Skip to main content Accessibility help
×
Home
Hostname: page-component-568f69f84b-2wqtr Total loading time: 0.611 Render date: 2021-09-21T03:40:29.269Z Has data issue: true Feature Flags: { "shouldUseShareProductTool": true, "shouldUseHypothesis": true, "isUnsiloEnabled": true, "metricsAbstractViews": false, "figures": true, "newCiteModal": false, "newCitedByModal": true, "newEcommerce": true, "newUsageEvents": true }

Effect of maternal diet on the epigenome: implications for human metabolic disease

Published online by Cambridge University Press:  25 January 2011

Karen A. Lillycrop*
Affiliation:
School of Biological Sciences, Institute of Developmental Sciences, University of Southampton, Southampton SO16 6YD, UK
*Corresponding
Corresponding author: Dr Karen A. Lillycrop, fax +44 2380 797089, email kal@soton.ac.uk
Rights & Permissions[Opens in a new window]

Abstract

The rapid increase in the incidence of chronic non-communicable diseases over the past two decades cannot be explained solely by genetic and adult lifestyle factors. There is now considerable evidence that the fetal and early postnatal environment also strongly influences the risk of developing such diseases in later life. Human studies have shown that low birth weight is associated with an increased risk of CVD, type II diabetes, obesity and hypertension, although recent studies have shown that over-nutrition in early life can also increase susceptibility to future metabolic disease. These findings have been replicated in a variety of animal models, which have shown that both maternal under- and over-nutrition can induce persistent changes in gene expression and metabolism within the offspring. The mechanism by which the maternal nutritional environment induces such changes is beginning to be understood and involves the altered epigenetic regulation of specific genes. The demonstration of a role for altered epigenetic regulation of genes in the developmental induction of chronic diseases raises the possibility that nutritional or pharmaceutical interventions may be used to modify long-term cardio-metabolic disease risk and combat this rapid rise in chronic non-communicable diseases.

Type
Conference on ‘Nutrition and health: cell to community’
Copyright
Copyright © The Author 2011

Abbreviations:
Dnmt

DNA methyltransferase

GR

glucocorticoid receptor

PR

protein restricted

The incidence of chronic non-communicable disease has risen sharply over the last 20 years with an estimated 18 million people dying from CVD per year(1). This rise in CVD has been amplified by a rapid rise in the rate of obesity and type II diabetes across the world, which are major risk factors for CVD. This increase in the incidence of chronic non-communicable diseases over the past two decades cannot be explained solely by genetic and adult lifestyle factors. There is now substantial evidence that the fetal and early postnatal environment strongly influences the risk of developing cardio-metabolic disease. Epidemiological studies show that a poor intra-uterine environment induced by maternal diet, placental insufficiency or endocrine factors, such as stress, induces changes in the embryo and fetus, which increase its future risk of a range of non-communicable diseases(Reference Godfrey and Barker2). These findings have been replicated in animal models where restricted nutrition during pregnancy induces dyslipidaemia, obesity, hypertension, hyperinsulinaemia and hyperleptinaemia in the offspring(Reference Bertram and Hanson3, Reference Armitage, Khan and Taylor4). This association between poor intra-uterine growth and increased risk of disease in later life may reflect a mismatch between the future environment ‘predicted’ by the embryo/fetus, based on signals from the mother during gestation, and the actual environment experienced in later life(Reference Burdge and Lillycrop5). The mechanism by which cues about nutrient availability in the postnatal environment are transmitted to the fetus and the process by which different, stable phenotypes are induced are beginning to be understood. A number of recent studies suggest that changes in the epigenetic regulation of genes in the embryo are central to the induction of a phenotype that persists into adulthood(Reference Burdge and Lillycrop5). Because the phenotypic attributes induced include responses to environmental challenges such as diet, these epigenetic processes affect the risk of later disease.

The developmental origins of human cardio-metabolic disease

Human epidemiological studies in the UK provided the first evidence that early-life environment was associated with later disease risk. David Barker and colleagues found a strong geographical relationship between infant mortality and the incidence of CVD 50–60 years later, suggesting that a poor early-life environment increased susceptibility to CVD in later life(Reference Barker and Osmond6). Subsequent retrospective studies in both developed and developing countries have confirmed this association between birth weight and CVD, and have also shown that low birth weight is associated with an increased risk of hypertension, insulin resistance, type II diabetes, dyslipidaemia and obesity in later life(Reference Godfrey and Barker2, Reference Barker and Osmond6). This association between birth weight and metabolic disease in later life was observed even within the normal birth weight range and has been shown to have a continuous relationship with disease risk. At the highest birth weight, the risk of disease again increased, resulting in a U- or J-shaped relationship between birth weight and later disease risk(Reference Curhan, Willett and Rimm7, Reference McCance, Pettitt and Hanson8). However, birth weight in all these studies is thought to be simply a crude indicator of the intra-uterine environment that might have been compromised through a variety of maternal, environmental or placental factors(Reference Hanson and Gluckman9). There is growing awareness that the factors that compromise fetal growth or nutrition need not be severe; for example, fetal growth is known to be constrained in those who are born to smaller mothers, in primigravida or in very young mothers(Reference Gluckman and Hanson10).

The role of maternal diet, however, on subsequent disease susceptibility has been most clearly shown in studies of the Dutch Hunger Winter, a famine that 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 did not have reduced birth weights compared to unexposed individuals, but did as adults exhibit an increased risk of obesity and CVD, whereas individuals whose mothers were exposed in the later stages of gestation had reduced birth weights and showed an increased incidence of insulin resistance and hypertension(Reference Painter, Roseboom and Bleker11), suggesting that the timing of the nutritional constraint during pregnancy is also important in determining the future risk of disease.

Early catch-up growth in infants born pre-term, and who were fed formula milk also show increased risk of cardio-metabolic disease in later life(Reference Singhal, Cole and Fewtrell12, Reference Singhal13), including obesity(Reference Harder, Bergmann and Kallischnigg14). A number of studies have also shown greater incidence of obesity in adults who were formula fed as opposed to being breast fed during infancy(Reference Harder, Bergmann and Kallischnigg14, Reference Owen, Martin and Whincup15), although not all studies have found this(Reference Owen, Martin and Whincup16). Fat mass is important for the onset of reproductive function, particularly in females(Reference Gluckman and Hanson17). In an evolutionary context, it is logical that catch-up growth in children born with a lower birth weight is characterised by greater adiposity relative to lean body mass, possibly as a mechanism to reach puberty at a similar age to peers born at greater weights. Although obesity is a risk factor for CVD, it has little negative effect in terms of potential reproductive success and so the trade-off associated with this strategy in terms of fitness is small.

Over-nutrition in early life also increases susceptibility to future obesity which may account for the U- or J-shaped relationships observed between birth weight and risk of obesity or insulin resistance in later life. Dorner and Plagemann(Reference Dorner and Plagemann18) have reported that children of obese women are themselves more likely to become overweight and develop insulin resistance in later life(Reference Dorner and Plagemann18). Gestational weight gain irrespective of pre-pregnancy weight is positively associated with obesity at the age of 3 years (Reference Oken, Taveras and Kleinman19) and even moderate weight gain between successive pregnancies has been shown to result in a significant increase in large for gestational age births(Reference Villamor and Cnattingius20). However, maternal weight loss through bariatic surgery prevents the transmission of obesity to children compared to the offspring of mothers who did not undergo the surgery and remained obese(Reference Kral, Biron and Simard21).

