Skip to main content Accessibility help
Hostname: page-component-55b6f6c457-b6fb2 Total loading time: 0.629 Render date: 2021-09-25T21:01:43.031Z Has data issue: true Feature Flags: { "shouldUseShareProductTool": true, "shouldUseHypothesis": true, "isUnsiloEnabled": true, "metricsAbstractViews": false, "figures": true, "newCiteModal": false, "newCitedByModal": true, "newEcommerce": true, "newUsageEvents": true }

Maternal diet as a modifier of offspring epigenetics

Published online by Cambridge University Press:  10 April 2015

K. A. Lillycrop*
Centre for Biological Sciences, Faculty of Natural and Environmental Sciences, University of Southampton, Southampton, UK
G. C. Burdge
Human Development and Health, Faculty of Medicine, University of Southampton, Southamptom, UK
*Address for correspondence: Dr K. A. Lillycrop, Institute of Developmental Sciences Building (MP887), Southampton General Hospital, Tremona Road, Southampton, SO16 6YD, UK. (Email
Rights & Permissions[Opens in a new window]


There has been a substantial body of evidence, which has shown that genetic variation is an important determinant of disease risk. However, there is now increasing evidence that alterations in epigenetic processes also play a role in determining susceptibility to disease. Epigenetic processes, which include DNA methylation, histone modifications and non-coding RNAs play a central role in regulating gene expression, determining when and where a gene is expressed as well as the level of gene expression. The epigenome is highly sensitive to a variety of environmental factors, especially in early life. One factor that has been shown consistently to alter the epigenome is maternal diet. This review will focus on how maternal diet can modify the epigenome of the offspring, producing different phenotypes and altered disease susceptibilities.

© Cambridge University Press and the International Society for Developmental Origins of Health and Disease 2015 


Non-communicable disease (NCD) such as diabetes, cardiovascular disease (CVD) and obesity account for 60% of all deaths globally, with the incidence of NCDs projected to rise further by 2030.Reference Hossain, Kawar and El Nahas 1 This increase in NCDs is not restricted to industrialized nations but is also increasingly seen in developing nations.Reference Ramachandran and Snehalatha 2 Although it is widely established that genotype plays a critical role in determining NCD risk, the failure of genome-wide association studies to find genetic variants that explain a substantial proportion of NCD riskReference Manolio, Collins and Cox 3 together with the rapid rise in incidence of NCDs over the past two decades have suggested that environmental factors such as diet and level of physical activity are also likely to play a major role in the development of NCDs. Early life environment in particular has been shown to play a critical role in the development of many human diseases, and the mechanism by which early life environment may influence disease risk has been suggested to involve the altered epigenetic regulation of genes. This review will focus on the evidence that early life nutrition, particularly maternal diet, can modify the epigenome of the offspring leading to persistent phenotypic changes and an altered risk for NCDs in later life.

Early life environment and future disease risk

The association between the quality of the early life environment and subsequent risk for chronic disease in later life has been well described. Such studies have shown that low birth weight even within the normal range is associated with an increased risk for CVD and the metabolic syndrome (hypertension, insulin resistance, type 2 diabetes, dyslipidaemia and obesity) in later life.Reference Godfrey and Barker 4 Although in many of these studies, a J- or U-shaped relationship between birth weight and disease risk was seen, with babies born with the highest birth weight also being at increased risk for disease.Reference Curhan, Willett and Rimm 5 , Reference McCance, Pettitt and Hanson 6 However, birth weight in these studies is thought to be only a very crude indicator of the intrauterine environment, which may have been compromised through a variety of maternal, environmental or placental factors.Reference Hanson and Gluckman 7

One maternal factor that has consistently been shown to influence later phenotype is maternal nutrition. This has been most clearly shown in studies of the Dutch Hunger Winter, a famine, which occurred in the Netherlands during the winter of 1944. These studies have shown that individuals whose mothers were exposed to famine periconceptually and in the first trimester of pregnancy exhibit an increased risk of obesity and CVD in adulthood, whereas individuals whose mothers were exposed in the later stages of gestation showed increased incidence of insulin resistance and hypertension in later life.Reference Roseboom, de and Painter 8

These findings from human epidemiological studies, which show an association between the quality of early life environment and future disease risk, have been replicated in a variety of animal models where nutrition in particular both before and after pregnancy can be precisely controlled. Early animal studies focussed on the effects of maternal undernutrition or protein restriction attempting to replicate the effects of famine on long-term offspring health, although more recently given the growing epidemic of obesity in both industrialized and developing countries, animal models have been established to investigate the effect of energy-rich diets during pregnancy on the phenotype of the offspring. Interestingly, offspring born to dams fed these different diets exhibited persistent metabolic changes often leading to features similar to human cardio-metabolic disease such as obesity, insulin resistance, hypertension and raised serum cholesterol levels.Reference Bertram and Hanson 9 , Reference Samuelsson, Matthews and Argenton 10 For instance, feeding rats a protein-restricted diet (PR) during pregnancy has been reported to result in impaired glucose homoeostasis,Reference Burns, Desai and Cohen 11 vascular dysfunction,Reference Torrens, Poston and Hanson 12 impaired immunity,Reference Calder and Yaqoob 13 increased susceptibility to oxidative stress,Reference Langley, Seakins, Grimble and Jackson 14 increased fat deposition and altered feeding behaviour,Reference Bellinger, Lilley and Langley-Evans 15 , Reference Bellinger, Sculley and Langley-Evans 16 whereas offspring from dams fed an obesogenic diet (16% fat, 33% sugar) also produced offspring with impaired glucose homoeostasis, increased resistance artery endothelial dysfunction, hypertension, increased adiposity and reduced locomoter activity.Reference Samuelsson, Matthews and Argenton 10 Interestingly, the metabolic alterations induced in the offspring by perturbations in the maternal diet are dependent on the timing of the nutritional challenge, which may reflect the critical phase of development of different organ systems, with respect to the timing of the nutritional constraint. Bertram et al. Reference Bertram and Hanson 17 have shown in the guinea pig model that female offspring born to dams fed a PR diet in the first half of pregnancy (1–35 days) have raised mean arterial blood pressure, which was associated with an increased intraventricular septum and anterior left ventricle wall (LVW) thickness. In contrast, the offspring from dams fed a PR diet in late gestation (36–70 days) were growth restricted but did not display alterations in blood pressure or LV structure. Animal studies have also shown an interaction between prenatal and postnatal environments.Reference Ozanne and Hales 18 , Reference Zambrano, Bautista and Deas 19 For example, dyslipidaemia and impaired glucose homoeostasis induced by feeding dams a PR diet during pregnancy were exacerbated in adult male and female rats fed a diet containing 10% (w/w) fat after weaning compared with a 4% (w/w) fat post-weaning diet.Reference Zambrano, Bautista and Deas 19

Interestingly, a number of recent studies have shown that paternal diet can also influence future disease risk in the offspring. Carone et al. Reference Carone, Fauquier and Habib 20 showed that offspring of males fed a low-protein diet from weaning until sexual maturity exhibited an increase in the expression of many genes involved in lipid and cholesterol biosynthesis in the liver as well as differences in the levels of several lipid metabolites, whereas Ng et al.Reference Ng, Lin and Laybutt 21 have shown that a paternal high-fat diet (HFD) exposure induces increased body weight, adiposity, impaired glucose tolerance and insulin sensitivity in female offspring. The mechanism by which alterations in early life nutrition may induce such long-term changes in metabolism and phenotype has been suggested to involve the altered epigenetic regulation of genes.

