavior. Journal of Abnormal Psychology. 1976;85:341–349. doi: 10.1037//0021-843x.85.4.341. [DOI] [PubMed] [Google Scholar]
  43. Schirmer K, Fischer BB, Madureira DJ, Pillai S. Transcriptomics in ecotoxicology. Analytical & Bioanalytical Chemistry. 2010;397:917–923. doi: 10.1007/s00216-010-3662-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Simonini MV, Camargo LM, Dong E, Maloku E, Veldic M, Costa E, Guidotti A. The benzamide MS-275 is a potent, long-lasting brain region-selective inhibitor of histone deacetylases. Proceedings of the National Academy of Science. 2006;103:1587–1592. doi: 10.1073/pnas.0510341103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Strahl BD, Allis CD. The language of covalent histone modifications. Nature. 2000;403:41–45. doi: 10.1038/47412. [DOI] [PubMed] [Google Scholar]
  46. Suderman M, McGowan PO, Hallett M, Meaney MJ, Szyf M. Epigenetic response to childhood abuse in the human hippocampus. 2012 Unpublished manuscript. [Google Scholar]
  47. Suomi SJ, Collins ML, Harlow HF, Ruppenthal GC. Effects of maternal and peer separations on young monkeys. Journal of Child Psychology and Psychiatry. 1976;17:101–112. doi: 10.1111/j.1469-7610.1976.tb00382.x. [DOI] [PubMed] [Google Scholar]
  48. Szyf M, McGowan P, Meaney M. The social environment and the epigenome. Envrionmental and Molecular Mutagenesis. 2008;49:46–60. doi: 10.1002/em.20357. [DOI] [PubMed] [Google Scholar]
  49. Van Weerd JH, Koshiba-Takeuchi K, Kwon C, Takeuchi JK. Epigenetic factors and cardiac development. Cardiovascular Research. 2011;91(2):203–211. doi: 10.1093/cvr/cvr138. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Weaver IC, Brown SE, Hellstrom IC, Meaney MJ, Szyf M. MBD2 mediates epigenetic programming of the glucocorticoid receptor. 2012 Unpublished manuscript. [Google Scholar]
  51. Weaver IC, Cervoni N, Champagne FA, D'Alessio AC, Sharma S, Seckl JR, Meaney MJ. Epigenetic programming by maternal behavior. Nature Neuroscience. 2004;7:847–854. doi: 10.1038/nn1276. [DOI] [PubMed] [Google Scholar]
  52. Weaver IC, D'Alessio AC, Brown SE, Hellstrom IC, Dymov S, Sharma S, Meaney MJ. The transcription factor nerve growth factor-inducible protein a mediates epigenetic programming: altering epigenetic marks by immediate-early genes. Journal of Neuroscience. 2007;27:1756–1768. doi: 10.1523/JNEUROSCI.4164-06.2007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Weidle UH, Grossmann A. Inhibition of histone deacetylases: a new strategy to target epigenetic modifications for anticancer treatment. Anticancer Research. 2000;20:1471–1485. [PubMed] [Google Scholar]
  54. Williams K, Christensen J, Pedersen MT, Johansen JV, Cloos PA, Rappsilber J, Helin K, et al. TET1 and hydroxymethylcytosine in transcription and DNA methylation fidelity. Nature. 2011;473:343–348. doi: 10.1038/nature10066. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Wolffe AP, Jones PL, Wade PA. DNA demethylation. Proceedings of the National Academy of Science. 1999;96:5894–5896. doi: 10.1073/pnas.96.11.5894. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Yuan LW, Gambee JE. Histone acetylation by p300 is involved in CREB-mediated transcription on chromatin. Biochimica et Biophysica Acta. 2001;1541:161–169. doi: 10.1016/s0167-4889(01)00141-0. [DOI] [PubMed] [Google Scholar]
  57. Zhou Z, Hong EJ, Cohen S, Zhao WN, Ho HY, Schmidt L, Greenberg ME. Brain-specific phosphorylation of MeCP2 regulates activity-dependent Bdnf transcription, dendritic growth, and spine maturation. Neuron. 2006;52:255–269. doi: 10.1016/j.neuron.2006.09.037. [DOI] [PMC free article] [PubMed] [Google Scholar]

RESOURCES