Experimental models of induced cardio-metabolic disease

Animal models have been used extensively to investigate the mechanism by which nutrition in early life induces persistent alterations in the metabolism and physiology of the offspring(Reference Armitage, Khan and Taylor4). These studies have generally been performed using sheep or rodents and have involved feeding either a low-protein diet, a global dietary restriction or even a high-fat or junk food diet through pregnancy and/or lactation. Interestingly, offspring born to such dams fed these different diets exhibit to varying extents characteristics of human subjects with cardio-metabolic disease including obesity, insulin resistance, hypertension and raised serum cholesterol levels.

Maternal protein restriction

The best-studied and most characterised animal model of nutritional induction of an altered metabolic phenotype is feeding rats a protein restricted (PR) diet from conception throughout pregnancy(Reference Langley-Evans22). In some studies, this nutritional constraint continued during lactation. Offspring from PR dams show a number of features of human cardio-metabolic disease including hypertension(Reference Langley-Evans, Phillips and Jackson23), increased fat deposition and altered feeding behaviour(Reference Bellinger, Lilley and Langley-Evans24Reference Lucas, Baker and Desai26), impaired glucose homeostasis, dyslipidaemia(Reference Burdge, Slater-Jefferies and Grant27), vascular dysfunction(Reference Torrens, Hanson and Gluckman28), impaired immunity(Reference Calder and Yaqoob29) and increased susceptibility to oxidative stress(Reference Langley-Evans and Sculley30). The phenotype of the offspring, however, does vary according to the exact composition of the diet(Reference Burdge, Lillycrop and Jackson31). This indicates that even small variations in maternal diet can affect the risk of disease in later life.

Animal studies have also shown a clear interaction between prenatal and postnatal environments(Reference Ozanne and Hales32, Reference Zambrano, Bautista and Deas33). Even modest variations in the diet fed after weaning can exacerbate the effects of maternal under-nutrition on the phenotype of the offspring. For example, dyslipidaemia and impaired glucose homeostasis 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 to a 4% (w/w) fat post-weaning diet(Reference Burdge, Lillycrop and Jackson31).

Global dietary restriction

A number of groups have also used global dietary restriction during pregnancy to investigate how maternal diet can influence disease susceptibility in later life. Woodall and co-workers used a global nutrient restriction of 30% ad libitum fed throughout gestation, which results in a rat model of intra-uterine growth retardation(Reference Woodall, Johnston and Breier34). Offspring born to dams fed this diet during pregnancy are significantly smaller at birth than control offspring. They also exhibit higher systolic blood pressure, hyperinsulinaemia, hyperleptinaemia, hyperphagia, reduced locomotion and obesity. These metabolic alterations are all augmented by feeding a high-fat postnatal diet. However, even modest global nutrient restriction during pregnancy has been shown to induce alterations in metabolism and the hypothalamic–pituitary–adrenal axis. In guinea pigs fed an 85% ad libitum diet throughout gestation, alterations in cholesterol homeostasis was observed in the male offspring(Reference Kind, Clifton and Katsman35). In sheep, a 15% global nutrient restriction during the first half of pregnancy led to reduced adrenocorticotrophic hormone and cortisol responses to exogenous corticotropin-releasing hormone and arginine vasopressin administration, and also a blunted cortisol response to adrenocorticotrophic hormone(Reference Hawkins, Steyn and McGarrigle36).

High-fat diet during pregnancy

With the current rapid rise in incidence of obesity and type II diabetes across the globe, a number of new animal models of over-nutrition during pregnancy have also been developed. Feeding rats a diet high in saturated fats during pregnancy produces offspring with insulin resistance, abnormal cholesterol metabolism and raised adult blood pressure, interestingly very similar outcomes to those observed in offspring born to dams fed either a PR or globally restricted diet during gestation(Reference Guo and Jen37, Reference Brown, Rogers and Dunn38). For instance, offspring from rats fed a ‘junk food diet’ of 16% fat, 33% sugar throughout pregnancy and lactation exhibited higher blood pressure, greater adiposity and insulin resistance in comparison with control offspring(Reference Samuelsson, Matthews and Argenton39).

Phenotype induction and altered transcription

The induction during early life of persistent changes to the phenotype of the offspring by perturbations in maternal diet implies stable alterations to gene transcription which, in turn, results in altered activities of metabolic pathways and homeostatic control processes. Feeding a PR diet to pregnant rats increased glucocorticoid receptor (GR) expression and reduced expression of 11β-hydroxysteroid dehydrogenase type II, the enzyme that inactivates corticosteroids, in the liver, lung, kidney and brain in the offspring(Reference Bertram and Hanson3). In the liver, increased GR activity up-regulates phosphoenolpyruvate carboxykinase expression and activity and so increases capacity for gluconeogenesis. This may contribute to the induction of insulin resistance in this model(Reference Burns, Desai and Cohen40). Altered expression of GR has also been reported in the lung, liver, adrenal and kidney of the offspring of sheep fed a restricted diet during pregnancy(Reference Burns, Desai and Cohen40Reference Gnanalingham, Mostyn and Dandrea43). Feeding a PR diet to pregnant rats up-regulates glucokinase expression in the liver of the offspring, which implies increased capacity for glucose uptake(Reference Bogdarina, Murphy and Burns44).

Restricting maternal protein intake during pregnancy and/or lactation in rats also alters the expression of specific genes involved in lipid homeostasis. Expression of acetyl-CoA carboxylase and fatty acid synthase were increased in the liver of the offspring of rats fed a PR diet during pregnancy and lactation(Reference Maloney, Gosby and Phuyal45). PPAR-α expression has also been reported to be increased in the liver of the offspring of rats fed a PR diet during pregnancy and was accompanied by up-regulation of its target gene acyl-CoA oxidase(Reference Burdge, Phillips and Dunn46, Reference Lillycrop, Phillips and Jackson47).

Long-term changes in gene expression have also been reported in adult offspring of dams fed a global under-nutrition or a high-fat diet during pregnancy. Gluckman et al. have showed that expression of PPARα and GR are both down-regulated in adult offspring born to dams fed a global nutrient restricted diet of 30% ad libitum during pregnancy(Reference Gluckman, Lillycrop and Vickers48), while in offspring from dams fed a ‘junk food diet’ during pregnancy there were persistent alterations in the expression of PPARγ2, 11β-hydroxysteroid dehydrogenase type I and the β2 and β3 adrenoreceptors in adipose tissue(Reference Samuelsson, Matthews and Argenton39). Long-term changes in the expression of PPARγ2 and the adrenoreceptors may lead to increased adipogenesis and decrease lipolysis in these rats.

To gain further understanding of the mechanisms by which maternal diet may induce such changes to the expression of genes, recent studies have investigated the specificity of induced changes in the transcriptome of the offspring using microarray analysis in animal models. The analysis of the changes in the hepatic transcriptome of adult offspring from control and PR-fed dams showed that only 1·3% of genes were changed in response to maternal protein restriction(Reference Lillycrop, Rodford and Garratt49), suggesting that maternal protein restriction alters the expression of a relatively small subset of genes. Significant alterations in pathways involved in ion transport, developmental process and response to steroid hormone and reactive oxygen species pathways were observed in PR v. control offspring. Alterations in these pathways are consistent with previous phenotypic studies, which show that ion transport(Reference Jansson and Powell50), cell commitment in blastocysts(Reference Kwong, Wild and Roberts51), response to reactive oxygen species(Reference Langley-Evans and Sculley30) and steroid hormones(Reference Langley-Evans, Phillips and Benediktsson52, Reference Bertram, Trowern and Copin53) are altered by maternal diet.