Introduction to epigenetics

Conrad Waddington (1905–1975) first introduced the term epigenetics in the 1940s to describe the process by which the same genotype can give rise to multiple phenotypes during development.Reference Waddington 22 However, in recent years, the definition of epigenetics has subsequently been narrowed to ‘the study of mitotically and/or meiotically heritable changes in gene function that cannot be explained by changes in DNA sequence’.Reference Bird 23 Epigenetic processes include DNA methylation, histone modifications and non-coding RNAs (ncRNAs). Together these processes determine when and where a gene is switched on and the level of gene activity. Epigenetic processes not only play a key role in regulating gene expression but are also central to the mechanism, which allow an organism to adapt to the environment.

DNA methylation

DNA methylation is a common modification in eukaryotic organisms. DNA methylation occurs primarily on the fifth position of cytosine (5mC) within a CpG (cytosine and guanine nucleotides linked by phosphate) dinucleotide, although non-CpG methylation is prevalent in embryonic stem cells.Reference Ramsahoye, Biniszkiewicz and Lyko 24 Low levels of methylation at the promoter regions are associated generally with transcriptional activity, whereas high levels of methylation are associated with transcriptional silencing.Reference Bird 23 DNA methylation induces transcriptional silencing by preventing the binding of transcription factors to the DNA or by recruiting the methyl CpG binding protein 2 (MeCP2) to the DNA, which in turn recruits histone-modifying complexes.Reference Fuks, Hurd and Wolf 25

Methylation of CpGs is largely established during embryogenesis or during early postnatal life. Following fertilization, DNA methylation markers on the maternal and paternal genomes are largely erased with the exception of the imprinted genes. This is followed by global de novo methylation just before blastocyst implantation,Reference Santos, Hendrich, Reik and Dean 26 during which 70% of CpGs are methylated, mainly in the repressive heterochromatin regions and in repetitive sequences such as retrotransposable elements. Lineage-specific methylation of tissue-specific genes also occurs throughout prenatal development and early postnatal life, which is essential for cell specification. The de novo methylation of DNA is catalysed by DNA methyltransferases (DNMT) 3a and 3b,Reference Okano, Bell, Haber and Li 27 and is maintained through mitosis by methylation of the hemi-methylated DNA by DNMT1.Reference Bacolla, Pradhan, Roberts and Wells 28 Once DNA methylation patterns are established during development, these markers were thought to be relatively stably and generally maintained throughout life. This premise was supported by the initial failure to identify a DNA demethylase or a mechanism for DNA demethylation.Reference Ooi and Bestor 29 However, this concept has now been challenged as active demethylation and has been demonstrated in a number of studies. For example, active demethylation in mammals has been observed on the paternal genomic DNA in the zygote upon fertilization,Reference Reik, Santos, Mitsuya, Morgan and Dean 30 on the synaptic plasticity gene reelin in the hippocampus upon contextual fear conditioningReference Miller and Sweatt 31 and on the interferon gamma (IFNγ) gene upon antigen exposure of memory CD8 T cells.Reference Kersh, Fitzpatrick and Murali-Krishna 32 Moreover, a number of potential DNA demethylases have been identified such as ten–eleven translocation (Tet) proteins,Reference Tahiliani, Koh and Shen 33 , Reference Ito, D'Alessio and Taranova 34 methyl binding domain protein (MBD)2b,Reference Bhattacharya, Ramchandani, Cervoni and Szyf 35 MBD4,Reference Zhu, Zheng and Angliker 36 the DNA repair endonucleases XPG (Gadd45a)Reference Barreto, Schafer and Marhold 37 and a G/T mismatch repair DNA glycosylase,Reference Jost 38 although these function by not removing the methyl group directly from cytosine, but through a multi-step processes linked either to DNA repair mechanisms or through further modification of 5mC.

Histone modifications

DNA methylation works in concert with histone modifications to regulate gene expression. In eukaryotic cells, DNA is wrapped around a core of eight histone proteins, two molecules of histone H2A, H2B, H3 and H4. This forms the basic unit of chromatin, called a nucleosome. Each nucleosome is then folded upon itself to form a solenoid or 30-nm fibre, which is then further coiled and compacted to form a 200-nm fibre. This folding is necessary to reduce the effective size of DNA; however, it is has now become very clear that the histones also play a critical role in regulating gene expression. The amino terminal tail domain of the histones are subjected to a large number of modifications including acetylation, methylation, ubiquitination, sumoylation and phosphorylation.Reference Turner 39 The establishment of these markers on the histone tails is often referred to as the histone code and leads to the binding of effector proteins that, in turn, bring about specific cellular processes. Histone acetylation, induced through histone acetyl transferases, is associated with transcriptional activity and an open chromatin state. Methylation of lysine (K) residues within the histone tail can either be an active or repressive mark depending on the specific lysine involved. For example, histone H3K4 methylation is associated with gene activation,Reference Strahl, Ohba, Cook and Allis 40 whereas histone H3K9 methylation is linked to gene silencing.Reference Nakayama, Rice, Strahl, Allis and Grewal 41

Crosstalk between DNA methylation and histone modification is well established. Methylated CpGs are bound by MeCP2, which then recruits both histone deacetylases (HDACs) – which remove acetyl groups from the histones – and histone methyl transferases, this results in a closed chromatin structure and transcriptional silencing.Reference Fuks, Hurd and Wolf 25 Recent studies have also shown that a number of histone modifying enzymes such as HDAC1 and HDAC2,Reference Fuks, Hurd, Deplus and Kouzarides 42 Reference Rountree, Bachman and Baylin 44 as well as components of the polycomb repressive histone complex 2,Reference Vire, Brenner and Deplus 45 can recruit DNMT1 to the DNA and induce DNA methylation.


