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Review

Considering Maternal Dietary Modulators for Epigenetic Regulation and Programming of the Fetal Epigenome

by
Abalo Chango
1,* and
Igor P. Pogribny
2
1
Polytechnic Institute LaSalle Beauvais, Department of Nutrition and Health Sciences, EGEAL UP:2012.10.101, F-60026 Beauvais Cedex, France
2
Division of Biochemical Toxicology, Food and Drug Administration National Center for Toxicological Research, Jefferson, AR 72079, USA
*
Author to whom correspondence should be addressed.
Nutrients 2015, 7(4), 2748-2770; https://0-doi-org.brum.beds.ac.uk/10.3390/nu7042748
Submission received: 31 December 2014 / Revised: 16 February 2015 / Accepted: 19 March 2015 / Published: 14 April 2015
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Abstract

:
Fetal life is characterized by a tremendous plasticity and ability to respond to various environmental and lifestyle factors, including maternal nutrition. Identification of the role of dietary factors that can modulate and reshape the cellular epigenome during development, including methyl group donors (e.g., folate, choline) and bioactive compounds (e.g., polyphenols) is of great importance; however, there is insufficient knowledge of a particular effect of each type of modulator and/or their combination on fetal life. To enhance the quality and safety of food products for proper fetal health and disease prevention in later life, a better understanding of the underlying mechanisms of dietary epigenetic modulators during the critical prenatal period is necessary. This review focuses on the influence of maternal dietary components on DNA methylation, histone modification, and microRNAs, and summarizes current knowledge of the effect and importance of dietary components on epigenetic mechanisms that control the proper expression of genetic information. Evidence reveals that some components in the maternal diet can directly or indirectly affect epigenetic mechanisms. Understanding the underlying mechanisms of how early-life nutritional environment affects the epigenome during development is of great importance for the successful prevention of adult chronic diseases through optimal maternal nutrition.

1. Introduction

Accumulating evidence demonstrates clearly that heritable changes in gene expression driven by epigenetic mechanisms play an important role not only in early development, but also in the predisposition to future disease development. Currently, the critical role of epigenetic abnormalities, especially DNA methylation, in the pathogenesis of major human non communicable diseases, including cancer, metabolic syndrome, and cardiovascular and autoimmune disease, is well established [1,2,3,4,5,6]. DNA methylation is indispensable for proper embryonic development as emphasized by Gaudet et al. [7]. Early embryonic development is of special interest as it is a crucial period in establishing individual epigenetic marks in the genome [8,9]. Additionally, it has been hypothesized that successful health maintenance and health management in later life relies on better understanding of how early life nutrition affects the epigenome and influences the expression of genetic information and disease etiology [10,11] in adulthood.
A major finding in the field of nutrition is discovering that dietary components may reshape the genome in utero and that epigenetic changes induced during early life may permanently alter the phenotype in the adult organism (Figure 1) [12,13]. A number of reviews have focused on maternal nutrition and its impact on epigenetic mechanisms along with studies addressing different types of exposure, such as nutritional factors, glucocorticoids, and endocrine-disrupting chemicals [11,14,15]. Because a maternal diet and/or early nutrition of the newborn may affect the phenotype later in adulthood [14,15,16], susceptibility of epigenetic mechanisms to the nutritional environment is a critical element in fetal development. However, insufficient knowledge exists in addressing how nutritional factors influence epigenetic mechanisms during fetal development and how to prevent potential negative effects on health. The impact of nutrition on genomic DNA methylation through one-carbon metabolism is well-documented. Specifically, it has been demonstrated that dietary deficiency or excess of the methyl group donors needed for the cellular methylation reactions can alter epigenetic patterns, which may persist for a long period and alter gene expression causing phenotypic changes. In contrast, the impact of diet on other epigenetic mechanisms, including histone modification, chromatin modifying proteins, and microRNA (miRNA) expression is poorly defined. Some dietary components may induce favorable epigenetic effects on the organism (health promoters), while others may cause rather unfavorable or negative epigenetic health effects. In this respect, it is of great importance to identify both the favorable and unfavorable epigenetic impact of dietary components.
This review highlights the nutritional epigenetic aspects of the contemporary maternal diet and summarizes current knowledge of the effect and importance of dietary components on DNA methylation, histone modifications, and miRNA expression in controlling the proper expression of development-related genes. Understanding the underlying mechanisms of how early-life nutritional environment affects our health can be valuable for successful prevention of adult chronic diseases through optimal maternal nutrition.
Dietary components (amino acids, high-fat or high-glucose diet, vitamins, bioactive factors,) can affect genome function and gene expression in utero and during early life, influencing epigenetic mechanisms through folate-mediated one-carbon metabolism or transmethylation pathways to affect DNA methylation, histone, or non-coding miRNAs.
Nutrients 07 02748 g001 1024
Figure 1. Overview of epigenetic mechanisms providing the link between the nutritional environment and phenotypical changes.
Figure 1. Overview of epigenetic mechanisms providing the link between the nutritional environment and phenotypical changes.
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2. Epigenetic Mechanisms and Epigenome Stability

Epigenetics is defined as heritable changes in gene expression that are not due to any alteration in the primary DNA sequence. Epigenetics (in contrast to genetics, which represents fixed information, i.e., the primary DNA sequence), signifies the way genetic information is organized, maintained, and read. Epigenetic modifications include the best-known and much studied methylation of DNA, modifications of the histone proteins that bind to DNA, the nucleosome positioning along DNA [17], and small and long non-coding RNAs (ncRNAs), including miRNAs.
In mammalian DNA, cytosines in the CpG dinucleotide context are commonly methylated. DNA methylation is involved in the normal development and maintenance of cellular homeostasis and functions in adult organisms, particularly for X-chromosome inactivation in females, genomic imprinting, silencing of repetitive DNA elements, regulation of chromatin structure, and control of gene expression. DNA methylation is well balanced in normal cells; however, it should be noted that genetic [18], environmental [19], and stochastic factors have distinct effects on DNA methylation patterns at individual genomic regions. In addition, DNA methylation at specific CpG-sites can also vary over time within an individual [20,21]. The DNA methylation reaction is catalyzed by a family of DNA methyltransferases (DNMTs) [22]. DNA methylation is initiated and established by means of the de novo DNMTs, DNMT3A and DNMT3B [22]. Approximately 70%–90% of CpG dinucleotides in the mammalian genome are methylated; however, CpG sites are not distributed uniformly across the genome [23,24,25] and are concentrated in short regions (<4 kb) of DNA with a high G + C content and a high frequency of CpG dinucleotides called “CpG islands”. In normal cells, CpG sites located in CpG islands are unmethylated. In contrast, most of the remaining CpG sites of the genome are methylated. Cytosine methylation is a stable modification of the genomic DNA and the pattern of DNA methylation is inherited during DNA replication. This epigenetic process also dynamically changes during the lifespan in certain cells and tissues of an organism and is susceptible to nutritional and other environmental influences.
The second well-studied and more complex epigenetic mechanism that regulates chromatin structure and accessibility and transcriptional activities inside a cell involves modifications of histone proteins. These post-translational modifications of histone proteins play an important part in a wide array of cellular processes, including regulation of gene transcription, DNA repair, cell cycle, and metabolic control [26]. The histone modifications function by either influencing chromatin packaging or by recruiting and/or occluding other protein complexes. Histones (H2A, H2B, H3, and H4) are evolutionary conserved proteins that have a globular carboxy-terminal domain critical to a nucleosome formation and a flexible amino-terminal tail that protrudes from the nucleosome core and contacts adjacent nucleosomes in a higher-order structure. The amino-terminal tails of histones are subject to at least eight types of post-translational modifications, including acetylation, methylation, phosphorylation, ubiquitylation, sumoylation, biotinylation, and ADP ribosylation [26]. Acetylation and methylation of histone lysine residues are the most studied post-translational histone modifications.
Typically, histone acetylation, catalyzed by histone acetyltransferase (HAT) enzymes, is associated with the formation of open chromatin structure and active gene transcription. In contrast, histone lysine deacetylation, catalyzed by several different classes of histone deacetylases (HDACs), is associated with gene silencing [27]. For instance, transcriptional activation is associated with acetylation of residues K9 (lysine 9) and K14 (lysine 14), and methylation of residues K4 (lysine 4), K36 (lysine 36) in histone H3. Gene repression has been linked to H3K9, H3K27, and H4K20 methylation [28]. Deacetylated lysines are positively charged and interact strongly with the negatively charged DNA, which leads to chromatin condensation at gene promoters and transcriptional gene repression by limiting access to the transcription machinery [27]. A number of histone-modifying enzymes have been identified, including histone lysine and arginine methyltransferases, histone lysine demethylases, and HAT and HDAC proteins. The altered expression and/or activity of several histone-modifying enzymes has been linked to disease development [29].
Recently, extensive studies have indicated the existence and importance of another mechanism of epigenetic regulation of gene function mediated by means of miRNAs and other small and long ncRNAs. Currently, miRNAs are recognized as major regulatory gatekeepers of protein-coding genes in the human genome. They are small non-coding RNAs, 16–29 nucleotides-long, that function primarily as negative gene regulators at the post-transcriptional level. Following transcription, primary miRNAs form a stem-loop structure, which is recognized by the RNase III-type enzyme Drosha-creating precursor miRNAs. These precursor miRNAs are transported from the nucleus to the cytoplasm by Exportin-5. In the cytoplasm, the pre-miRNAs are further regulated by Dicer, an RNAase III enzyme, generating miRNA:miRNA hybrids. After unwinding, one strand of the duplex is degraded, and another strand is a mature miRNA. miRNAs can induce mRNA cleavage if complementarity to the 3′-untranslated region (3′-UTR) of target mRNAs is perfect, or translational repression if complementarity is imperfect. Currently, more than 2800 mammalian miRNAs that potentially target up to 60% of protein-coding genes involved in cell development and differentiation have been annotated [30,31]. In addition to these miRNAs, 3707 novel miRNAs have been identified recently, many of which are human-specific and tissue specific [31]. This finding indicates that the human genome contains a substantially greater number of uncharacterized miRNAs that may be involved in disease development [31].
All components of the cellular epigenome (i.e., DNA methylation, histone modifications, and miRNAs) are tightly and interdependently connected. For instance, DNA methylation depends on the pattern of histone modifications and functioning of histone modifying proteins. Likewise, the status of histone modifications relies on DNA methylation. Similarly, the expression of many miRNAs is epigenetically regulated either by DNA methylation or histone modifications [32]. On the other hand, several miRNAs directly target DNMTs and other chromatin modifying genes.