Developmental plasticity

These findings together demonstrate that the prenatal and early postnatal period play a critical role in the induction of metabolic disease in later life. Gluckman and Hanson have suggested that the changes induced by maternal under- or over-nutrition may reflect an adaptive response of the fetus to environmental cues acting through the process of developmental plasticity which allows an organism to adjust its developmental programme resulting in long-term changes in its metabolism and physiology in order to be better adapted to the future environment(Reference Gluckman and Hanson54). For instance, poor maternal nutrition may signal to the fetus that nutrients are scarce and an uncertain life course lies ahead. The fetus may then adapt its metabolism to conserve energy demands, increase its propensity to store fat, accelerate puberty and invest less in bone and muscle mass. If in the postnatal environment nutrition is indeed poor, then the organism's metabolism will be matched to the environment and that individual would be of low disease risk. In support of this, there is evidence that in both rat and pig models of maternal over-nutrition during pregnancy that continued high-fat feeding in postnatal life does not lead to deleterious effects(Reference Norman and LeVeen55, Reference Khan, Dekou and Hanson56). However, if the offspring does not predict correctly the environment experienced after birth, then it is at increased risk of developing CVD and metabolic disease because its metabolism and homoeostatic capacity is mismatched to that environment. This mismatch pathway may explain why a nutritional constraint in early life followed by an adequate or nutritionally rich postnatal diet will result in an increased risk of metabolic disease in later life. This would also explain why human populations undergoing socio-economic change or migration from rural to urban areas show increased risk of chronic disease(Reference Gluckman and Hanson57). One important feature of such adaptive changes during development is that different phenotypes can be generated from a single genome depending on the environment that the organism experiences and there is now increasing evidence that the mechanism by which different phenotypes are generated from a single genome is through the altered epigenetic regulation of genes.

Epigenetic mechanisms and regulation of transcription

The term epigenetics literally means on top of genetics and refers to processes that induce heritable changes in gene expression without altering the gene sequence. The major epigenetic processes are DNA methylation, histone modification and microRNA. Epigenetic processes are integral in determining when and where specific genes are expressed. Alterations therefore in the epigenetic regulation of genes may lead to profound changes in phenotype(Reference Li, Beard and Jaenisch58Reference DeBaun, Niemitz and Feinberg60). To date, most studies on the effect of early-life nutrition on the epigenetic regulation of genes have focused on DNA methylation.

Methylation at the 5′ position of cytosine in DNA within a CpG dinucleotide (p denotes the intervening phosphate group) is a common modification in mammalian genomes and constitutes a stable epigenetic mark that is transmitted through DNA replication and cell division(Reference Bird61). CpG dinucleotides are not randomly distributed throughout the genome but are clustered at the 5′ ends of genes/promoters in regions known as CpG islands. Hypermethylation of these CpG islands is associated with transcriptional repression, while hypomethylation of CpG islands is associated with transcriptional activation(Reference Bird61, Reference Bird62). DNA methylation can induce transcriptional silencing by either blocking the binding of transcription factors or through promoting the binding of the methyl CpG-binding protein 2. The latter binds to methylated cytosines and, in turn, recruits histone modifying complexes to the DNA(Reference Fuks, Hurd and Wolf63). Methyl CpG-binding protein 2 recruits both histone deacetylases, which remove acetyl groups from the histones, and histone methyl transferases that methylate Lys9 on His3, resulting in a closed chromatin structure and transcriptional silencing(Reference Fuks, Hurd and Wolf63Reference Zegerman, Canas and Pappin65). MicroRNA, which are small non-coding RNA, can also regulate gene expression, they have been shown to modulate gene expression at the post-transcriptional level through the induction of mRNA degradation or translational repression of a target mRNA(Reference Kuehbacher, Urbich and Dimmeler66). However, more recent studies have shown that the human microRNA can also induce chromatin remodelling(Reference Kim, Saetrom and Snove67) and direct DNA methylation(Reference Bayne and Allshire68), suggesting that DNA methylation, histone modifications and microRNA may work in concert to regulate gene expression.

DNA methylation is important for asymmetrical silencing of imprinted genes(Reference Li, Beard and Jaenisch58), X chromosome inactivation and silencing of retrotransposons(Reference Walsh, Chaillet and Bestor69, Reference Waterland and Jirtle70). DNA methylation is also critical for cell differentiation by silencing the expression of specific genes during the development and differentiation of individual tissues(Reference Bird61, Reference Bird62). Methylation of CpG is largely established during embryogenesis or in early postnatal life. Following fertilisation, maternal and paternal genomes undergo extensive demethylation. Following this, global de novo methylation occurs(Reference Reik and Walter71, Reference Reik, Dean and Walter72) during which 70% CpG are methylated, mainly in repressive heterochromatin regions and in repetitive sequences such as retrotransposable elements. At these early stages of development, the polycomb proteins, which are a group of histone modifying proteins play a critical role in maintaining the pluripotent nature of the embryonic stem cells by silencing cell determination genes such as Pax, Hox and Dlx (Reference Azuara, Perry and Sauer73), which are required for development, through polycomb-induced methylation of Lys27 on histone His3. As development proceeds, loss of polycomb proteins from their target genes(Reference Tiwari, McGarvey and Licchesi74) together with lineage-specific DNA methylation lead to the establishment of structurally and functionally distinct cell types. These epigenetic marks are essentially maintained throughout life. However, environmental perturbations during periods when methylation patterns are induced may impair the programme of gene silencing or activation with potential long-term adverse consequences.

Environmental challenges in early life alter the epigenome

A number of studies on isolated embryos have shown that variations in nutrient availability can alter the epigenome. Mouse embryos cultured in Whitten's medium without amino acids showed bi-allelic expression of the imprinted H19 gene, while those cultured in medium containing amino acids showed mono-allelic expression(Reference Doherty, Mann and Tremblay75). Differential methylation of the insulin-like growth factor-2 and H19 genes also occurred when embryos were cultured with or without fetal calf serum(Reference Khosla, Dean and Reik76). In human subjects, assisted reproductive technologies using in vitro fertilisation and intracytoplasmic sperm injection are associated with increased risk of Angelman's syndrome(Reference Cox, Burger and Lip59, Reference Orstavik, Eiklid and van der Hagen77) and Beckwith–Weidemann syndrome(Reference DeBaun, Niemitz and Feinberg60) which are caused by decreased methylation of the regulatory regions of the UBE3A, and H19 and insulin-like growth factor-2 genes(Reference Cox, Burger and Lip59, Reference DeBaun, Niemitz and Feinberg60). However, whether these effects are due to the nutrient composition of the medium or some other aspect of the in vitro environment is not known. Alterations to the epigenetic regulation of imprinted genes produce dramatic alterations to the phenotype of the offspring including structural abnormalities in the skeleton and other tissues, and metabolic defects that are evident at birth. Such changes are in marked contrast to the effects of environmental constraint associated with cardio-metabolic disease which are not associated with gross structural abnormalities.