Data from the ENCODE project have shown that, although over 74% of the eukaryotic genome is transcribed, only 1–2% of the genome encodes for proteins,Reference Djebali, Davis and Merkel 46 suggesting that a large proportion of the transcripts in the cell do not encode for proteins. These RNAs have been termed ncRNAs and are grouped into two classes. Long ncRNAs are longer than 200 nucleotides, whereas short ncRNAs are <200 nucleotides. Short ncRNAs include microRNAs (miRNAs), small interfering RNAs and piwi-interacting RNAs.Reference Bartel 47 Small ncRNAs can induce mRNA degradation and/or translational repression,Reference Bartel 47 and when targeted to the promoter region of a gene they can induce both DNA methylation and repressive histone modifications.Reference Tan, Zhang and Wu 48 The mechanism by which long ncRNAss work is less well understood but may involve the recruitment of histone modifying complexes to the DNA to create repressive domains covering many kilobases. In mammals, long ncRNAs have been shown to be essential for X-chromosome inactivation and genomic imprinting.Reference Mercer, Dinger and Mattick 49

Early life nutrition and the epigenome

Although DNA methylation was originally thought to be a very stable modification and once established methylation patterns were largely maintained throughout the life-course, there is now growing evidence that a number of environmental factors such as nutrition, stress, placental insufficiency, endocrine disruptors and pollution, especially in early life, can alter the epigenome leading to long-term phenotypic changes in the offspring.Reference Feil and Fraga 51 In this study, we will focus on the effect of early life nutrition on the epigenome and its long-term effects.

One of the best examples of how nutrition can alter phenotype through the altered epigenetic regulation of genes is seen in studies on the honeybee. Female larvae incubated in the presence of Royal Jelly predominantly develop in to Queen bees, whereas those incubated in the absence of Royal Jelly develop into sterile worker bees, although they are genetically identical.Reference Maleszka 52 However, knockdown of DNMT3, the major DNMT in bees, increased the proportion of larvae developing into queen bees as opposed to sterile workers,Reference Kucharski, Maleszka, Foret and Maleszka 53 suggesting that nutrition can profoundly affect developmental fate and it does so through the altered methylation of DNA.

Nutrition has also been shown to influence DNA methylation in rodents. In agouti viable yellow (Avy) mice, coat colour is determined by the methylation status of an intracisternal-A particle (IAP) in the 5′ upstream region of the agouti gene that acts as a cryptic promoter directing expression of the agouti gene, which encodes for a paracrine signalling protein that induces follicular melanocytes to switch from producing black eumelanin to yellow phaeomelanin. Supplementation of the diet of the pregnant Avy mice with folic acid, cobalamin, choline and betaine induced a graded shift in coat colour of the litter from predominately yellow (agouti) to brown (pseudo-agouti).Reference Tobi, Lumey and Talens 54 This shift was accompanied by the hypermethylation of seven CpG dinucleotides, 600 bp downstream of the Avy IAP insertion site.

There is also evidence in models of nutritional programming where perturbations in maternal diet are associated with persistent metabolic changes in the offspring that these metabolic changes are accompanied by epigenetic changes in key metabolic genes or genes involved in appetite control. For example, feeding pregnant rats a PR diet induced hypomethylation of the glucocorticoid receptor (GR) and peroxisome proliferator activated receptor (PPAR)α promoters in the livers of juvenile and adult offspring; this was accompanied by an increase in GR and PPARα expression and in the metabolic processes that they control.Reference Lillycrop, Phillips, Jackson, Hanson and Burdge 55 Reference Burdge, Phillips, Dunn, Jackson and Lillycrop 57 In contrast, global dietary restriction during pregnancy increased the level of DNA methylation of PPARα and the GR in the liver of the offspring,Reference Gluckman, Lillycrop and Vickers 58 suggesting that the effects of maternal nutrition on the epigenome of the offspring depend upon the nature of the maternal nutrient challenge. Such nutrition-related responses are consistent with the concept that induced epigenetic changes that underpin physiological change may provide a means of adapting to an adverse environment.Reference Gluckman, Hanson and Spencer 59

Feeding a HFD during pregnancy and lactation has also been shown to induce epigenetic and phenotypic changes in the offspring. Vucetic et al. Reference Vucetic, Kimmel, Totoki, Hollenbeck and Reyes 60 showed increased expression of the μ-opioid receptor and preproenkephalin in the nucleus accumbens, prefrontal cortex and hypothalamus of mice from dams that consumed HF diet during pregnancy, and this was accompanied by the hypomethylation of the promoter regions of these genes. Maternal obesity and diabetes has also been reported to induce subtle but widespread changes in DNA methyaltion in the liver of the offpring.Reference Li, Young and Maloney 61

Although most studies to date have concentrated on identifying changes in DNA methylation associated with perturbations in maternal diet or body compoisiton, there is growing evidence that early life nutrition can also induce persistant changes in both histone modifications and miRNAs. In islet cells, a decrease in hepatic nuclear factor (HNF) 3a expression in the liver of PR offspring was accompanied by a minimal change in DNA methylation but substantial changes in histone modifications at the HNF4a promoter, such as a reduction in H3K4 methylation and an increase in H3K9me2 and H3K27me3.Reference Sandovici, Smith and Nitert 62 Dietary restriction from E10 to E21, which induced an increase in IGF1A and IGF1B (insulin growth factors) expression, was also accompanied by changes in the histone markers at the IGF1 gene with a decrease in H3K4me2 and an increase in H3K4me3 being observed.Reference Tosh, Fu and Callaway 63 Marked changes in miRNA expression have also been documented in both the liver and skeletal muscles of the offspring in response to matenral undernutrition during either the peri-conceptual or the pre-implanatation period. Reference Lie, Morrison and Williams-Wyss 64 , Reference Lie, Morrison and Williams-Wyss 65

Alterations in paternal diet in rodents have also been associated with epigenetic changes in the offspring. Feeding male rats a PR diet before mating induced widespread changes in DNA methylation (10–20%) in the liver of the offspring compared with controls, including an increase in methylation at an intergenic CpG island 50 kb upstream of the PPARα gene.Reference Carone, Fauquier and Habib 20 Interestingly, however, cytosine methylation patterns were highly correlative in the sperm from control, low-protein or calorie-restricted fathers, suggesting that the sperm epigenome may be more refractory to differences in diet. A decrease in H3K27 me3 levels at the monoamine oxidase (MAOA) and elongation factor Tu GTP binding domain containing 1 (EFTUD1) promoters were seen, however, in the sperm from the low-protein-fed fathers compared with controls, suggesting that differences in diet may be transmitted through modifications in the histone code.Reference Carone, Fauquier and Habib 20 Paternal high-fat feeding has been reported to induce the hypomethylation of the interleukin 13 receptor alpha 2 (IL13RA2) promoter in the islet cells of female offspring.Reference Ng, Lin and Laybutt 21 Altered expressions of 23 miRNAs were also detected in the testis of the high-fat-fed fathers, suggesting that miRNAs may play a role in the transmission of obesity and impaired metabolic health to the offspring.