3. Evidence that Dietary Methyl Group Donors Are Involved in Early Epigenetic Mechanisms

3.1. The Folate-Mediated One-Carbon Metabolism and DNA Methylation

Genomic DNA methylation is the addition of a methyl group from the universal methyl donor, S-adenosyl-l-methionine (AdoMet) to carbon five in the cytosine pyridine ring, resulting in the formation of 5-methylcytosine (5metC) in DNA (Figure 2). As a consequence, DNA methylation depends upon the availability of methyl groups from AdoMet. This finding has identified the critical role of AdoMet as a key metabolite in the mechanism of DNA methylation. Folate, methionine, choline, betaine, and methylcobalamine affect DNA methylation through the FOCM pathway [33]. The major sources of methyl groups in human foods come from methionine (~10 mmol of methyl/day), 5methylTHF (~5–10 mmol of methyl/day), and from choline (~30 mmoles methyl/day) [34]. Dietary deficiency in any of the factors leads to loss of DNA methylation in humans and experimental animals.
In general, nutrition conditions interfere with the epigenome in, at least, three ways (Table 1). First, nutrients influence the supply of methyl groups for the formation of AdoMet (e.g., methionine supplying or synthesis, homocysteine re-methylation, 5methylTHF supplying, MTHFR enzyme down regulation or activity). Additionally, nutrients modify utilization of methyl groups by mechanisms including shifts in methyl transferase activity in the trans-methylation reaction, and mechanisms related to a DNA demethylation activity. Secondly, nutrients modify chromatin remodeling, or lysine or arginine residues at the N-terminal of histone tails. Finally, nutrients may alter the expression of miRNAs that regulate the level of key FOCM pathway proteins [35,36].
Alterations in the supply of methyl groups appear to be a common mechanism associated with epigenetic aberrations. Methyl group deficiency resulting from dietary methyl source inadequacies, and/or other life-style factors (e.g., alcohol, tobacco, and stress), can lead to global and/or specific DNA methylation changes. For instance, studies on viable yellow (Avy/a) mice have shown an association between epigenetic variation in the gene involved in coat coloring and methyl donor supply. Specifically, Wolff et al. [37] reported that feeding pregnant agouti mice methyl-supplemented diets alters epigenetic regulation of the offspring. This finding was confirmed in several independent studies [38,39]. The effect of folate deficiency on the phenotype in agouti mice is, probably, the major evidence demonstrating the strong relationship between nutritional factors and epigenetic alterations in the induction of phenotypic generational and trans-generational effects [40,41].
Nutrients 07 02748 g002 1024
Figure 2. The folate-mediated one-carbon metabolism and interactions with dietary contents. AdoMet: adenosylmethionine, AdoHcy: adenosylhomocysteine, BHMT: Betaine-hydroxymethyl-transferase, DGM: dimethylglycine, EGCG: epigallocatechin-3-gallate, K/R-histone: lysine (K) and arginine (R) in the histone tail, MTs: methyl-transferases; MS-B12: methionine synthase linked to the cobalamine (Vitamin B12).
Figure 2. The folate-mediated one-carbon metabolism and interactions with dietary contents. AdoMet: adenosylmethionine, AdoHcy: adenosylhomocysteine, BHMT: Betaine-hydroxymethyl-transferase, DGM: dimethylglycine, EGCG: epigallocatechin-3-gallate, K/R-histone: lysine (K) and arginine (R) in the histone tail, MTs: methyl-transferases; MS-B12: methionine synthase linked to the cobalamine (Vitamin B12).
Nutrients 07 02748 g002
Table
Table 1. Epigenetic processes and possible effects of dietary components.
Table 1. Epigenetic processes and possible effects of dietary components.
Epigenetic ProcessesMolecular Interference
DNA methylation/demethylationMethyl group supply and availability and alteration of AdoMet synthesis
Expression of FOCM pathway genes
Aberrant functioning of methyl-CpG-binding proteins
DNA-cytosine demethylation
Chromatin remodeling, histones post-translational modificationsHistone (lysine/arginine) methylation or demethylation
Histone acetylation or deacetylation
Chromatin remodeling proteins-complex activities
Others and unknown chromatin modifications
miRNA regulation: activation/inhibitionSpecific miRNA activation
Specific miRNA inhibition
The effect of diet on the phenotype determinism through epigenetic mechanisms has been reported in several independent studies. Specifically, Elango et al. [42] and Hunt et al. [43] demonstrated that either queen or worker phenotype in honeybees is determined through epigenetic changes in DNA methylation patterns induced by different types of honey. This indicates that the genome uses DNA methylation to control the expression of genes involved in core biological mechanisms. Growing evidence showed the significance of DNA methylation aberrations in the pathogenesis of a number of pathologies. Ghoshal et al. [44] reported substantial alterations in the expression of DNMTs and methyl CpG binding proteins at early stages of hepatocarcinogenesis induced by folate and methyl deficiency in Fisher 344 rats. Padmanabhan et al. [45] showed the importance of methionine synthase reductase (MSR), an enzyme involved in the utilization of methyl groups from the folate cycle, in intrauterine growth restriction, developmental delay, neural tube, heart, and placental defects, through trans-generational epigenetic inheritance in mice.
Some dietary components (e.g., EGCG, genistein, zinc, iron) may interact with FOCM at the MTs pathways. Choline is a methyl source that contributes to methionine synthesis throughout the BHMT pathway. The methyl groups from 5methylTHF or methylcobalamine (Vitamin B12) are provided throughout the methionine synthesis (MS) pathway.

3.2. Dietary Methyl Group Donors and Histone Modifications

Several reports have focused on the direct effect of dietary methyl group inadequacy on the modification of histone proteins. Pogribny et al. [46] demonstrated that feeding rats a methyl donor-deficient diet resulted in loss of histone H3K9 and H4K20 methylation accompanied by a decreased level of Suv4-20h2 and RIZ1 histone methyltransferases. In contrast, feeding mice a methyl donor-balanced diet up-regulates RIZ1, resulting in greater histone H3K9 methylation [47]. Additionally, Luka et al. [48] showed that nuclear lysine-specific demethylase 1 (LSD1), a flavin-containing enzyme that removes the methyl groups from lysines 4 and 9 of histone 3 with the generation of formaldehyde from the methyl group, is a folate-binding protein. Using a natural pentaglutamate form of THF, the authors observed binding with the highest affinity (Kd = 2.8 μM) to LSD1. The fact that folate participates in the enzymatic demethylation of histones suggests a new role of folate in the epigenetic control of gene expression at histone level.