Maternal diet and altered epigenetic regulation

Differences in the micronutrient intake during pregnancy in the agouti mouse have been shown to induce differences in the coat colour of the offspring. The murine Agouti viable yellow mutation results from the insertion of an intracisternal-A particle retrotransposon upstream of the agouti gene, which regulates the production of yellow-pigmented fur. Supplementation of pregnant mice with methyl donors and cofactors, betaine, choline, folic acid and vitamin B12 shifted the distribution of coat colour of the offspring from yellow (agouti) to brown (pseudo-agouti)(Reference Wolff, Kodell and Moore78). This shift is due to increased methylation of seven CpG dinucleotides 600 bp downstream of the Agouti viable yellow intracisternal A particle insertion site that acts as a cryptic promoter directing the expression of the agouti gene(Reference Waterland and Jirtle70).

We have also shown that feeding pregnant rats a PR diet-induced hypomethylation of the GR and PPARα promoters in the livers of juvenile and adult offspring, which was accompanied by increased mRNA expression of these genes(Reference Lillycrop, Phillips and Jackson47, Reference Burdge, Slater-Jefferies and Torrens79). This was the first evidence that moderate changes in macronutrient intake during pregnancy can alter the epigenome. This was associated with an increase in histone modifications at the GR promoter that facilitate transcription; acetylation of histones H3 and H4 and methylation of histone H3 at Lys4, while those that suppress gene expression were reduced or unchanged(Reference Lillycrop, Slater-Jefferies and Hanson80). Altered methylation status of the liver PPARα promoter was due to hypomethylation of four specific CpG dinucleotides, two of which predicted the level of the mRNA transcript, in juvenile offspring, which persisted in adults(Reference Lillycrop, Phillips and Torrens81). Because the altered CpG corresponded to transcription factor-binding sites, this suggests a mechanism by which changes in the epigenetic regulation of genes established during development determines changes in transcription in response to specific stimuli, and thus the capacity of the tissue to respond to metabolic challenge. The angiotensin receptor 1b promoter is also hypomethylated in adrenal glands from PR offspring(Reference Bogdarina, Welham and King82). Maternal global under-nutrition also induces in the offspring a phenotype that resembles human metabolic syndrome(Reference Heijmans, Tobi and Stein83). In contrast to the effect of the maternal PR diet, adult female offspring of dams which experienced 70% reduction in total nutrient intake during pregnancy showed hypermethylation and decreased expression of the GR and PPARα promoters in their liver(Reference Gluckman, Lillycrop and Vickers48). Thus, the effects of maternal nutrition on the epigenome of the offspring depend on the nature of the maternal nutrient challenge.

In human subjects, Heijmans and co-workers have reported hypomethylation of the imprinted insulin-like growth factor-2 gene in genomic DNA isolated from whole blood from individuals who were exposed to famine in utero during the Dutch Hunger Winter compared to unexposed same-sex siblings(Reference Heijmans, Tobi and Stein83). The same group also found that the insulin-like growth factor promoter was hypomethylated in individuals whose mothers were peri-conceptually exposed to famine, while IL-10, leptin, ATP-binding cassette A1 and the guanine nucleotide-binding protein were hypermethylated(Reference Tobi, Lumey and Talens84). These studies show that a nutritional challenge in early life can result in a change in DNA methylation which is detectable 60 years later, suggesting, as in the animal studies, early-life environment can induce long-term alterations to the epigenetic regulation of genes.

There is also evidence that an over-rich early nutritional environment can alter the epigenetic regulation of genes. Plagemann et al. (Reference Plagemann, Harder and Brunn85) showed that neonatal overfeeding induced by raising rat pups in small litters induces the hypermethylation of two CpG dinucleotides within the Pro-opiomelanocortin promoter, which are essential for Pro-opiomelanocortin induction by leptin and insulin(Reference Plagemann, Harder and Brunn85). Consequently, Pro-opiomelanocortin expression is not up-regulated in these rats despite hyperinsulinaemia and hyperleptinaemia(Reference Plagemann, Harder and Brunn85). Thus, overfeeding during early postnatal life when the circuitry within the hypothalamus is still developing can alter the methylation of a gene critical for appetite control, resulting in the long-term altered regulation of this system and an increased disposition towards obesity in later life.

Reversal or prevention of altered phenotype and epigenotype

Induction of an altered phenotype in the offspring of rats fed PR diet during pregnancy can be prevented by supplementation of the PR diet with glycine or folic acid(Reference Burdge, Lillycrop and Jackson31, Reference Jackson, Dunn and Marchand86, Reference Brawley, Torrens and Anthony87). Increasing the folic acid content of the PR diet (PR supplemented with folic acid) also prevented the hypomethylation of the PPARα and GR promoters and restored levels of GR and PPARα expression to levels seen in control offspring. Folic acid supplementation of PR diet during pregnancy also up-regulated DNA methyltransferase (Dnmt) 1 expression(Reference Lillycrop, Slater-Jefferies and Hanson80). This suggests that impaired 1-carbon metabolism plays a central role in the induction of the altered epigenetic regulation of GR and PPARα and in the induction of an altered phenotype by maternal protein restriction. A comparison of the hepatic transcriptome in offspring from control, PR and PR supplemented with folic acid dams revealed, while 1·3% of genes were altered in response to maternal PR, only 0·7% of genes in the liver were changed between control and PR-supplemented-with-folic-acid offspring(Reference Lillycrop, Rodford and Garratt49), suggesting that while folic acid supplementation can prevent many of the changes induced by maternal protein restriction, it cannot prevent all changes and induces folate-specific changes in gene expression. Moreover detailed analysis of the PPARα promoter showed that although increased maternal folic acid intake prevented hypomethylation of the majority of CpG dinucleotides induced by the PR diet alone, two CpG were hypermethylated(Reference Lillycrop, Phillips and Torrens81). Thus, increasing maternal folic acid intake does not simply prevent the effects of the PR diet, but may induce subtle changes in gene regulation.

However, it has also become apparent that the period of epigenetic plasticity may extend beyond the early intra-uterine period. Burdge et al. (Reference Burdge, Lillycrop and Phillips88) have shown that increasing folic acid intake in the juvenile-pubertal period in rats whose mothers were fed protein sufficient or restricted diets during pregnancy, altered their phenotype and epigenotype(Reference Burdge, Lillycrop and Phillips88). However, supplementation of the diet of juvenile-pubertal rats of dams fed a PR diet did not simply reverse the altered epigenotype induced by maternal PR, but induced a different pattern of epigenetic changes including hypermethylation of the PPARα promoter(Reference Burdge, Lillycrop and Phillips88). These results showed that in contrast to supplementation of the maternal PR diet with folic acid, supplementation during the juvenile-pubertal period induced, irrespective of the maternal diet, impaired lipid homeostasis including down-regulation of hepatic fatty acid β-oxidation, hepatosteatosis and increased weight gain. These findings suggest that the period between weaning and adulthood in rats represents a period of increased plasticity, where it may be possible to reverse the adverse effects of prenatal nutrition by nutritional interventions before adulthood. However, these data also indicate that any intervention must be undertaken with care with respect to the intervention and background diet to avoid inducing further deleterious epigenetic changes.