Epigenome is also susceptible to nutritional factors in later life

Although many studies have shown that the epigenome is highly sensitive to environmental factors during the perinatal and prenatal period, the period of epigenetic plasticity may extend into postnatal life. Plagemann et al. Reference Plagemann, Harder and Brunn 66 showed that neonatal overfeeding induced by raising rat pups in small litters induces the hypermethylation of two CpG dinucleotides within the pro-opiomelanocortin promoter. Folic acid supplementation in the juvenile-pubertal period has also been shown to induce the hypermethylation of the PPARα gene; this was accompanied by a decrease in PPARα expression and levels of fatty acid β-oxidation,Reference Burdge, Lillycrop and Phillips 67 whereas Ly et al. Reference Ly, Lee and Chen 68 showed that folic acid supplementation during the peri-pubertal period led to an increased risk for mammary adenocarcinomas and a decrease in DNMT activity.

There is also evidence that even in adulthood there is some plasticity of the epigenome. For instance, feeding a diet deficient in methyl donors to post-weaning mice led to the permanent loss of IGF2 imprinting and dysregulation of its mRNA expression,Reference Waterland, Lin, Smith and Jirtle 69 whereas feeding a diet deficient in choline, folate, methionine and vitamin B12 for 4 weeks to adult rats induced the hypomethylation of the proto-oncogenes c-Myc, c-Fos and c-Ras. Moreover, this effect persisted for 3 weeks after re-feeding.Reference Christman, Sheikhnejad, Dizik, Abileah and Wainfan 70

Macronutrient intake during adulthood can also influence the epigenome. Hoile et al. Reference Hoile, Irvine and Kelsall 71 showed that feeding adult rats fish oil-enriched diet for 9 weeks led to a transient decrease in the expression of the fatty acid desaturase 2 (FADS2) gene and increase in FADS2 promoter methylation. These effects were reversed by feeding a standard diet for a further 4 weeks. Such findings suggest that, although the epigenome may be most susceptible to environmental factors during early life when methylation patterns are being established, there is also some plasticity in later life. Although these effects may be more transient, such continued plasticity in later life does offer the opportunity for intervention to reverse or reset developmentally induced epigenetic markers.

Evidence that early nutrition can alter the epigenome in humans

Studies in animal models, where the diet pre- and post-pregnancy, as well as genetic background, can be carefully controlled, have been instrumental in demonstrating long-term effects that alterations in early life nutrition can have on the phenotype and in providing insights into the mechanism underlying this phenomena. Evidence that maternal diet in humans can induce long-term epigenetic and phenotypic changes in the offspring is more limited, although alterations in the methylation of a number of genes in DNA isolated from the whole blood of individuals who were exposed peri-conceptionally to famine during the Dutch Hunger Winter have been reported.Reference Heijmans, Tobi and Stein 72 , Reference Tobi, Lumey and Talens 73 Specifically, a decrease in methylation of the imprinted IGF2 gene and an increase in methylation of interleukin-10, leptin, ATP binding cassette A1 and guanine nucleotide binding protein were observed in those individuals whose mothers were exposed to famine during pregnancy compared with their non-exposed siblings. Interestingly, these methylation changes were predominantly seen in those individuals who had been exposed in utero during early gestation rather than late gestation, suggesting that the peri-conceptual period is a period of extreme sensitivity to nutritional status. Furthermore, these measurements were made 60 years after the famine, suggesting that maternal nutritional constraint induces long-term epigenetic alterations in the offspring, consistent with the observations from animal models. Altered methylation of 5 CpG sites in the IGF2 gene was also detected in the peripheral blood cells of children whose mothers took 400 µg of folic acid per day during the peri-conceptional period compared with children whose mothers did not take folic acid supplementation.Reference Steegers-Theunissen, Obermann-Borst and Kremer 74 More recent studies have reported widespread sex-specific changes in the epigenome associated with peri-conceptual micronutrient intakeReference Khulan, Cooper and Skinner 75 and an association between the DNA methylation status of human metastable epialleles with maternal nutritional intake at conception.Reference Dominguez-Salas, Moore and Baker 76 Plasticity in the human epigenome may also persist into adulthood, as studies have shown that HFD fed during adulthood induced changes in the methylation of 6508 genes in skeletal muscles, and such changes were interestingly only partially reversed after 6–8 weeks of a normocaloric diet.Reference Jacobsen, Brons and Bork-Jensen 77 The changes in DNA methylation in all these human studies are considerably smaller than those found in animal studies, which may reflect the fact that in animal models the perturbation in maternal diet is more defined, the postnatal environment is precisely controlled and the genetic background is identical. Interestingly, in a recent study, Teh et al.,Reference Teh, Pan and Chen 78 where they screened the genotypes and methylomes of 237 neonates, found 1423 variable methylated regions, and in 75% of the cases these were best explained by an interaction between different in utero environments and genotype, suggesting that the effect of early life environment is moderated by genetic background.

Epigenetic biomarkers predictive of later disease risk

If a similar mechanism does operate in humans as in animals, with early life environment inducing the altered epigenetic regulation of genes, then it should be possible to detect these altered epigenetic markers and use them as predictors of future metabolic capacity and disease risk. The potential issue with detecting such markers in humans is that there is limited tissue availability; readily accessible tissues include cord, cord blood, placenta, buccal and blood, but as DNA methylation patterns are often tissue specific, it is not clear whether the methylation status in such tissues would reflect methylation patterns in more metabolically relevant cell types. However, a number of studies have shown inter-tissue methylation correlations.Reference Murphy, Huang and Hoyo 79 , Reference Waterland, Kellermayer and Laritsky 80 For instance, Talens et al. Reference Talens, Boomsma and Tobi 81 have shown that, for a number of non-imprinted genes, DNA methylation levels measured in blood were also equivalent in buccal cells, despite the fact that these cell types stem from different germ layers (mesoderm and ectoderm, respectively), whereas Byun et al.Reference Byun, Siegmund and Pan 82 reported that, using the IlluminaGoldenGate Bead Array, which integrated 1505 CpG sites in 807 genes, the intra-individual correlations for over 11 tissues ranged from 0.738 to 0.941. It may also depend on when the environmental constraint occurred. An environmental challenge during very early development is likely to affect all germ layers and an imprint of this altered epigenetic mark maybe detectable in all tissues, whereas exposures occurring later on in gestation may induce only tissue-specific effects.