3.3. Dietary Methyl Group Donors and miRNAs

Stone et al. [36] applied computational miRNA target prediction methods and Monte Carlo-based statistical analyses to investigate the role of miRNAs in the regulation of folate-mediated one-carbon metabolism pathway and identified two candidates, “master regulators” miRNAs, miR-22 and miR-125, and “master co-regulators” miRNAs, miR-344-5p/484 and miR-488, that may influence the expression of a significant number of genes involved in FOCM. Interestingly, miR-22 and miR-125 were significantly up-regulated in cells grown under low-folate conditions. Although only a few experimental studies showing a link between miRNAs and FOCM, these in silico simulations suggest that miRNAs could play an important role in the regulation of the FOCM. Additionally, a recent report by Franchina et al. [49] revealed the involvement of mirR-22, miR-24 and miR-34a in folate pathway. Although only few studies showing a link between miRNAs and FOCM, these in silico simulations suggest that miRNAs could play an important role in this metabolism regulation. Indeed, it has been demonstrated recently that miR-22 and miR-29b directly target rat Mthfr and Mat1 genes, respectively [50].

3.4. Dietary Methyl Group Donors and Fetal Programming

Increased folate demand during pregnancy is necessary to accommodate both fetal development and placental functionality [51,52]. Exogenous stressors in the maternal environment combined with a maladaptation of the placental response result in a small placenta, as is typical of intrauterine growth restriction and preeclampsia [53]. Fryer et al. [54] found that levels of folate-associated intermediates in cord blood during late pregnancy are negatively correlated with the level of methylation of LINE-1 repetitive elements in cord lymphocyte samples in offspring of mothers taking daily folic acid supplements during pregnancy. These data support the fact that folate and other one-carbon intermediates may determine clinical programming effects via DNA methylation. Dietary restriction of methyl donors during the periconceptual period results in adverse phenotypes in progeny ewes, which has been associated with changes in the DNA methylation status of ~4% of CpG islands studied in the progeny. These findings imply that modification of the epigenetic status of a small subset of genes may be a cause of the programming events [55].
Fetal life is characterized by a tremendous plasticity and ability to respond to environmental and lifestyle factors, including maternal nutrition. From the single cell to the blastocyst stage of the embryogenesis many changes in global DNA methylation and histone modifications occur. DNA methylation is reduced progressively with cleavage divisions; DNMT1 protein is seemingly excluded from the nucleus during the first three cleavage divisions [56] accounting for the loss of DNA methylation by a passive mechanism. Almost all DNA methylation patterns are erased as preimplantational embryo development proceeds [56], and many different types of sequences lose methylation at this stage. DNMT3 predominantly mediates de novo DNA methylation, in which the hypermethylated inner cell mass will give rise to the embryo while trophoblastic cells remain hypomethylated. Thus, embryonic development is characterized by a wave of demethylation followed by re-establishment of methylation patterns in developing embryos, which can induce the removal of acquired epigenetic modification. Exposure to a high-fat diet in utero might cause a metabolic syndrome-like phenomenon through epigenetic modifications of the expression of insulin-like growth factor 2 (IGF2), a candidate in developmental programming and determinant of later adult disease risk [12,57].
Taking into account these observations, an altered nutritional status during early life could produce changes in epigenetic marks that have lifelong phenotypic consequences [39,58]. Identifying critical windows of sensitivity to epigenetic modulation by dietary compounds is needed to prevent the development of metabolic diseases.

4. Epigenetic Effects of Common Macronutrients Derivatives, Micronutrients and Bioactive Compounds in Modern Diet

Some of the most investigated dietary factors capable of interfering with the epigenetic processes have been reported [59]. The effects of macronutrient derivatives (e.g., methionine, choline, and betaine) [60,61,62,63], and micronutrients such as vitamins (e.g., B-vitamins, D vitamin, and retinoic acid [64,65,66,67], microminerals or trace elements (e.g., iron, zinc and selenium) [68,69,70] and bioactive compounds (e.g., phytochemicals including polyphenols) [71,72] on epigenetic processes are summarized in Table 2, Table 3 and Table 4, respectively. These dietary compounds are an integral part of everyday nutrition in human populations worldwide, are frequently present in maternal diets, and have been reported to influence epigenetic mechanisms (Figure 2). For example, an inadequate dietary protein amount, methionine-deficient diet, high-fat diet, or high-glucose diet have been reported to modulate the epigenetic process (Table 2). The phytochemicals lycopene in tomatoes, genistein in soybeans, resveratrol in grapes and berries, sulforaphane in broccoli, epigallocatechin-3-gallate (EGCG) in green tea, or curcumin and allyl sulfur compounds present in spices are among a growing list of agents used in the modern diet that might affect epigenetic mechanisms. We have summarized bioactive agents that are most frequently present in the maternal diet (Table 4). For instance, green tea commonly used by mothers in European countries contains high amount of EGCG. Those who consume black tea or coffee more regularly, have a greater intake of the respective major components of these beverages, theophylline or caffeic acid. Coffee polyphenols such as caffeic acid or chlorogenic acid are catechol-containing polyphenols that act in a similar way to the tea polyphenols. However, the specific epigenetic modulations of these phenolic compounds are not well documented. They can be demethylating agents, inhibiting DNMT1-catalyzed DNA methylation in a concentration-dependent manner, predominantly through a non-competitive mechanism [73].
Several other dietary epigenetic modulators have been investigated for further understanding of molecular mechanisms underpinning epigenetic effects in the context of chemoprevention [74,75,76,77,78]. Some have shown potential to reverse methylation-induced silencing and change the expression of various genes (i.e., DNMT inhibitors). For example, EGCG of green tea extract is a demethylating agent that inhibits catechol-O-methyltransferase (COMT), the enzyme responsible for the inactivation of catechol molecules [79]. This enzyme introduces the methyl group from AdoMet onto the catecholamine group forming AdoHcy, a potent inhibitor of DNMTs. On the other hand, EGCG can form hydrogen bonds with different residues in the catalytic pocket of DNMTs acting as a direct inhibitor of DNMT1. Lycopene, a bright red carotene and carotenoid pigment found in tomatoes and other red fruits and vegetables modulates the expression of numerous genes relevant to cell cycle control [80]; however, lycopene and apo-10'-lycopenal are not effective demethylating agents of GSTP1 in the human LNCaP prostate cancer cell line [81]. It has been demonstrated that treatment of the MV4-11 leukemia cell line with curcumin decreases global DNA methylation [82]. Genistein, a major phytoestrogen in soybeans, induces a dose-dependent inhibition of DNMTs. Furthermore, prenatal exposure to genistein affects fetal erythropoiesis and exerts lifelong alterations in gene expression and DNA methylation of hematopoietic cells [83]. Sulforaphane, a bioactive component of cruciferous vegetables, down-regulates DNMT1 and induces demethylation of the Cyclin D2 (CCND2) gene in the human colorectal adenocarcinoma Caco-2 cell line [84]. A wide variety of cruciferous vegetables contain isothiocyanate compounds, which are known to affect the epigenome. For example, isothiocyanates, metabolites of glucosinolates present in cruciferous vegetables, lead to demethylation and re-expression of GSTP1 [85]. Resveratrol, a polyphenol phytoalexin in grape peel and a weak inhibitor of DNMT activity, increases the ability of adenosine analogues to reduce DNA methylation and increase the expression of RARβ2 in human breast cancer MCF-7 cells [86].
A number of bioactive agents, in addition to their ability to affect DNA methylation, induce changes in histone modifications and regulate gene expression [87]. For instance, EGCG has been shown to affect HAT and HDAC activities as it has been reported to be the most potent HAT inhibitor [88]. Quercetin, a flavonoid abundant in onions, green tea, apples, and berries, has been reported to exhibit potential to activate HATs and inhibit HDACs [89]. Resveratrol, butyrate, sulforaphane, and diallyl sulfide inhibit HDACs, whereas curcumin inhibits HAT activity via covalent binding to HAT enzymes. In addition to the HAT-inhibitory effect, it has been shown that curcumin also prevents histone hyperacetylation by induction of HDACs [73]. Although it is accepted that curcumin functions as a histone modifier, its activity toward other histone modifying enzymes such as HDACs, SIRTs, and HMTs remains controversial.
In regard to miRNAs, the understanding of the effect of dietary components on miRNA expression is currently limited; however, few studies have identified effects on specific miRNA targets. Ross and Davis [90] reported that bioactive food components protect against cancer through modulation of miRNA expression. Natural food compounds, including EGCG, curcumin, genistein, sulforaphane, and resveratrol, have anticancer properties through miRNA regulation [91].