Supplementation of the maternal diet with methyl donors has also been shown to prevent the transgenerational amplification of obesity observed in Agouti viable yellow mice(Reference Waterland, Travisano and Tahiliani89), supporting the hypothesis that altered epigenetic regulation also underlies the mechanism by which maternal obesity can increase the risk of offspring obesity. The effect of methyl supplementation on body weight was independent of epigenetic changes at the Agouti viable yellow locus, suggesting that maternal obesity alters the epigenetic regulation at other genetic loci which may influence appetite and energy homeostasis and that methyl supplementation blocks such epigenetic dysregulation.

Treatment with leptin between postnatal days 3 and 13 of neonatal rats born to dams which experienced 70% global reduction in food intake during pregnancy normalised energetic intake, locomotor activity, body weight, fat mass and fasting plasma glucose, insulin and leptin concentrations in adult offspring in contrast to saline-treated offspring of undernourished dams which developed all these features on a high-fat diet(Reference Vickers, Gluckman and Coveny90). This again shows that developmental metabolic programming is potentially reversible by an intervention late in the phase of developmental plasticity. The ability of leptin to reverse these metabolic effects has been suggested to occur as a result of leptin administration giving a false developmental cue signalling adiposity to the pups that were actually thin and thus therefore setting their metabolic phenotype to be more appropriate to a high-nutrition environment. Strikingly, the corrective effects of leptin were paralleled by effects on methylation and expression of PPARα and GR(Reference Gluckman, Lillycrop and Vickers48). This suggests that neonatal leptin intervention may exert its corrective adaptive effects through epigenetic mechanisms.

Mechanisms for induced changes in the epigenome

Methylation of CpG dinucleotides is catalysed by Dnmt3a and Dnmt3b, and is maintained through mitosis by gene-specific methylation of hemimethylated DNA by Dnmt1(Reference Yoder, Soman and Verdine91). Although traditionally DNA methylation has been regarded as a stable epigenetic mark, active demethylation has been observed for paternal genomic DNA in the zygote upon fertilisation(Reference Reik, Dean and Walter72). Rapid demethylation has also been reported of the synaptic plasticity gene reelin in the hippocampus upon contextual fear conditioning(Reference Miller, Gavin and White92) and on interferon-γ upon antigen exposure of memory CD8 T cells(Reference Kersh, Fitzpatrick and Murali-Krishna93). A number of DNA demethylases have now been proposed; these include MBD2b(Reference Bhattacharya, Ramchandani and Cervoni94), MBD4(Reference Zhu, Zheng and Angliker95), the DNA repair endonucleases XPG (Gadd45a)(Reference Barreto, Schafer and Marhold96) and a G/T mismatch repair DNA glycosylase(Reference Jost97).

The mechanism by which nutrition in early life alters the epigenome is not known but feeding a PR diet to rats during pregnancy induced a reduction in Dnmt1 expression, but not in the expression of Dnmt3a and Dnmt3b(Reference Lillycrop, Slater-Jefferies and Hanson80). This suggests that hypomethylation of the GR and PPARα promoters in the liver of the offspring may be induced by a failure to maintain methylation patterns during mitosis(Reference Lillycrop, Slater-Jefferies and Hanson80, Reference Burdge, Hanson and Slater-Jefferies98). This is supported by the finding that a decrease in Dnmt1 expression induced by the maternal PR diet was prevented by increasing the folic acid content of the PR diet during pregnancy. Folic acid supplementation of the PR diet during pregnancy also prevented the hypomethylation of GR and PPARα and many of the phenotypic changes induced by PR(Reference Lillycrop, Slater-Jefferies and Hanson80). Although a reduction in Dnmt1 activity might be expected to result in global demethylation, abolition of Dnmt1 expression appears only to affect a subset of genes(Reference Jackson-Grusby, Beard and Possemato99). This indicates that Dnmt1 is targeted to specific genes, and there are now a number of reports that have shown that Dnmt1 interacts with a number of histone-modifying enzymes and is targeted to specific DNA sites(Reference Fuks, Burgers and Brehm100, Reference Rountree, Bachman and Baylin101). As recent findings have suggested that DNA methylation may involve continual demethylation–remethylation cycles(Reference Vire, Brenner and Deplus102, Reference Szyf103), nutritional challenges in early life which alter the activity of the Dnmt1 may shift this equilibrium towards demethylation.

Conclusion

Traditionally DNA sequence was believed to be the sole determinant of phenotype and phenotypic variation was a result of genetic mutation or recombination. There is now evidence that epigenetic mechanisms allow the developing fetus to adapt to nutritional cues from the mother and adjust its developmental trajectory to produce a phenotype matched to the predicted postnatal environment. Studies from both animal and human subjects suggest that these altered epigenetic marks induced by early environmental challenges are stably maintained throughout the life course raising the possibility that these altered marks may be used as predictive markers of later phenotype and disease risk. Animal studies also suggest that these altered epigenetic marks can be prevented and/or reversed at specific time periods implying that it may be possible either through nutritional or pharmaceutical interventions to reverse such epigenetic marks and reduce the incidence of non-communicable diseases. However, there is still much we have to learn in terms of which early-life exposures can alter the epigenome, which pathways are affected, what are the critical developmental periods and when the epigenome is most susceptible to environmental cues and can interventions be targeted to specific epigenetic marks. With this increased level of understanding of the relationship between epigenetics, the environment and disease susceptibility, it may be possible to make real progress in the prevention and treatment of chronic diseases and halt the rapid rise in non-communicable diseases currently seen throughout the world.

Acknowledgements

The author declares no conflict of interest.