Interestingly, Godfrey et al. Reference Godfrey, Sheppard and Gluckman 83 have reported that the methylation of a single CpG site in the promoter region of the nuclear receptor RXRA was strongly related to childhood adiposity in both boys and girls in two independent cohorts; with RXRA promoter methylation explaining over 25% of the variance in age- and sex-adjusted fat mass in children at 6 and 9 years of age. This suggests that a far greater proportion of individual vulnerability to NCD may arise during development than has been considered previously and that developmentally induced epigenetic changes may mediate this effect. Such findings also suggest that the detection of such methylation changes even in peripheral tissues may be useful markers of later disease risk. However, contrary to many of the initial studies, which suggest that once DNA methylation patterns are established in early life they are then stably maintained, there is growing evidence that DNA methylation can be dynamically regulated in response to a number of environmental stimuli. For instance, an acute exercise bout over a 20-min period induced hypomethylation of the peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC1α) and mitochondrial transcription factor A promoters in muscle tissues,Reference Barres, Yan and Egan 84 whereas TarantiniReference Tarantini, Bonzini and Apostoli 85 found an association between concentrations of PM10 particles over a 3-day period and levels of inducible nitric oxide synthase methylation. Such sensitivity to the environment could confound the contributions that developmentally induced epigenetic markers have on later phenotype, limiting the usefulness of any epigenetic predictive markers for disease risk. The factors that induce such dynamic changes in DNA methylation are not fully understood nor why the methylation of some CpGs appears to be stable and others very plastic, primarily as data on methylation stability from longitudinal studies, especially in children when the epigenome may well be more sensitive to the environment, are limited. One study that has examined DNA methylation stability over time in children found that methylation of the genes MAOA, dopamine receptor D4 (DRD4) and serotonin transporter (SLC6A4) is highly dynamic between the age of 5 and 10 years. Although the stability of CpG loci may be very loci-dependent, Clarke-Harris et al. Reference Clarke-Harris, Wilkin and Hosking 87 have reported year on year stability of 7 CpG sites within the PGC1α promoter in peripheral blood cells in children from 5 to 14 years of age, suggesting that at least for these CpG sites methylation is set up in early life and stably maintained thereafter, despite changes in exercise, pollution or the onset of puberty. Moreover, four of the seven CpGs analysed at 5–7 years predicted adiposity in the children aged 9–14, consistent with the paradigm that developmentally induced epigenetic markers make a significant contribution to later phenotype. Interestingly, the CpGs analysed in this latter study were located upstream of the region shown to be hypomethylated in muscles in response to acute exercise, whether the difference in stability relates to the differential location of these CpG sites within PGC1α promoter, tissue-specific differences between blood and muscle or whether the change in methylation in response to exercise occur on top of a developmentally induced imprint is not clear. A better understanding of the factors influencing variation in DNA methylation and their role in mediating DNA methylation dynamics will be important to elucidate the role of these factors in producing DNA methylation differences that may underlie the development of complex diseases as well as for the development of epigenetic biomarkers predictive of later disease risk.


There is now increasing evidence to suggest that early life nutrition can induce persistent metabolic and physiological changes in the offspring through the altered epigenetic regulation of genes leading to an altered susceptibility to disease in later life. The ability of the environment to influence that epigenome may allow an organism to adapt to its environment by modulating the expression of its genes and the processes that they control. The epigenome appears to be most susceptible to environmental factors in early life when methylation markers are being established; however, it is also clear that the environment can alter DNA methylation even in adulthood, suggesting that these epigenetic processes function as part of a life-long adaptation mechanism. Preliminary studies have also suggested that it may be possible to detect these altered epigenetic markers in early life even in peripheral tissues and use these markers as potential predictive biomarkers to identify those individuals at increased risk for disease. However, there are still many factors and mechanisms that we have to learn to completely understand the exact contributions that developmentally induced epigenetic markers have on later phenotype and disease risk. For instance, how does maternal nutritional status induce epigenetic changes in the offspring, are histones or ncRNAs involved? What are the critical developmental periods? Do these differ depending on the tissue? What makes one CpG stable, another susceptible to the environment, and does this change during the lifecourse, is it tissue dependent? And can interventions be targeted to specific epigenetic markers? Understanding this relationship between epigenetics, the environment and disease susceptibility may then make it possible to make real progress in the prevention and treatment of chronic diseases and halt the rapid rise in NCDs, which are seen throughout the world at present.



Financial Support

This research received no specific grant from any funding agency, commercial, or not-for-profit sectors.