5. Future Considerations of Dietary Epigenetic Modulators

It is well-established that maternal diet may have a lifelong effect on an offspring’s genome and potentially influence susceptibility to complex diseases in adulthood. In light of this, awareness of nutrient supply during pregnancy is currently unsatisfactory and should be improved to protect against adverse fetal programming and susceptibility to complex diseases in adulthood. Emerging evidence has revealed that some components in the maternal diet can directly or indirectly affect DNA methylation, histone modifications, or miRNA expression (Figure 1). The field of nutritional epigenetics is growing rapidly and we are only beginning to understand the complexity of gene regulation through this mechanism. However, it is clear that some dietary components contribute actively to epigenetic mechanisms and modulate the expression of a number of genes. The particular effect of each type of those dietary epigenetic modulators or their combination on fetal life remains questionable because of insufficient data and serious methodological limitations. Additionally, it is conceivable to anticipate that new or unsuspected biological activity may emerge from a manufactured or engineered diet. A major feature of epigenetic mechanisms is their modulation responsiveness, which makes possible early-life nutritional intervention to modify long-term disease risk. However, this modification may be possible only for specific windows of epigenetic change, which makes the identification of such windows of great importance. Additionally, improving the environment to which the fetus/infant is exposed during critical windows of development may be as important as other public health efforts to prevent long term diseases.
Although it is conceivable that dietary components should positively affect maternal health and fetal development, the first question arising at this level is of the influence on fetal programming in an excess or deficiency of dietary factors. The second question is on the impact of these “dietary epigenetic modulators” on an individual genetically predisposed (individual susceptibility) for developing a particular disease, including transgenerational effects. Finally, the question of the combined effects of different dietary epigenetic modulators or chronic exposures to a dietary epigenetic modulator requires investigation, taking into account genetic profiles characterized by the presence of identified functional single nucleotide polymorphisms [92,93].
Table
Table 2. Relevant studies on macronutrients, macronutrient derivatives (choline, betaine), nutrition condition and epigenetic interference.
Table 2. Relevant studies on macronutrients, macronutrient derivatives (choline, betaine), nutrition condition and epigenetic interference.
MacronutrientDietary CompoundsEpigenetic Interference
Nutrition ConditionDNMT PathwayHistone ModificationmicroRNAs
ProteinLow protein diet[93,94][94][95]
LipidsHigh-fat[96,97,98,99][12,100][101,102]
Fatty acids[103]
Choline[104,105][106][107]
Betaine[108]
CarbohydrateHigh-glucose[109][110,111]
Fiber: butyrate[112,113,114][112]
Nutrition conditionsUndernutrition: Calorie restriction[113,115][113,114]
Overfeeding: High calories[116]
Table
Table 3. The effects of micronutrients, vitamins, and trace elements on epigenetic processes.
Table 3. The effects of micronutrients, vitamins, and trace elements on epigenetic processes.
MicronutrientDietary Compound SourceEpigenetic Interference
DNMT, DNA MethylationHistone ModificationmiRNAs
VitaminsFolate/methyl-deficient diet Vegetables, cereals, yeast[117,118,119,120][121,122,123][124,125]
Ascorbate Fruits and vegetables[126]
Retinoic acid Yellow and orange fruits[65,127,128][129,130,131,132][131,133]
Biotin Yeast, egg yolk, grains[122,134]
Tocopherol (vitamine E) Grains, nuts and oils[135][136]
Trace elementsZinc Meat, seafood, whole grains[137]
Copper Seafood, nuts, legumes, meats[138]
Selenium Meat, seafood, whole grains[139,140]
Table
Table 4. The effects of dietary phytochemicals effect on epigenetic processes summarized from literature *.
Table 4. The effects of dietary phytochemicals effect on epigenetic processes summarized from literature *.
Dietary Compounds SourceEpigenetic Interference
DNMT PathwayHistone ModificationmiRNA
Epigallocatechin-3-gallate Green teaKnown
6-methoxy-2E,9E-humuladien-8-one GingerKnown
Allylmercaptant, allyl-derivates GarlicKnownKnown
Anacardic acid Cashew nutKnown
Biochanin A SoyKnownKnown
Caffeic acid, chlorogenic acid CoffeeKnownKnown
Catechin Green teaKnownKnown
Coumaric acid, cinnamic acid CinnamonKnownKnown
Curcumin CurcumaKnownKnownKnown
Epicatechin Apples, cocoaKnown
Epigallocatechin-3-gallate Green teaKnownKnown
Genistein SoyKnownKnownKnown
Isothiocyanates BroccoliKnown
Lycopene Tomatoes, apricotsKnownKnown
Protocatechuric acid OlivesKnown
QuercetinC itrus, buckwheat, apple, berries, teaKnownKnown
Resveratrol Grape, blueberries, peanutKnownKnown
Rosmarinic RosemaryKnown
Sinapic acid MustardKnown
Sulforaphane BroccoliKnownKnown
Syringic acid Red grapeKnownKnown
Theophylline Black and green teaKnown
*: Relevant references: [71,83,85,87,89,141,142,143,144].
Depending on the tissues, hyper- or hypo-methylation, or other epigenetic modifications induced by diet may be beneficial for some genes, but deleterious for the normal expression of other genes. In this context, a strategy for food safety and disease prevention should be considered and exercised in interpreting and/or extrapolating the results of experimental studies and in vitro studies of “dietary epigenetic modulators” to humans. Future research will help to enhance our understanding of their impacts on the nutritional programming of epigenetic states in early life and effect on biological function. One anticipated result is that these “dietary epigenetic modulators” could be identified as nutraceuticals and the next, and most important step, would be to determine the effective and optimal doses to achieve various beneficial effects during the mother-child metabolic interaction. The daily diet of humans consists of approximately 50–60 mmol of methyl groups. Perhaps, we need to reconsider the optimal need during the perinatal period and investigate events that can influence epigenome, inducing significant long-term health effects in adulthood. Determining the impact of domestic cooking modes or industrial treatment on the functional quality of these “dietary epigenetic modulators” also requires investigation. Addressing these questions may open up a new research field of nutritional epigenetics that should contribute to public policy guidance that will teach optimal, rather than minimal, dose levels to meet both fetal and maternal needs and health.

6. Conclusions

In conclusion, dietary components have a strong impact upon epigenetic processes and metabolic programing during sensitive periods of fetal and early postnatal periods. Understanding how nutritional manipulations alter the epigenetic machinery to affect metabolic genes may help to better identify strategies for the successful prevention of adult chronic diseases.

Author Contributions

Abalo Chango designed the manuscript, figures and tables, wrote a part of the manuscript and reviewed the final version. Igor Pogribny wrote a part of the manuscript, read, reviewed and approved the final version.

Conflicts of Interest

The authors declare no conflict of interest.

Disclaimer

The views expressed in this paper do not necessarily represent those of the U.S. Food and Drug Administration.