References

1.WHO (2009) Cardiovascular Diseases. Geneva: WHO.Google Scholar
2.Godfrey, KM & Barker, DJ (2001) Fetal programming and adult health. Public Health Nutr 4, 611624.CrossRefGoogle ScholarPubMed
3.Bertram, CE & Hanson, MA (2001) Animal models and programming of the metabolic syndrome. Br Med Bull 60, 103121.CrossRefGoogle ScholarPubMed
4.Armitage, JA, Khan, IY, Taylor, PD et al. (2004) Developmental programming of the metabolic syndrome by maternal nutritional imbalance: how strong is the evidence from experimental models in mammals? J Physiol 561, 355377.CrossRefGoogle ScholarPubMed
5.Burdge, GC & Lillycrop, KA (2010) Nutrition, epigenetics, and developmental plasticity: implications for understanding human disease. Annu Rev Nutr 30, 315–39.CrossRefGoogle ScholarPubMed
6.Barker, DJ & Osmond, C (1986) Infant mortality, childhood nutrition, and ischaemic heart disease in England and Wales. Lancet 1, 10771081.CrossRefGoogle Scholar
7.Curhan, GC, Willett, WC, Rimm, EB et al. (1996) Birth weight and adult hypertension, diabetes mellitus, and obesity in US men. Circulation 94, 32463250.CrossRefGoogle Scholar
8.McCance, DR, Pettitt, DJ, Hanson, RL et al. . (1994) Birth weight and non-insulin dependent diabetes: thrifty genotype, thrifty phenotype, or surviving small baby genotype? BMJ 308, 942945.CrossRefGoogle ScholarPubMed
9.Hanson, MA & Gluckman, PD (2005) Developmental processes and the induction of cardiovascular function: conceptual aspects. J Physiol 565, 2734.CrossRefGoogle ScholarPubMed
10.Gluckman, PD & Hanson, MA (2008) Developmental and epigenetic pathways to obesity: an evolutionary-developmental perspective. Int J Obes 32, Suppl. 7, S62S71.CrossRefGoogle Scholar
11.Painter, RC, Roseboom, TJ & Bleker, OP (2005) Prenatal exposure to the Dutch famine and disease in later life: an overview. Reprod Toxicol 20, 345352.CrossRefGoogle ScholarPubMed
12.Singhal, A, Cole, TJ, Fewtrell, M et al. . (2004) Breastmilk feeding and lipoprotein profile in adolescents born preterm: follow-up of a prospective randomised study. Lancet 363, 15711578.CrossRefGoogle ScholarPubMed
13.Singhal, A (2006) Early nutrition and long-term cardiovascular health. Nutr Rev 64, S44S49.CrossRefGoogle ScholarPubMed
14.Harder, T, Bergmann, R, Kallischnigg, G et al. . (2005) Duration of breastfeeding and risk of overweight: a meta-analysis. Am J Epidemiol 162, 397403.CrossRefGoogle ScholarPubMed
15.Owen, CG, Martin, RM, Whincup, PH et al. . (2005) Effect of infant feeding on the risk of obesity across the life course: a quantitative review of published evidence. Pediatrics 115, 13671377.CrossRefGoogle Scholar
16.Owen, CG, Martin, RM, Whincup, PH et al. (2005) The effect of breastfeeding on mean body mass index throughout life: a quantitative review of published and unpublished observational evidence. Am J Clin Nutr 82, 12981307.Google ScholarPubMed
17.Gluckman, PD & Hanson, MA (2006) Evolution, development and timing of puberty. Trends Endocrinol Metab 17, 7–12.CrossRefGoogle ScholarPubMed
18.Dorner, G & Plagemann, A (1994) Perinatal hyperinsulinism as possible predisposing factor for diabetes mellitus, obesity and enhanced cardiovascular risk in later life. Horm Metab Res 26, 213221.CrossRefGoogle ScholarPubMed
19.Oken, E, Taveras, EM, Kleinman, KP et al. (2007) Gestational weight gain and child adiposity at age 3 years. Am J Obstet Gynecol 196, 322328.CrossRefGoogle ScholarPubMed
20.Villamor, E & Cnattingius, S (2006) Interpregnancy weight change and risk of adverse pregnancy outcomes: a population-based study. Lancet 368, 11641170.CrossRefGoogle ScholarPubMed
21.Kral, JG, Biron, S, Simard, S et al. (2006) Large maternal weight loss from obesity surgery prevents transmission of obesity to children who were followed for 2 to 18 years. Pediatrics 118, e1644e1649.CrossRefGoogle ScholarPubMed
22.Langley-Evans, SC (2009) Nutritional programming of disease: unravelling the mechanism. J Anat 215, 3651.CrossRefGoogle ScholarPubMed
23.Langley-Evans, SC, Phillips, GJ & Jackson, AA (1994) In utero exposure to maternal low protein diets induces hypertension in weanling rats, independently of maternal blood pressure changes. Clin Nutr 13, 319324.CrossRefGoogle ScholarPubMed
24.Bellinger, L, Lilley, C & Langley-Evans, SC (2004) Prenatal exposure to a maternal low-protein diet programmes a preference for high-fat foods in the young adult rat. Br J Nutr 92, 513520.CrossRefGoogle Scholar
25.Bellinger, L, Sculley, DV & Langley-Evans, SC (2006) Exposure to undernutrition in fetal life determines fat distribution, locomotor activity and food intake in ageing rats. Int J Obes 30, 729738.CrossRefGoogle ScholarPubMed
26.Lucas, A, Baker, BA, Desai, M et al. (1996) Nutrition in pregnant or lactating rats programs lipid metabolism in the offspring. Br J Nutr 76, 605612.CrossRefGoogle ScholarPubMed
27.Burdge, GC, Slater-Jefferies, JL, Grant, RA et al. . (2008) Sex, but not maternal protein or folic acid intake, determines the fatty acid composition of hepatic phospholipids, but not of triacylglycerol, in adult rats. Prostaglandins Leukot Essent Fatty Acids 78, 7379.CrossRefGoogle Scholar
28.Torrens, C, Hanson, MA, Gluckman, PD et al. (2009) Maternal undernutrition leads to endothelial dysfunction in adult male rat offspring independent of postnatal diet. Br J Nutr 101, 2733.CrossRefGoogle ScholarPubMed
29.Calder, PC & Yaqoob, P (2000) The level of protein and type of fat in the diet of pregnant rats both affect lymphocyte function in the offspring. Nutr Res 20, 995–1005.CrossRefGoogle Scholar
30.Langley-Evans, SC & Sculley, DV (2005) Programming of hepatic antioxidant capacity and oxidative injury in the ageing rat. Mech Ageing Dev 126, 804812.CrossRefGoogle ScholarPubMed
31.Burdge, GC, Lillycrop, KA, Jackson, AA et al. (2008) The nature of the growth pattern and of the metabolic response to fasting in the rat are dependent upon the dietary protein and folic acid intakes of their pregnant dams and post-weaning fat consumption. Br J Nutr 99, 540549.CrossRefGoogle ScholarPubMed
32.Ozanne, SE & Hales, CN (2004) Lifespan: catch-up growth and obesity in male mice. Nature 427, 411412.CrossRefGoogle ScholarPubMed
33.Zambrano, E, Bautista, CJ, Deas, M et al. (2006) 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 571, 221230.CrossRefGoogle ScholarPubMed
34.Woodall, SM, Johnston, BM, Breier, BH et al. (1996) Chronic maternal undernutrition in the rat leads to delayed postnatal growth and elevated blood pressure of offspring. Pediatr Res 40, 438443.CrossRefGoogle Scholar
35.Kind, KL, Clifton, PM, Katsman, AI et al. (1999) Restricted fetal growth and the response to dietary cholesterol in the guinea pig. Am J Physiol 277, R1675R1682.Google ScholarPubMed
36.Hawkins, P, Steyn, C, McGarrigle, HH et al. (2000) Effect of maternal nutrient restriction in early gestation on responses of the hypothalamic-pituitary-adrenal axis to acute isocapnic hypoxaemia in late gestation fetal sheep. Exp Physiol 85, 8596.CrossRefGoogle ScholarPubMed