Conflicts of Interest



1. Hossain, P, Kawar, B, El Nahas, M. Obesity and diabetes in the developing world – a growing challenge. N Engl J Med. 2007; 356, 213215.CrossRefGoogle ScholarPubMed
2. Ramachandran, A, Snehalatha, C. Rising burden of obesity in Asia. J Obes. 2010; 2010, vol. 2010, Article ID 868573, 8 pages, 2010. doi:10.1155/2010/868573.CrossRefGoogle Scholar
3. Manolio, TA, Collins, FS, Cox, NJ, et al. Finding the missing heritability of complex diseases. Nature. 2009; 461, 747753.CrossRefGoogle ScholarPubMed
4. Godfrey, KM, Barker, DJ. Fetal programming and adult health. Public Health Nutr. 2001; 4, 611624.CrossRefGoogle ScholarPubMed
5. Curhan, GC, Willett, WC, Rimm, EB, et al. Birth weight and adult hypertension, diabetes mellitus, and obesity in US men. Circulation. 1996; 94, 32463250.CrossRefGoogle ScholarPubMed
6. McCance, DR, Pettitt, DJ, Hanson, RL, et al. Birth weight and non-insulin dependent diabetes: thrifty genotype, thrifty phenotype, or surviving small baby genotype? BMJ. 1994; 308, 942945.CrossRefGoogle ScholarPubMed
7. Hanson, MA, Gluckman, PD. Developmental origins of health and disease: new insights. Basic Clin Pharmacol Toxicol. 2008; 102, 9093.CrossRefGoogle ScholarPubMed
8. Roseboom, T, de, RS, Painter, R. The Dutch famine and its long-term consequences for adult health. Early Hum Dev. 2006; 82, 485491.CrossRefGoogle ScholarPubMed
9. Bertram, CE, Hanson, MA. Animal models and programming of the metabolic syndrome. Br Med Bull. 2001; 60, 103121.CrossRefGoogle ScholarPubMed
10. Samuelsson, AM, Matthews, PA, Argenton, M, et al. Diet-induced obesity in female mice leads to offspring hyperphagia, adiposity, hypertension, and insulin resistance: a novel murine model of developmental programming. Hypertension. 2008; 51, 383392.CrossRefGoogle ScholarPubMed
11. Burns, SP, Desai, M, Cohen, RD, et al. Gluconeogenesis, glucose handling, and structural changes in livers of the adult offspring of rats partially deprived of protein during pregnancy and lactation. J Clin Invest. 1997; 100, 17681774.CrossRefGoogle ScholarPubMed
12. Torrens, C, Poston, L, Hanson, MA. Transmission of raised blood pressure and endothelial dysfunction to the F2 generation induced by maternal protein restriction in the F0, in the absence of dietary challenge in the F1 generation. Br J Nutr. 2008; 100, 760766.CrossRefGoogle ScholarPubMed
13. Calder, PC, Yaqoob, P. The level of protein and type of fat in the diet of pregnant rats both affect lymphocyte function in the offspring. Nutr Res. 2000; 20, 9951005.CrossRefGoogle Scholar
14. Langley, SC, Seakins, M, Grimble, RF, Jackson, AA. The acute phase response of adult rats is altered by in utero exposure to maternal low protein diets. J Nutr. 1994; 124, 15881596.Google ScholarPubMed
15. Bellinger, L, Lilley, C, Langley-Evans, SC. Prenatal exposure to a maternal low-protein diet programmes a preference for high-fat foods in the young adult rat. Br J Nutr. 2004; 92, 513520.CrossRefGoogle ScholarPubMed
16. Bellinger, L, Sculley, DV, Langley-Evans, SC. Exposure to undernutrition in fetal life determines fat distribution, locomotor activity and food intake in ageing rats. Int J Obes. 2006; 30, 729738.CrossRefGoogle ScholarPubMed
17. Bertram, CE, Hanson, MA. Prenatal programming of postnatal endocrine responses by glucocorticoids. Reproduction. 2002; 124, 459467.CrossRefGoogle ScholarPubMed
18. Ozanne, SE, Hales, CN. Lifespan: catch-up growth and obesity in male mice. Nature. 2004; 427, 411412.CrossRefGoogle ScholarPubMed
19. Zambrano, E, Bautista, CJ, Deas, M, et al. A low maternal protein diet during pregnancy and lactation has sex- and window of exposure-specific effects on offspring growth and food intake, glucose metabolism and serum leptin in the rat. J Physiol. 2006; 571(Pt 1), 221230.CrossRefGoogle ScholarPubMed
20. Carone, BR, Fauquier, L, Habib, N, et al. Paternally induced transgenerational environmental reprogramming of metabolic gene expression in mammals. Cell. 2010; 143, 10841096.CrossRefGoogle ScholarPubMed
21. Ng, SF, Lin, RC, Laybutt, DR, et al. Chronic high-fat diet in fathers programs beta-cell dysfunction in female rat offspring. Nature. 2010; 467, 963966.CrossRefGoogle ScholarPubMed
22. Waddington, CH. Canalization of development and the inheritance of aquired characters. Nature. 1942; 150, 563565.CrossRefGoogle Scholar
23. Bird, A. DNA methylation patterns and epigenetic memory. Genes Dev. 2002; 16, 621.CrossRefGoogle ScholarPubMed
24. Ramsahoye, BH, Biniszkiewicz, D, Lyko, F, et al. Non-CpG methylation is prevalent in embryonic stem cells and may be mediated by DNA methyltransferase 3a. Proc Natl Acad Sci U S A. 2000; 97, 52375242.CrossRefGoogle ScholarPubMed
25. Fuks, F, Hurd, PJ, Wolf, D, et al. The methyl-CpG-binding protein MeCP2 links DNA methylation to histone methylation. J Biol Chem. 2003; 278, 40354040.CrossRefGoogle ScholarPubMed
26. Santos, F, Hendrich, B, Reik, W, Dean, W. Dynamic reprogramming of DNA methylation in the early mouse embryo. Dev Biol. 2002; 241, 172182.CrossRefGoogle ScholarPubMed
27. Okano, M, Bell, DW, Haber, DA, Li, E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell. 1999; 99, 247257.CrossRefGoogle Scholar
28. Bacolla, A, Pradhan, S, Roberts, RJ, Wells, RD. Recombinant human DNA (cytosine-5) methyltransferase. II. Steady-state kinetics reveal allosteric activation by methylated dna. J Biol Chem. 1999; 274, 3301133019.CrossRefGoogle ScholarPubMed
29. Ooi, SK, Bestor, TH. The colorful history of active DNA demethylation. Cell. 2008; 133, 11451148.CrossRefGoogle ScholarPubMed
30. Reik, W, Santos, F, Mitsuya, K, Morgan, H, Dean, W. Epigenetic asymmetry in the mammalian zygote and early embryo: relationship to lineage commitment? Philos Trans R Soc Lond B Biol Sci. 2003; 358, 14031409.CrossRefGoogle ScholarPubMed
31. Miller, CA, Sweatt, JD. Covalent modification of DNA regulates memory formation. Neuron. 2007; 53, 857869.CrossRefGoogle ScholarPubMed
32. Kersh, EN, Fitzpatrick, DR, Murali-Krishna, K, et al. Rapid demethylation of the IFN-gamma gene occurs in memory but not naive CD8 T cells. J Immunol. 2006; 176, 40834093.CrossRefGoogle Scholar
33. Tahiliani, M, Koh, KP, Shen, Y, et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science. 2009; 324, 930935.CrossRefGoogle ScholarPubMed