References

  1. Baylin, S.B.; Jones, P.A. A decade of exploring the cancer epigenome-biological and translational implications. Nat. Rev. Cancer 2011, 11, 726–734. [Google Scholar] [CrossRef] [PubMed]
  2. Rodenhiser, D.; Mann, M. Epigenetics and human disease: Translating basic biology into clinical applications. CMAJ 2006, 174, 341–348. [Google Scholar] [CrossRef] [PubMed]
  3. Hewagama, A.; Richardson, B. The genetics and epigenetics of autoimmune diseases. J. Autoimmun. 2009, 33, 3–11. [Google Scholar] [CrossRef] [PubMed]
  4. Lopez-Pedrera, C.; Perez-Sanchez, C.; Ramos-Casals, M.; Santos-Gonzalez, M.; Rodriguez-Ariza, A.; Cuadrado, M.J. Cardiovascular risk in systemic autoimmune diseases: Epigenetic mechanisms of immune regulatory functions. Clin. Dev. Immunol. 2012, 2012. [Google Scholar] [CrossRef]
  5. Barres, R.; Zierath, J.R. DNA methylation in metabolic disorders. Am. J. Clin. Nutr. 2011, 93, 897S–900S. [Google Scholar] [CrossRef] [PubMed]
  6. Brookes, E.; Shi, Y. Diverse epigenetic mechanisms of human disease. Annu. Rev. Genet. 2014, 48, 237–268. [Google Scholar] [CrossRef] [PubMed]
  7. Gaudet, F.; Hodgson, J.G.; Eden, A.; Jackson-Grusby, L.; Dausman, J.; Gray, J.W.; Leonhardt, H.; Jaenisch, R. Induction of tumors in mice by genomic hypomethylation. Science 2003, 300, 489–492. [Google Scholar] [CrossRef] [PubMed]
  8. Reik, W.; Dean, W.; Walter, J. Epigenetic reprogramming in mammalian development. Science 2001, 293, 1089–1093. [Google Scholar] [CrossRef] [PubMed]
  9. Smith, Z.D.; Meissner, A. DNA methylation: Roles in mammalian development. Nat. Rev. Genet. 2013, 14, 204–220. [Google Scholar] [CrossRef] [PubMed]
  10. Saffery, R.; Novakovic, B. Epigenetics as the mediator of fetal programming of adult onset disease: What is the evidence? Acta Obstet. Gynecol. Scand. 2014, 93, 1090–1098. [Google Scholar] [CrossRef] [PubMed]
  11. Jiang, X.; West, A.A.; Caudill, M.A. Maternal choline supplementation: A nutritional approach for improving offspring health? Trends Endocrinol. Metab. 2014, 25, 263–273. [Google Scholar] [CrossRef] [PubMed]
  12. Masuyama, H.; Hiramatsu, Y. Effects of a high-fat diet exposure in utero on the metabolic syndrome-like phenomenon in mouse offspring through epigenetic changes in adipocytokine gene expression. Endocrinology 2012, 153, 2823–2830. [Google Scholar] [CrossRef] [PubMed]
  13. Thornburg, K.L.; Shannon, J.; Thuillier, P.; Turker, M.S. In utero life and epigenetic predisposition for disease. Adv. Genet. 2010, 71, 57–78. [Google Scholar] [PubMed]
  14. Hogg, K.; Price, E.M.; Hanna, C.W.; Robinson, W.P. Prenatal and perinatal environmental influences on the human fetal and placental epigenome. Clin. Pharmacol. Ther. 2012, 92, 716–726. [Google Scholar] [CrossRef] [PubMed]
  15. Mathers, J.C. Early nutrition: Impact on epigenetics. Forum Nutr. 2007, 60, 42–48. [Google Scholar] [PubMed]
  16. Szyf, M. The early life environment and the epigenome. Biochim. Biophys. Acta 2009, 1790, 878–885. [Google Scholar] [CrossRef] [PubMed]
  17. Sharma, S.; Kelly, T.K.; Jones, P.A. Epigenetics in cancer. Carcinogenesis 2010, 31, 27–36. [Google Scholar] [CrossRef] [PubMed]
  18. Bell, J.T.; Pai, A.A.; Pickrell, J.K.; Gaffney, D.J.; Pique-Regi, R.; Degner, J.F.; Gilad, Y.; Pritchard, J.K. DNA methylation patterns associated with genetic and gene expression variation in HapMap cell lines. Genome Biol. 2011, 12. [Google Scholar] [CrossRef] [PubMed]
  19. Pogribny, I.P.; Rusyn, I. Environmental toxicants, epigenetics, and cancer. Adv. Exp. Med. Biol. 2013, 754, 215–232. [Google Scholar] [PubMed]
  20. Fraga, M.F.; Ballestar, E.; Paz, M.F.; Ropero, S.; Setien, F.; Ballestar, M.L.; Heine-Suñer, D.; Cigudosa, J.C.; Urioste, M.; Benitez, J.; et al. Epigenetic differences arise during the lifetime of monozygotic twins. Proc. Natl. Acad. Sci. USA 2005, 102, 10604–10609. [Google Scholar] [CrossRef] [PubMed]
  21. Talens, R.P.; Boomsma, D.I.; Tobi, E.W.; Kremer, D.; Jukema, J.W.; Willemsen, G.; Putter, H.; Slagboom, P.E.; Heijmans, B.T. Variation, patterns, and temporal stability of DNA methylation: Considerations for epigenetic epidemiology. FASEB J. 2010, 24, 3135–3144. [Google Scholar] [CrossRef] [PubMed]
  22. Ooi, S.K.; O’Donnell, A.H.; Bestor, T.H. Mammalian cytosine methylation at a glance. J. Cell Sci. 2009, 122, 2787–2791. [Google Scholar] [CrossRef] [PubMed]
  23. Das, R.; Dimitrova, N.; Xuan, Z.; Rollins, R.A.; Haghighi, F.; Edwards, J.R.; Ju, J.; Bestor, T.H.; Zhang, M.Q. Computational prediction of methylation status in human genomic sequences. Proc. Natl. Acad. Sci. USA 2006, 103, 10713–10716. [Google Scholar] [CrossRef] [PubMed]
  24. Rollins, R.A.; Haghighi, F.; Edwards, J.R.; Das, R.; Zhang, M.Q.; Ju, J.; Bestor, T.H. Large-scale structure of genomic methylation patterns. Genome Res. 2006, 16, 157–163. [Google Scholar] [CrossRef] [PubMed]
  25. Mikkelsen, T.S.; Ku, M.; Jaffe, D.B.; Issac, B.; Lieberman, E.; Giannoukos, G.; Alvarez, P.; Brockman, W.; Kim, T.K.; Koche, R.P.; et al. Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature 2007, 448, 553–560. [Google Scholar] [CrossRef] [PubMed]
  26. Kouzarides, T. Chromatin modifications and their function. Cell 2007, 128, 693–705. [Google Scholar] [CrossRef] [PubMed]
  27. Ropero, S.; Esteller, M. The role of histone deacetylases (HDACs) in human cancer. Mol. Oncol. 2007, 1, 19–25. [Google Scholar] [CrossRef] [PubMed]
  28. Iizuka, M.; Smith, M.M. Functional consequences of histone modifications. Curr. Opin. Genet. Dev. 2003, 13, 154–160. [Google Scholar] [CrossRef] [PubMed]
  29. Butler, J.S.; Koutelou, E.; Schibler, A.C.; Dent, S.Y. Histone-modifying enzymes: Regulators of developmental decisions and drivers of human disease. Epigenomics 2012, 4, 163–177. [Google Scholar] [CrossRef] [PubMed]
  30. Friedman, R.C.; Farh, K.K.; Burge, C.B.; Bartel, D.P. Most mammalian mRNAs are conserved targets of microRNAs. Genome Res. 2009, 19, 92–105. [Google Scholar] [CrossRef] [PubMed]
  31. Londin, E.; Loher, P.; Telonis, A.G.; Quann, K.; Clark, P.; Jing, Y.; Hatzimichael, E.; Kirino, Y.; Honda, S.; Lally, M.; et al. Analysis of 13 cell types reveals evidence for the expression of numerous novel primate- and tissue-specific microRNAs. Proc. Natl. Acad. Sci. USA 2015, 112, E1106–E1115. [Google Scholar] [CrossRef]
  32. Denis, H.; Ndlovu, M.N.; Fuks, F. Regulation of mammalian DNA methyltransferases: A route to new mechanisms. EMBO Rep. 2011, 12, 647–656. [Google Scholar] [CrossRef] [PubMed]
  33. Waterland, R.A. Assessing the effects of high methionine intake on DNA methylation. J. Nutr. 2006, 136, 1706S–1710S. [Google Scholar] [PubMed]