37.Guo, F & Jen, KL (1995) High-fat feeding during pregnancy and lactation affects offspring metabolism in rats. Physiol Behav 57, 681686.CrossRefGoogle Scholar
38.Brown, SA, Rogers, LK, Dunn, JK et al. . (1990) Development of cholesterol homeostatic memory in the rat is influenced by maternal diets. Metabolism 39, 468473.CrossRefGoogle ScholarPubMed
39.Samuelsson, AM, Matthews, PA, Argenton, M et al. (2008) Diet-induced obesity in female mice leads to offspring hyperphagia, adiposity, hypertension, and insulin resistance: a novel murine model of developmental programming. Hypertension 51, 383392.CrossRefGoogle ScholarPubMed
40.Burns, SP, Desai, M, Cohen, RD et al. . (1997) 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 100, 17681774.CrossRefGoogle ScholarPubMed
41.Whorwood, CB, Firth, KM, Budge, H et al. (2001) Maternal undernutrition during early to midgestation programs tissue-specific alterations in the expression of the glucocorticoid receptor, 11beta-hydroxysteroid dehydrogenase isoforms, and type 1 angiotensin II receptor in neonatal sheep. Endocrinology 142, 28542864.CrossRefGoogle ScholarPubMed
42.Brennan, KA, Gopalakrishnan, GS, Kurlak, L et al. (2005) Impact of maternal undernutrition and fetal number on glucocorticoid, growth hormone and insulin-like growth factor receptor mRNA abundance in the ovine fetal kidney. Reproduction 129, 151159.CrossRefGoogle ScholarPubMed
43.Gnanalingham, MG, Mostyn, A, Dandrea, J et al. (2005) Ontogeny and nutritional programming of uncoupling protein-2 and glucocorticoid receptor mRNA in the ovine lung. J Physiol 565, 159169.CrossRefGoogle ScholarPubMed
44.Bogdarina, I, Murphy, HC, Burns, SP et al. (2004) Investigation of the role of epigenetic modification of the rat glucokinase gene in fetal programming. Life Sci 74, 14071415.CrossRefGoogle ScholarPubMed
45.Maloney, CA, Gosby, AK, Phuyal, JL et al. . (2003) Site-specific changes in the expression of fat-partitioning genes in weanling rats exposed to a low-protein diet in utero. Obes Res 11, 461468.CrossRefGoogle ScholarPubMed
46.Burdge, GC, Phillips, ES, Dunn, RL et al. . (2004) 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 24, 639646.CrossRefGoogle Scholar
47.Lillycrop, KA, Phillips, ES, Jackson, AA et al. . (2005) Dietary protein restriction of pregnant rats induces and folic acid supplementation prevents epigenetic modification of hepatic gene expression in the offspring. J Nutr 135, 13821386.Google Scholar
48.Gluckman, PD, Lillycrop, KA, Vickers, MH et al. . (2007) Metabolic plasticity during mammalian development is directionally dependent on early nutritional status. Proc Natl Acad Sci USA 104, 1279612800.CrossRefGoogle ScholarPubMed
49.Lillycrop, KA, Rodford, J, Garratt, ES et al. . (2010) Maternal protein restriction with or without folic acid supplementation during pregnancy alters the hepatic transcriptome in adult male rats. Br J Nutr 103, 17111719.CrossRefGoogle ScholarPubMed
50.Jansson, T & Powell, TL (2000) Placental nutrient transfer and fetal growth. Nutrition 16, 500502.CrossRefGoogle Scholar
51.Kwong, WY, Wild, AE, Roberts, P et al. . (2000) Maternal undernutrition during the preimplantation period of rat development causes blastocyst abnormalities and programming of postnatal hypertension. Development 127, 41954202.Google Scholar
52.Langley-Evans, SC, Phillips, GJ, Benediktsson, R et al. (1996) Protein intake in pregnancy, placental glucocorticoid metabolism and the programming of hypertension in the rat. Placenta 17, 169172.CrossRefGoogle Scholar
53.Bertram, C, Trowern, AR, Copin, N et al. . (2001) The maternal diet during pregnancy programs altered expression of the glucocorticoid receptor and type 2 11beta-hydroxysteroid dehydrogenase: potential molecular mechanisms underlying the programming of hypertension in utero. Endocrinology 142, 28412853.CrossRefGoogle Scholar
54.Gluckman, PD & Hanson, MA (2004) Developmental origins of disease paradigm: a mechanistic and evolutionary perspective. Pediatr Res 56, 311317.CrossRefGoogle ScholarPubMed
55.Norman, JF & LeVeen, RF (2001) Maternal atherogenic diet in swine is protective against early atherosclerosis development in offspring consuming an atherogenic diet post-natally. Atherosclerosis 157, 4147.CrossRefGoogle ScholarPubMed
56.Khan, I, Dekou, V, Hanson, M et al. (2004) Predictive adaptive responses to maternal high-fat diet prevent endothelial dysfunction but not hypertension in adult rat offspring. Circulation 110, 10971102.CrossRefGoogle Scholar
57.Gluckman, PD & Hanson, MA (2005) The Fetal Matrix: Evolution, Developmental and Disease. Cambridge: Cambridge University Press.Google Scholar
58.Li, E, Beard, C & Jaenisch, R (1993) Role for DNA methylation in genomic imprinting. Nature 366, 362365.CrossRefGoogle ScholarPubMed
59.Cox, GF, Burger, J, Lip, V et al. . (2002) Intracytoplasmic sperm injection may increase the risk of imprinting defects. Am J Hum Genet 71, 162164.CrossRefGoogle ScholarPubMed
60.DeBaun, MR, Niemitz, EL & Feinberg, AP (2003) Association of in vitro fertilization with Beckwith–Wiedemann syndrome and epigenetic alterations of LIT1 and H19. Am J Hum Genet 72, 156160.CrossRefGoogle Scholar
61.Bird, A (2002) DNA methylation patterns and epigenetic memory. Genes Dev 16, 6–21.CrossRefGoogle ScholarPubMed
62.Bird, A (2001) Molecular biology. Methylation talk between histones and DNA. Science 294, 21132115.CrossRefGoogle ScholarPubMed
63.Fuks, F, Hurd, PJ, Wolf, D et al. . (2003) The methyl-CpG-binding protein MeCP2 links DNA methylation to histone methylation. J Biol Chem 278, 40354040.CrossRefGoogle ScholarPubMed
64.Lachner, M, O'Carroll, D, Rea, S et al. (2001) Methylation of histone H3 lysine 9 creates a binding site for HP1 proteins. Nature 410, 116120.CrossRefGoogle ScholarPubMed
65.Zegerman, P, Canas, B, Pappin, D et al. (2002) Histone H3 lysine 4 methylation disrupts binding of nucleosome remodeling and deacetylase (NuRD) repressor complex. J Biol Chem 277, 1162111624.CrossRefGoogle ScholarPubMed
66.Kuehbacher, A, Urbich, C & Dimmeler, S (2008) Targeting microRNA expression to regulate angiogenesis. Trends Pharmacol Sci 29, 1215.CrossRefGoogle ScholarPubMed
67.Kim, DH, Saetrom, P, Snove, O et al. (2008) MicroRNA-directed transcriptional gene silencing in mammalian cells. Proc Natl Acad Sci USA 105, 1623016235.CrossRefGoogle ScholarPubMed
68.Bayne, EH & Allshire, RC (2005) RNA-directed transcriptional gene silencing in mammals. Trends Genet 21, 370373.CrossRefGoogle ScholarPubMed
69.Walsh, CP, Chaillet, JR & Bestor, TH (1998) Transcription of IAP endogenous retroviruses is constrained by cytosine methylation. Nat Genet 20, 116117.CrossRefGoogle ScholarPubMed
70.Waterland, RA & Jirtle, RL (2003) Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Mol Cell Biol 23, 52935300.CrossRefGoogle Scholar
71.Reik, W & Walter, J (2001) Genomic imprinting: parental influence on the genome. Nat Rev Genet 2, 2132.CrossRefGoogle ScholarPubMed