34. Ito, S, D'Alessio, AC, Taranova, OV, et al. Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification. Nature. 2010; 466, 11291133.CrossRefGoogle ScholarPubMed
35. Bhattacharya, SK, Ramchandani, S, Cervoni, N, Szyf, M. A mammalian protein with specific demethylase activity for mCpG DNA. Nature. 1999; 397, 579583.Google ScholarPubMed
36. Zhu, B, Zheng, Y, Angliker, H, et al. 5-methylcytosine DNA glycosylase activity is also present in the human MBD4 (G/T mismatch glycosylase) and in a related avian sequence. Nucleic Acids Res. 2000; 28, 41574165.CrossRefGoogle Scholar
37. Barreto, G, Schafer, A, Marhold, J, et al. Gadd45a promotes epigenetic gene activation by repair-mediated DNA demethylation. Nature. 2007; 445, 671675.CrossRefGoogle ScholarPubMed
38. Jost, JP. 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, 46844688.CrossRefGoogle ScholarPubMed
39. Turner, BM. Histone acetylation and an epigenetic code. Bioessays. 2000; 22, 836845.3.0.CO;2-X>CrossRefGoogle ScholarPubMed
40. Strahl, BD, Ohba, R, Cook, RG, Allis, CD. Methylation of histone H3 at lysine 4 is highly conserved and correlates with transcriptionally active nuclei in tetrahymena. Proc Natl Acad Sci U S A. 1999; 96, 1496714972.CrossRefGoogle ScholarPubMed
41. Nakayama, J, Rice, JC, Strahl, BD, Allis, CD, Grewal, SI. Role of histone H3 lysine 9 methylation in epigenetic control of heterochromatin assembly. Science. 2001; 292, 110113.CrossRefGoogle ScholarPubMed
42. Fuks, F, Hurd, PJ, Deplus, R, Kouzarides, T. The DNA methyltransferases associate with HP1 and the SUV39H1 histone methyltransferase. Nucleic Acids Res. 2003; 31, 23052312.CrossRefGoogle ScholarPubMed
43. Fuks, F, Burgers, WA, Brehm, A, Hughes-Davies, L, Kouzarides, T. DNA methyltransferase Dnmt1 associates with histone deacetylase activity. Nat Genet. 2000; 24, 8891.Google ScholarPubMed
44. Rountree, MR, Bachman, KE, Baylin, SB. DNMT1 binds HDAC2 and a new co-repressor, DMAP1, to form a complex at replication foci. Nat Genet. 2000; 25, 269277.CrossRefGoogle Scholar
45. Vire, E, Brenner, C, Deplus, R, et al. The polycomb group protein EZH2 directly controls DNA methylation. Nature. 2006; 439, 871874.CrossRefGoogle ScholarPubMed
46. Djebali, S, Davis, CA, Merkel, A, et al. Landscape of transcription in human cells. Nature. 2012; 489, 101108.CrossRefGoogle ScholarPubMed
47. Bartel, DP. MicroRNAs: target recognition and regulatory functions. Cell. 2009; 136, 215233.CrossRefGoogle ScholarPubMed
48. Tan, Y, Zhang, B, Wu, T, et al. Transcriptional inhibiton of Hoxd4 expression by miRNA-10a in human breast cancer cells. BMC Mol Biol. 2009; 10, 12.CrossRefGoogle ScholarPubMed
49. Mercer, TR, Dinger, ME, Mattick, JS. Long non-coding RNAs: insights into functions. Nat Rev Genet. 2009; 10, 155159.CrossRefGoogle ScholarPubMed
50. Drinkwater, RD, Blake, TJ, Morley, AA, Turner, DR. Human lymphocytes aged in vivo have reduced levels of methylation in transcriptionally active and inactive DNA. Mutat Res. 1989; 219, 2937.CrossRefGoogle ScholarPubMed
51. Feil, R, Fraga, MF. Epigenetics and the environment: emerging patterns and implications. Nat Rev Genet. 2011; 13, 97109.Google ScholarPubMed
52. Maleszka, R. Epigenetic integration of environmental and genomic signals in honey?bees. Epigenetics. 2008; 3, 188192.CrossRefGoogle ScholarPubMed
53. Kucharski, R, Maleszka, J, Foret, S, Maleszka, R. Nutritional control of reproductive status in honeybees via DNA methylation. Science. 2008; 319, 18271830.CrossRefGoogle ScholarPubMed
54. Waterland, RA, Jirtle, RL. Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Mol Cell Biol. 2003; 23, 52935300.CrossRefGoogle ScholarPubMed
55. Lillycrop, KA, Phillips, ES, Jackson, AA, Hanson, MA, Burdge, GC. Dietary protein restriction of pregnant rats induces and folic acid supplementation prevents epigenetic modification of hepatic gene expression in the offspring. J Nutr. 2005; 135, 13821386.Google ScholarPubMed
56. Lillycrop, KA, Slater-Jefferies, JL, Hanson, MA, et al. Induction of altered epigenetic regulation of the hepatic glucocorticoid receptor in the offspring of rats fed a protein-restricted diet during pregnancy suggests that reduced DNA methyltransferase-1 expression is involved in impaired DNA methylation and changes in histone modifications. Br J Nutr. 2007; 97, 10641073.CrossRefGoogle ScholarPubMed
57. Burdge, GC, Phillips, ES, Dunn, RL, Jackson, AA, Lillycrop, KA. Effect of reduced maternal protein consumption during pregnancy in the rat on plasma lipid concentrations and expression of peroxisomal proliferator-activated receptors in the liver and adipose tissue of the offspring. Nutr Res. 2004; 24, 639646.CrossRefGoogle Scholar
58. Gluckman, PD, Lillycrop, KA, Vickers, MH, et al. Metabolic plasticity during mammalian development is directionally dependent on early nutritional?status. Proc Natl Acad Sci U S A. 2007; 104, 1279612800.CrossRefGoogle ScholarPubMed
59. Gluckman, PD, Hanson, MA, Spencer, HG. Predictive adaptive responses and human evolution. Trends Ecol Evol. 2005; 20, 527533.CrossRefGoogle ScholarPubMed
60. Vucetic, Z, Kimmel, J, Totoki, K, Hollenbeck, E, Reyes, TM. Maternal high-fat diet?alters methylation and gene expression of dopamine and opioid-related?genes. Endocrinology. 2010; 151, 47564764.CrossRefGoogle ScholarPubMed
61. Li, CC, Young, PE, Maloney, CA, et?al. Maternal obesity and diabetes induces latent metabolic defects and widespread epigenetic changes in isogenic?mice. Epigenetics. 2013; 8, 602611.CrossRefGoogle ScholarPubMed
62. Sandovici, I, Smith, NH, Nitert, MD, et al. Maternal diet and aging alter the epigenetic control of a promoter-enhancer interaction at the Hnf4a gene in rat pancreatic?islets. Proc Natl Acad Sci USA. 2011; 108, 54495454.CrossRefGoogle ScholarPubMed
63. Tosh, DN, Fu, Q, Callaway, CW, et al. Epigenetics of programmed obesity: alteration in IUGR rat hepatic IGF1 mRNA expression and histone structure in rapid vs. delayed postnatal catch-up?growth. Am J Physiol Gastrointest Liver Physiol. 2010; 299, G1023G1029.CrossRefGoogle ScholarPubMed