  34. Niculescu, M.D.; Zeisel, S.H. Diet, methyl donors and DNA methylation: Interactions between dietary folate, methionine and choline. J. Nutr. 2002, 132, 2333S–2335S. [Google Scholar] [PubMed]
  35. Hardy, T.M.; Tollefsbol, T.O. Epigenetic diet: Impact on the epigenome and cancer. Epigenomics 2011, 3, 503–518. [Google Scholar] [CrossRef] [PubMed]
  36. Stone, N.; Pangilinan, F.; Molloy, A.M.; Shane, B.; Scott, J.M.; Ueland, P.M.; Mills, J.L.; Kirke, P.N.; Sethupathy, P.; Brody, L.C. Bioinformatic and genetic association analysis of microrna target sites in one-carbon metabolism genes. PLoS ONE 2011, 6, e21851. [Google Scholar] [CrossRef] [PubMed]
  37. Wolff, G.L.; Kodell, R.L.; Moore, S.R.; Cooney, C.A. Maternal epigenetics and methyl supplements affect agouti gene expression in Avy/a mice. FASEB J. 1998, 12, 949–957. [Google Scholar] [PubMed]
  38. Cooney, C.A.; Dave, A.A.; Wolff, G.L. Maternal methyl supplements in mice affect epigenetic variation and DNA methylation of offspring. J. Nutr. 2002, 132, 2393S–2400S. [Google Scholar] [PubMed]
  39. Waterland, R.A.; Jirtle, R.L. Transposable elements: Targets for early nutritional effects on epigenetic gene regulation. Mol Cell Biol 2003, 23, 5293–5300. [Google Scholar] [CrossRef] [PubMed]
  40. Waterland, R.A.; Travisano, M.; Tahiliani, K.G.; Rached, M.T.; Mirza, S. Methyl donor supplementation prevents transgenerational amplification of obesity. Int. J. Obes. (Lond.) 2008, 32, 1373–1379. [Google Scholar] [CrossRef]
  41. Cropley, J.E.; Suter, C.M.; Beckman, K.B.; Martin, D.I. Germ-line epigenetic modification of the murine Avy allele by nutritional supplementation. Proc. Natl. Acad. Sci. USA 2006, 103, 17308–17312. [Google Scholar] [CrossRef] [PubMed]
  42. Elango, N.; Hunt, B.G.; Goodisman, M.A.; Yi, S.V. DNA methylation is widespread and associated with differential gene expression in castes of the honeybee, Apis mellifera. Proc. Natl. Acad. Sci. USA 2009, 106, 11206–11211. [Google Scholar] [CrossRef] [PubMed]
  43. Hunt, B.G.; Brisson, J.A.; Yi, S.V.; Goodisman, M.A. Functional conservation of DNA methylation in the pea aphid and the honeybee. Genome Biol. Evol. 2010, 2, 719–728. [Google Scholar] [PubMed]
  44. Ghoshal, K.; Li, X.; Datta, J.; Bai, S.; Pogribny, I.; Pogribny, M.; Huang, Y.; Young, D.; Jacob, S.T. A folate- and methyl-deficient diet alters the expression of DNA methyltransferases and methyl CpG binding proteins involved in epigenetic gene silencing in livers of F344 rats. J. Nutr. 2006, 136, 1522–1527. [Google Scholar] [PubMed]
  45. Padmanabhan, N.; Jia, D.; Geary-Joo, C.; Wu, X.; Ferguson-Smith, A.C.; Fung, E.; Bieda, M.C.; Snyder, F.F.; Gravel, R.A.; Cross, J.C.; et al. Mutation in folate metabolism causes epigenetic instability and transgenerational effects on development. Cell 2013, 155, 81–93. [Google Scholar] [CrossRef]
  46. Pogribny, I.P.; Tryndyak, V.P.; Muskhelishvili, L.; Rusyn, I.; Ross, S.A. Methyl deficiency, alterations in global histone modifications, and carcinogenesis. J. Nutr. 2007, 137, 216S–222S. [Google Scholar] [PubMed]
  47. Zhou, W.; Alonso, S.; Takai, D.; Lu, S.C.; Yamamoto, F.; Perucho, M.; Huang, S. Requirement of RIZ1 for cancer prevention by methyl-balanced diet. PLoS ONE 2008, 3, e3390. [Google Scholar] [CrossRef]
  48. Luka, Z.; Moss, F.; Loukachevitch, L.V.; Bornhop, D.J.; Wagner, C. Histone demethylase LSD1 is a folate-binding protein. Biochemistry 2011, 50, 4750–4756. [Google Scholar] [CrossRef] [PubMed]
  49. Franchina, T.; Amodeo, V.; Bronte, G.; Savio, G.; Ricciardi, G.R.; Picciotto, M.; Russo, A.; Giordano, A.; Adamo, V. Circulating miR-22, miR-24 and miR-34a as novel predictive biomarkers to pemetrexed-based chemotherapy in advanced non-small cell lung cancer. J. Cell Physiol. 2014, 229, 97–99. [Google Scholar] [PubMed]
  50. Koturbash, I.; Melnyk, S.; James, S.J.; Beland, F.A.; Pogribny, I.P. Role of epigenetic and miR-22 and miR-29b alterations in the downregulation of Mat1a and Mthfr genes in early preneoplastic livers in rats induced by 2-acetylaminofluorene. Mol. Carcinog. 2013, 52, 318–327. [Google Scholar] [CrossRef] [PubMed]
  51. Novakovic, B.; Saffery, R. The ever growing complexity of placental epigenetics—Role in adverse pregnancy outcomes and fetal programming. Placenta 2012, 33, 959–970. [Google Scholar] [CrossRef] [PubMed]
  52. Yajnik, C.S.; Deshmukh, U.S. Fetal programming: Maternal nutrition and role of one-carbon metabolism. Rev. Endocr. Metab. Disord. 2012, 13, 121–127. [Google Scholar] [CrossRef] [PubMed]
  53. Longtine, M.S.; Nelson, D.M. Placental dysfunction and fetal programming: The importance of placental size, shape, histopathology, and molecular composition. Semin. Reprod. Med. 2011, 29, 187–196. [Google Scholar] [CrossRef] [PubMed]
  54. Fryer, A.A.; Nafee, T.M.; Ismail, K.M.; Carroll, W.D.; Emes, R.D.; Farrell, W.E. LINE-1 DNA methylation is inversely correlated with cord plasma homocysteine in man: A preliminary study. Epigenetics 2009, 4, 394–398. [Google Scholar] [CrossRef] [PubMed]
  55. Sinclair, K.D.; Lea, R.G.; Rees, W.D.; Young, L.E. The developmental origins of health and disease: Current theories and epigenetic mechanisms. Soc. Reprod. Fertil. Suppl. 2007, 64, 425–443. [Google Scholar] [PubMed]
  56. Probst, A.V.; Dunleavy, E.; Almouzni, G. Epigenetic inheritance during the cell cycle. Nat. Rev. Mol. Cell Biol. 2009, 10, 192–206. [Google Scholar] [CrossRef] [PubMed]
  57. Jirtle, R.L.; Skinner, M.K. Environmental epigenomics and disease susceptibility. Nat. Rev. Genet. 2007, 8, 253–262. [Google Scholar] [CrossRef] [PubMed]
  58. Sinclair, K.D.; Singh, R. Modelling the developmental origins of health and disease in the early embryo. Theriogenology 2007, 67, 43–53. [Google Scholar] [CrossRef] [PubMed]
  59. Shenderov, B.A.; Midtvedt, T. Epigenomic programing: A future way to health? Microb. Ecol. Health Dis. 2014, 25. [Google Scholar] [CrossRef]
  60. Wilkinson, J. High maternal choline intake may prevent the development of stress-related disorders through epigenetic mechanisms. Epigenomics 2012, 4, 479–480. [Google Scholar] [CrossRef] [PubMed]
  61. Jiang, X.; Yan, J.; West, A.A.; Perry, C.A.; Malysheva, O.V.; Devapatla, S.; Pressman, E.; Vermeylen, F.; Caudill, M.A. Maternal choline intake alters the epigenetic state of fetal cortisol-regulating genes in humans. FASEB J. 2012, 26, 3563–3574. [Google Scholar] [CrossRef] [PubMed]
  62. Zeisel, S.H. Dietary choline deficiency causes DNA strand breaks and alters epigenetic marks on DNA and histones. Mutat. Res. 2012, 733, 34–38. [Google Scholar] [CrossRef] [PubMed]
  63. Oliva, J.; Bardag-Gorce, F.; Li, J.; French, B.A.; Nguyen, S.K.; Lu, S.C.; French, S.W. Betaine prevents Mallory-Denk body formation in drug-primed mice by epigenetic mechanisms. Exp. Mol. Pathol. 2009, 86, 77–86. [Google Scholar] [CrossRef] [PubMed]