72.Reik, W, Dean, W & Walter, J (2001) Epigenetic reprogramming in mammalian development. Science 293, 10891093.CrossRefGoogle ScholarPubMed
73.Azuara, V, Perry, P, Sauer, S et al. (2006) Chromatin signatures of pluripotent cell lines. Nat Cell Biol 8, 532538.CrossRefGoogle ScholarPubMed
74.Tiwari, VK, McGarvey, KM, Licchesi, JD et al. (2008) PcG proteins, DNA methylation, and gene repression by chromatin looping. PLoS Biol 6, 29112927.CrossRefGoogle ScholarPubMed
75.Doherty, AS, Mann, MR, Tremblay, KD et al. . (2000) Differential effects of culture on imprinted H19 expression in the preimplantation mouse embryo. Biol Reprod 62, 15261535.CrossRefGoogle ScholarPubMed
76.Khosla, S, Dean, W, Reik, W et al. . (2001) Culture of preimplantation embryos and its long-term effects on gene expression and phenotype. Hum Reprod Update 7, 419427.CrossRefGoogle ScholarPubMed
77.Orstavik, KH, Eiklid, K, van der Hagen, CB et al. (2003) Another case of imprinting defect in a girl with Angelman syndrome who was conceived by intracytoplasmic semen injection. Am J Hum Genet 72, 218219.CrossRefGoogle Scholar
78.Wolff, GL, Kodell, RL, Moore, SR et al. . (1998) Maternal epigenetics and methyl supplements affect agouti gene expression in Avy/a mice. FASEB J 12, 949957.Google ScholarPubMed
79.Burdge, GC, Slater-Jefferies, J, Torrens, C et al. (2007) Dietary protein restriction of pregnant rats in the F0 generation induces altered methylation of hepatic gene promoters in the adult male offspring in the F1 and F2 generations. Br J Nutr 97, 435439.CrossRefGoogle ScholarPubMed
80.Lillycrop, KA, Slater-Jefferies, JL, Hanson, MA et al. (2007) 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 97, 10641073.CrossRefGoogle Scholar
81.Lillycrop, KA, Phillips, ES, Torrens, C et al. . (2008) Feeding pregnant rats a protein-restricted diet persistently alters the methylation of specific cytosines in the hepatic PPARalpha promoter of the offspring. Br J Nutr 100, 278282.CrossRefGoogle Scholar
82.Bogdarina, I, Welham, S, King, PJ et al. (2007) Epigenetic modification of the renin-angiotensin system in the fetal programming of hypertension. Circ Res 100, 520526.CrossRefGoogle ScholarPubMed
83.Heijmans, BT, Tobi, EW, Stein, AD et al. . (2008) Persistent epigenetic differences associated with prenatal exposure to famine in humans. Proc Natl Acad Sci USA 105, 1704617049.CrossRefGoogle ScholarPubMed
84.Tobi, EW, Lumey, LH, Talens, RP et al. . (2009) DNA methylation differences after exposure to prenatal famine are common and timing- and sex-specific. Hum Mol Genet 18, 40464053.CrossRefGoogle ScholarPubMed
85.Plagemann, A, Harder, T, Brunn, M et al. . (2009) Hypothalamic proopiomelanocortin promoter methylation becomes altered by early overfeeding: an epigenetic model of obesity and the metabolic syndrome. J Physiol 587, 49634976.CrossRefGoogle ScholarPubMed
86.Jackson, AA, Dunn, RL, Marchand, MC et al. (2002) Increased systolic blood pressure in rats induced by a maternal low-protein diet is reversed by dietary supplementation with glycine. Clin Sci 103, 633639.CrossRefGoogle ScholarPubMed
87.Brawley, L, Torrens, C, Anthony, FW et al. . (2004) Glycine rectifies vascular dysfunction induced by dietary protein imbalance during pregnancy. J Physiol 554, 497504.CrossRefGoogle Scholar
88.Burdge, GC, Lillycrop, KA, Phillips, ES et al. . (2009) Folic acid supplementation during the juvenile-pubertal period in rats modifies the phenotype and epigenotype induced by prenatal nutrition. J Nutr 139, 10541060.CrossRefGoogle ScholarPubMed
89.Waterland, RA, Travisano, M, Tahiliani, KG et al. (2008) Methyl donor supplementation prevents transgenerational amplification of obesity. Int J Obes 32, 13731379.CrossRefGoogle ScholarPubMed
90.Vickers, MH, Gluckman, PD, Coveny, AH et al. (2005) Neonatal leptin treatment reverses developmental programming. Endocrinology 146, 42114216.CrossRefGoogle ScholarPubMed
91.Yoder, JA, Soman, NS, Verdine, GL et al. . (1997) DNA (cytosine-5)-methyltransferases in mouse cells and tissues. Studies with a mechanism-based probe. J Mol Biol 270, 385395.CrossRefGoogle ScholarPubMed
92.Miller, CA, Gavin, CF, White, JA et al. (2010) Cortical DNA methylation maintains remote memory. Nat Neurosci 13, 664666.CrossRefGoogle ScholarPubMed
93.Kersh, EN, Fitzpatrick, DR, Murali-Krishna, K et al. (2006) Rapid demethylation of the IFN-gamma gene occurs in memory but not naive CD8T cells. J Immunol 176, 40834093.CrossRefGoogle ScholarPubMed
94.Bhattacharya, SK, Ramchandani, S, Cervoni, N et al. (1999) A mammalian protein with specific demethylase activity for mCpG DNA. Nature 397, 579583.Google ScholarPubMed
95.Zhu, B, Zheng, Y, Angliker, H et al. . (2000) 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 28, 41574165.CrossRefGoogle Scholar
96.Barreto, G, Schafer, A, Marhold, J et al. (2007) Gadd45a promotes epigenetic gene activation by repair-mediated DNA demethylation. Nature 445, 671675.CrossRefGoogle ScholarPubMed
97.Jost, JP (1993) Nuclear extracts of chicken embryos promote an active demethylation of DNA by excision repair of 5-methyldeoxycytidine. Proc Natl Acad Sci USA 90, 46844688.CrossRefGoogle ScholarPubMed
98.Burdge, GC, Hanson, MA, Slater-Jefferies, JL et al. (2007) Epigenetic regulation of transcription: a mechanism for inducing variations in phenotype (fetal programming) by differences in nutrition during early life? Br J Nutr 97, 10361046.CrossRefGoogle Scholar
99.Jackson-Grusby, L, Beard, C, Possemato, R et al. . (2001) Loss of genomic methylation causes p53-dependent apoptosis and epigenetic deregulation. Nat Genet 27, 3139.Google ScholarPubMed
100.Fuks, F, Burgers, WA, Brehm, A et al. (2000) DNA methyltransferase Dnmt1 associates with histone deacetylase activity. Nat Genet 24, 8891.Google ScholarPubMed
101.Rountree, MR, Bachman, KE & Baylin, SB (2000) DNMT1 binds HDAC2 and a new co-repressor, DMAP1, to form a complex at replication foci. Nat Genet 25, 269277.CrossRefGoogle Scholar
102.Vire, E, Brenner, C, Deplus, R et al. (2006) The Polycomb group protein EZH2 directly controls DNA methylation. Nature 439, 871874.CrossRefGoogle ScholarPubMed
103.Szyf, M (2007) The dynamic epigenome and its implications in toxicology. Toxicol Sci 100, 7–23.CrossRefGoogle ScholarPubMed
You have Access
76
Cited by

Send article to Kindle

To send this article to your Kindle, first ensure no-reply@cambridge.org 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 @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘@kindle.com’ 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.

Effect of maternal diet on the epigenome: implications for human metabolic disease
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.

Effect of maternal diet on the epigenome: implications for human metabolic disease
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.

Effect of maternal diet on the epigenome: implications for human metabolic disease
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? *