64. Lie, S, Morrison, JL, Williams-Wyss, O, et al. Periconceptional undernutrition programs changes in insulin-signaling molecules and microRNAs in skeletal muscle in singleton and twin fetal?sheep. Biol Reprod. 2014; 306, E1013E1024.Google Scholar
65. Lie, S, Morrison, JL, Williams-Wyss, O, et al. Impact of embryo number and maternal undernutrition around the time of conception on insulin signaling and gluconeogenic factors and microRNAs in the liver of fetal?sheep. Am J Physiol Endocrinol Metab. 2014; 306, E1013E1024.CrossRefGoogle ScholarPubMed
66. Plagemann, A, Harder, T, Brunn, M, et al. Hypothalamic proopiomelanocortin promoter methylation becomes altered by early overfeeding: an epigenetic model of obesity and the metabolic syndrome. J Physiol. 2009; 587(Pt 20), 49634976.CrossRefGoogle ScholarPubMed
67. Burdge, GC, Lillycrop, KA, Phillips, ES, et al. Folic acid supplementation during the juvenile-pubertal period in rats modifies the phenotype and epigenotype induced by prenatal nutrition. J Nutr. 2009; 139, 10541060.CrossRefGoogle ScholarPubMed
68. Ly, A, Lee, H, Chen, J, et al. Effect of maternal and postweaning folic acid supplementation on mammary tumor risk in the offspring. Cancer Res. 2011; 71, 988997.CrossRefGoogle ScholarPubMed
69. Waterland, RA, Lin, JR, Smith, CA, Jirtle, RL. Post-weaning diet affects genomic imprinting at the insulin-like growth factor 2 (Igf2)?locus. Hum Mol Genet. 2006; 15, 705716.CrossRefGoogle ScholarPubMed
70. Christman, JK, Sheikhnejad, G, Dizik, M, Abileah, S, Wainfan, E. Reversibility of changes in nucleic acid methylation and gene expression induced in rat liver by severe dietary methyl deficiency. Carcinogenesis. 1993; 14, 551557.CrossRefGoogle ScholarPubMed
71. Hoile, SP, Irvine, NA, Kelsall, CJ, et al. Maternal fat intake in rats alters 20:4n-6 and 22:6n-3 status and the epigenetic regulation of Fads2 in offspring?liver. J Nutr Biochem. 2013; 24, 12131220.CrossRefGoogle ScholarPubMed
72. Heijmans, BT, Tobi, EW, Stein, AD, et al. Persistent epigenetic differences associated with prenatal exposure to famine in?humans. Proc Natl Acad Sci U S A. 2008; 105, 1704617049.CrossRefGoogle ScholarPubMed
73. Tobi, EW, Lumey, LH, Talens, RP, et al. DNA methylation differences after exposure to prenatal famine are common and timing- and sex-specific. Hum Mol Genet. 2009; 18, 40464053.CrossRefGoogle ScholarPubMed
74. Steegers-Theunissen, RP, Obermann-Borst, SA, Kremer, D, et al. Periconceptional maternal folic acid use of 400 microg per?day is related to increased methylation of the IGF2 gene in the very young?child. PLoS One. 2009; 4, e7845.CrossRefGoogle ScholarPubMed
75. Khulan, B, Cooper, WN, Skinner, BM, et al. Periconceptional maternal micronutrient supplementation is associated with widespread gender related changes in the epigenome: a study of a unique resource in the?Gambia. Hum Mol Genet. 2012; 21, 20862101.CrossRefGoogle ScholarPubMed
76. Dominguez-Salas, P, Moore, SE, Baker, MS, et al. Maternal nutrition at conception modulates DNA methylation of human metastable epialleles. Nat Commun. 2014; 5, 37463753.CrossRefGoogle ScholarPubMed
77. Jacobsen, SC, Brons, C, Bork-Jensen, J, et al. Effects of short-term high-fat overfeeding on genome-wide DNA methylation in the skeletal muscle of healthy young?men. Diabetologia. 2012; 55, 33413349.CrossRefGoogle ScholarPubMed
78. Teh, AL, Pan, H, Chen, L, et al. The effect of genotype and in utero environment on interindividual variation in neonate DNA methylomes. Genome Res. 2014; 24, 10641074.CrossRefGoogle ScholarPubMed
79. Murphy, SK, Huang, Z, Hoyo, C. Differentially methylated regions of imprinted genes in prenatal, perinatal and postnatal human tissues. PLoS One. 2012; 7, e40924.CrossRefGoogle ScholarPubMed
80. Waterland, RA, Kellermayer, R, Laritsky, E, et al. Season of conception in rural gambia affects DNA methylation at putative human metastable epialleles. PLoS Genet. 2010; 6, e1001252.CrossRefGoogle ScholarPubMed
81. Talens, RP, Boomsma, DI, Tobi, EW, et al. Variation, patterns, and temporal stability of DNA methylation: considerations for epigenetic epidemiology. FASEB J. 2010; 24, 31353144.CrossRefGoogle ScholarPubMed
82. Byun, HM, Siegmund, KD, Pan, F, et al. Epigenetic profiling of somatic tissues from human autopsy specimens identifies tissue- and individual-specific DNA methylation patterns. Hum Mol Genet. 2009; 18, 48084817.CrossRefGoogle ScholarPubMed
83. Godfrey, KM, Sheppard, A, Gluckman, PD, et al. Epigenetic gene promoter methylation at birth is associated with child's later adiposity. Diabetes. 2011; 60, 15281534.CrossRefGoogle ScholarPubMed
84. Barres, R, Yan, J, Egan, B, et al. Acute exercise remodels promoter methylation in human skeletal?muscle. Cell Metab. 2012; 15, 405411.CrossRefGoogle ScholarPubMed
85. Tarantini, L, Bonzini, M, Apostoli, P, et al. Effects of particulate matter on genomic DNA methylation content and iNOS promoter methylation. Environ Health Perspect. 2009; 117, 217222.CrossRefGoogle ScholarPubMed
86. Wong, CC, Caspi, A, Williams, B, et al. A longitudinal study of epigenetic variation in?twins. Epigenetics. 2010; 5, 516526.CrossRefGoogle Scholar
87. Clarke-Harris, R, Wilkin, TJ, Hosking, J, et al. Peroxisomal proliferator activated receptor-gamma-co-activator-1 alpha promoter methylation in blood at 5-7 years predicts adiposity from 9 to 14 years (EarlyBird?50). Diabetes. 2014; 63, 25282537.CrossRefGoogle Scholar
You have Access
Cited by

Send article to Kindle

To send this article to your Kindle, first ensure is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle. Find out more about sending to your Kindle.

Note you can select to send to either the or variations. ‘’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Maternal diet as a modifier of offspring epigenetics
Available formats

Send article to Dropbox

To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Dropbox.

Maternal diet as a modifier of offspring epigenetics
Available formats

Send article to Google Drive

To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Google Drive.

Maternal diet as a modifier of offspring epigenetics
Available formats

Reply to: Submit a response

Please enter your response.

Your details

Please enter a valid email address.

Conflicting interests

Do you have any conflicting interests? *