  64. Wei, L.N. Non-canonical activity of retinoic acid in epigenetic control of embryonic stem cell. Transcription 2013, 4. [Google Scholar] [CrossRef]
  65. Cheong, H.S.; Lee, H.C.; Park, B.L.; Kim, H.; Jang, M.J.; Han, Y.M.; Kim, S.Y.; Kim, Y.S.; Shin, H.D. Epigenetic modification of retinoic acid-treated human embryonic stem cells. BMB Rep. 2010, 43, 830–835. [Google Scholar] [CrossRef] [PubMed]
  66. Loewy, A.D.; Niles, K.M.; Anastasio, N.; Watkins, D.; Lavoie, J.; Lerner-Ellis, J.P.; Pastinen, T.; Trasler, J.M.; Rosenblatt, D.S. Epigenetic modification of the gene for the vitamin B(12) chaperone MMACHC can result in increased tumorigenicity and methionine dependence. Mol. Genet. Metab. 2009, 96, 261–267. [Google Scholar] [CrossRef] [PubMed]
  67. Karlic, H.; Varga, F. Impact of vitamin D metabolism on clinical epigenetics. Clin. Epigenet. 2011, 2, 55–61. [Google Scholar] [CrossRef]
  68. Tian, X.; Diaz, F.J. Acute dietary zinc deficiency before conception compromises oocyte epigenetic programming and disrupts embryonic development. Dev. Biol. 2013, 376, 51–61. [Google Scholar] [CrossRef] [PubMed]
  69. Kurita, H.; Ohsako, S.; Hashimoto, S.; Yoshinaga, J.; Tohyama, C. Prenatal zinc deficiency-dependent epigenetic alterations of mouse metallothionein-2 gene. J. Nutr. Biochem. 2013, 24, 256–266. [Google Scholar] [CrossRef] [PubMed]
  70. Hu, Y.; McIntosh, G.H.; Le Leu, R.K.; Nyskohus, L.S.; Woodman, R.J.; Young, G.P. Combination of selenium and green tea improves the efficacy of chemoprevention in a rat colorectal cancer model by modulating genetic and epigenetic biomarkers. PLoS ONE 2013, 8, e64362. [Google Scholar] [CrossRef] [PubMed]
  71. Shankar, S.; Kumar, D.; Srivastava, R.K. Epigenetic modifications by dietary phytochemicals: Implications for personalized nutrition. Pharmacol. Ther. 2013, 138, 1–17. [Google Scholar] [CrossRef] [PubMed]
  72. Parasramka, M.A.; Ho, E.; Williams, D.E.; Dashwood, R.H. MicroRNAs, diet, and cancer: New mechanistic insights on the epigenetic actions of phytochemicals. Mol. Carcinog. 2012, 51, 213–230. [Google Scholar] [CrossRef] [PubMed]
  73. Lee, W.J.; Zhu, B.T. Inhibition of DNA methylation by caffeic acid and chlorogenic acid, two common catechol-containing coffee polyphenols. Carcinogenesis 2006, 27, 269–277. [Google Scholar] [CrossRef] [PubMed]
  74. Lambert, J.D.; Yang, C.S. Cancer chemopreventive activity and bioavailability of tea and tea polyphenols. Mutat. Res. 2003, 523, 201–208. [Google Scholar] [CrossRef] [PubMed]
  75. Wolfram, S.; Raederstorff, D.; Preller, M.; Wang, Y.; Teixeira, S.R.; Riegger, C.; Weber, P. Epigallocatechin gallate supplementation alleviates diabetes in rodents. J. Nutr. 2006, 136, 2512–2518. [Google Scholar] [PubMed]
  76. Wolfram, S.; Wang, Y.; Thielecke, F. Anti-obesity effects of green tea: From bedside to bench. Mol. Nutr. Food Res. 2006, 50, 176–187. [Google Scholar] [CrossRef] [PubMed]
  77. Kopelovich, L.; Crowell, J.A.; Fay, J.R. The epigenome as a target for cancer chemoprevention. J. Natl. Cancer Inst. 2003, 95, 1747–1757. [Google Scholar] [CrossRef] [PubMed]
  78. Huang, J.; Plass, C.; Gerhauser, C. Cancer chemoprevention by targeting the epigenome. Curr. Drug Targets 2011, 12, 1925–1956. [Google Scholar] [CrossRef] [PubMed]
  79. Lu, H.; Meng, X.; Yang, C.S. Enzymology of methylation of tea catechins and inhibition of catechol-O-methyltransferase by (−)-epigallocatechin gallate. Drug Metab. Dispos. 2003, 31, 572–579. [Google Scholar] [CrossRef] [PubMed]
  80. Gerhauser, C. Cancer chemoprevention and nutriepigenetics: State of the art and future challenges. Top. Curr. Chem. 2013, 329, 73–132. [Google Scholar] [PubMed]
  81. Liu, A.G.; Erdman, J.W., Jr. Lycopene and apo-10ʹ-lycopenal do not alter DNA methylation of GSTP1 in LNCaP cells. Biochem. Biophys. Res. Commun. 2011, 412, 479–482. [Google Scholar] [CrossRef] [PubMed]
  82. Yu, J.; Peng, Y.; Wu, L.C.; Xie, Z.; Deng, Y.; Hughes, T.; He, S.; Mo, X.; Chiu, M.; Wang, Q.E.; et al. Curcumin down-regulates DNA methyltransferase 1 and plays an anti-leukemic role in acute myeloid leukemia. PLoS ONE 2013, 8, e55934. [Google Scholar] [CrossRef] [PubMed]
  83. Vanhees, K.; Coort, S.; Ruijters, E.J.; Godschalk, R.W.; van Schooten, F.J.; Barjesteh van Waalwijk van Doorn-Khosrovani, S. Epigenetics: Prenatal exposure to genistein leaves a permanent signature on the hematopoietic lineage. FASEB J. 2011, 25, 797–807. [Google Scholar] [CrossRef] [PubMed]
  84. Hsu, A.; Wong, C.P.; Yu, Z.; Williams, D.E.; Dashwood, R.H.; Ho, E. Promoter de-methylation of Cyclin D2 by sulforaphane in prostate cancer cells. Clin. Epigenet. 2011, 3. [Google Scholar] [CrossRef]
  85. Wang, L.G.; Beklemisheva, A.; Liu, X.M.; Ferrari, A.C.; Feng, J.; Chiao, J.W. Dual action on promoter demethylation and chromatin by an isothiocyanate restored GSTP1 silenced in prostate cancer. Mol. Carcinog. 2007, 46, 24–31. [Google Scholar] [CrossRef] [PubMed]
  86. Stefanska, B.; Rudnicka, K.; Bednarek, A.; Fabianowska-Majewska, K. Hypomethylation and induction of retinoic acid receptor beta 2 by concurrent action of adenosine analogues and natural compounds in breast cancer cells. Eur. J. Pharmacol. 2010, 638, 47–53. [Google Scholar] [CrossRef] [PubMed]
  87. Link, A.; Balaguer, F.; Goel, A. Cancer chemoprevention by dietary polyphenols: Promising role for epigenetics. Biochem. Pharmacol. 2010, 80, 1771–1792. [Google Scholar] [CrossRef] [PubMed]
  88. Lee, Y.H.; Kwak, J.; Choi, H.K.; Choi, K.C.; Kim, S.; Lee, J.; Jun, W.; Park, H.J.; Yoon, H.G. EGCG suppresses prostate cancer cell growth modulating acetylation of androgen receptor by anti-histone acetyltransferase activity. Int. J. Mol. Med. 2012, 30, 69–74. [Google Scholar] [PubMed]
  89. Lee, W.J.; Chen, Y.R.; Tseng, T.H. Quercetin induces FASL-related apoptosis, in part, through promotion of histone H3 acetylation in human leukemia HL-60 cells. Oncol. Rep. 2011, 25, 583–591. [Google Scholar] [PubMed]
  90. Ross, S.A.; Davis, C.D. The emerging role of microRNAs and nutrition in modulating health and disease. Annu. Rev. Nutr. 2014, 34, 305–336. [Google Scholar] [CrossRef] [PubMed]
  91. Wang, Y.; Li, Y.; Liu, X.; Cho, W.C. Genetic and epigenetic studies for determining molecular targets of natural product anticancer agents. Curr. Cancer Drug Targets 2013, 13, 506–518. [Google Scholar] [CrossRef] [PubMed]
  92. Williams, S.R.; Yang, Q.; Chen, F.; Liu, X.; Keene, K.L.; Jacques, P.; Chen, W.M.; Weinstein, G.; Hsu, F.C.; Beiser, A.; et al. Genome-wide meta-analysis of homocysteine and methionine metabolism identifies five one carbon metabolism loci and a novel association of ALDH1L1 with ischemic stroke. PLoS Genet. 2014, 10, e1004214. [Google Scholar] [CrossRef] [PubMed]
  93. Shea, T.B.; Rogers, E. Lifetime requirement of the methionine cycle for neuronal development and maintenance. Curr. Opin. Psychiatry 2014, 27, 138–142. [Google Scholar] [CrossRef] [PubMed]
  94. Lillycrop, K.A.; Slater-Jefferies, J.L.; Hanson, M.A.; Godfrey, K.M.; Jackson, A.A.; Burdge, G.C. 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, 1064–1073. [Google Scholar] [CrossRef] [PubMed]
  95. Sene Lde, B.; Mesquita, F.F.; de Moraes, L.N.; Santos, D.C.; Carvalho, R.; Gontijo, J.A.; Boer, P.A. Involvement of renal corpuscle microRNA expression on epithelial-to-mesenchymal transition in maternal low protein diet in adult programmed rats. PLoS ONE 2013, 8, e71310. [Google Scholar]
  96. Gillberg, L.; Jacobsen, S.C.; Ronn, T.; Brons, C.; Vaag, A. PPARGC1A DNA methylation in subcutaneous adipose tissue in low birth weight subjects—Impact of 5 days of high-fat overfeeding. Metabolism 2014, 63, 263–271. [Google Scholar] [CrossRef] [PubMed]
  97. Langie, S.A.; Achterfeldt, S.; Gorniak, J.P.; Halley-Hogg, K.J.; Oxley, D.; van Schooten, F.J.; Godschalk, R.W.; McKay, J.A.; Mathers, J.C. Maternal folate depletion and high-fat feeding from weaning affects DNA methylation and DNA repair in brain of adult offspring. FASEB J. 2013, 27, 3323–3334. [Google Scholar] [CrossRef] [PubMed]
  98. Jacobsen, S.C.; Brons, C.; Bork-Jensen, J.; Ribel-Madsen, R.; Yang, B.; Lara, E.; Hall, E.; Calvanese, V.; Nilsson, E.; Jorgensen, S.W.; 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, 3341–3349. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  99. Gallou-Kabani, C.; Gabory, A.; Tost, J.; Karimi, M.; Mayeur, S.; Lesage, J.; Boudadi, E.; Gross, M.S.; Taurelle, J.; Vige, A.; et al. Sex- and diet-specific changes of imprinted gene expression and DNA methylation in mouse placenta under a high-fat diet. PLoS ONE 2010, 5, e14398. [Google Scholar] [CrossRef] [PubMed]
  100. Aagaard-Tillery, K.M.; Grove, K.; Bishop, J.; Ke, X.; Fu, Q.; McKnight, R.; Lane, R.H. Developmental origins of disease and determinants of chromatin structure: Maternal diet modifies the primate fetal epigenome. J. Mol. Endocrinol. 2008, 41, 91–102. [Google Scholar] [CrossRef] [PubMed]
  101. Cirera, S.; Birck, M.; Busk, P.K.; Fredholm, M. Expression profiles of miRNA-122 and its target cat1 in minipigs (Sus scrofa) fed a high-cholesterol diet. Comp. Med. 2010, 60, 136–141. [Google Scholar] [PubMed]
  102. Takanabe, R.; Ono, K.; Abe, Y.; Takaya, T.; Horie, T.; Wada, H.; Kita, T.; Satoh, N.; Shimatsu, A.; Hasegawa, K. Up-regulated expression of microRNA-143 in association with obesity in adipose tissue of mice fed high-fat diet. Biochem. Biophys. Res. Commun. 2008, 376, 728–732. [Google Scholar] [CrossRef] [PubMed]
  103. Burdge, G.C.; Lillycrop, K.A. Fatty acids and epigenetics. Curr. Opin. Clin. Nutr. Metab. Care 2014, 17, 156–161. [Google Scholar] [CrossRef] [PubMed]
  104. Niculescu, M.D.; Craciunescu, C.N.; Zeisel, S.H. Dietary choline deficiency alters global and gene-specific DNA methylation in the developing hippocampus of mouse fetal brains. FASEB J. 2006, 20, 43–49. [Google Scholar] [CrossRef] [PubMed]
  105. Medici, V.; Shibata, N.M.; Kharbanda, K.K.; Islam, M.S.; Keen, C.L.; Kim, K.; Tillman, B.; French, S.W.; Halsted, C.H.; LaSalle, J.M. Maternal choline modifies fetal liver copper, gene expression, DNA methylation, and neonatal growth in the tx-j mouse model of Wilson disease. Epigenetics 2014, 9, 286–296. [Google Scholar] [CrossRef] [PubMed]
  106. Mehedint, M.G.; Niculescu, M.D.; Craciunescu, C.N.; Zeisel, S.H. Choline deficiency alters global histone methylation and epigenetic marking at the Re1 site of the calbindin 1 gene. FASEB J. 2010, 24, 184–195. [Google Scholar] [CrossRef]
  107. Wang, B.; Majumder, S.; Nuovo, G.; Kutay, H.; Volinia, S.; Patel, T.; Schmittgen, T.D.; Croce, C.; Ghoshal, K.; Jacob, S.T. Role of microRNA-155 at early stages of hepatocarcinogenesis induced by choline-deficient and amino acid-defined diet in C57BL/6 mice. Hepatology 2009, 50, 1152–1161. [Google Scholar] [CrossRef] [PubMed]
  108. Pellanda, H. Betaine homocysteine methyltransferase (BHMT)-dependent remethylation pathway in human healthy and tumoral liver. Clin. Chem. Lab. Med. 2013, 51, 617–621. [Google Scholar] [CrossRef] [PubMed]
  109. Li, M.; Cao, L.; Yang, Y. The role of epigenetic modification in glucose and lipid metabolism. Yi Chuan 2014, 36, 200–207. [Google Scholar] [PubMed]
  110. Ferrari, A.; Fiorino, E.; Giudici, M.; Gilardi, F.; Galmozzi, A.; Mitro, N.; Cermenati, G.; Godio, C.; Caruso, D.; de Fabiani, E.; et al. Linking epigenetics to lipid metabolism: Focus on histone deacetylases. Mol. Membr. Biol. 2012, 29, 257–266. [Google Scholar] [CrossRef] [PubMed]
  111. El-Osta, A.; Brasacchio, D.; Yao, D.; Pocai, A.; Jones, P.L.; Roeder, R.G.; Cooper, M.E.; Brownlee, M. Transient high glucose causes persistent epigenetic changes and altered gene expression during subsequent normoglycemia. J. Exp. Med. 2008, 205, 2409–2417. [Google Scholar] [CrossRef] [PubMed]
  112. Mali, P.; Chou, B.K.; Yen, J.; Ye, Z.; Zou, J.; Dowey, S.; Brodsky, R.A.; Ohm, J.E.; Yu, W.; Baylin, S.B.; et al. Butyrate greatly enhances derivation of human induced pluripotent stem cells by promoting epigenetic remodeling and the expression of pluripotency-associated genes. Stem Cells 2010, 28, 713–720. [Google Scholar] [CrossRef] [PubMed]
  113. Martin, S.L.; Hardy, T.M.; Tollefsbol, T.O. Medicinal chemistry of the epigenetic diet and caloric restriction. Curr. Med. Chem. 2013, 20, 4050–4059. [Google Scholar] [CrossRef] [PubMed]
  114. Qiu, X.; Brown, K.V.; Moran, Y.; Chen, D. Sirtuin regulation in calorie restriction. Biochim. Biophys. Acta 2010, 1804, 1576–1583. [Google Scholar] [CrossRef] [PubMed]
  115. Ganguly, A.; Chen, Y.; Shin, B.C.; Devaskar, S.U. Prenatal caloric restriction enhances DNA methylation and MeCP2 recruitment with reduced murine placental glucose transporter isoform 3 expression. J. Nutr. Biochem. 2014, 25, 259–266. [Google Scholar] [CrossRef] [PubMed]
  116. Plagemann, A.; Harder, T.; Brunn, M.; Harder, A.; Roepke, K.; Wittrock-Staar, M.; Ziska, T.; Schellong, K.; Rodekamp, E.; Melchior, K.; et al. Hypothalamic proopiomelanocortin promoter methylation becomes altered by early overfeeding: An epigenetic model of obesity and the metabolic syndrome. J. Physiol. 2009, 587, 4963–4976. [Google Scholar] [CrossRef] [PubMed]
  117. Cho, C.E.; Sanchez-Hernandez, D.; Reza-Lopez, S.A.; Huot, P.S.; Kim, Y.I.; Anderson, G.H. High folate gestational and post-weaning diets alter hypothalamic feeding pathways by DNA methylation in Wistar rat offspring. Epigenetics 2013, 8, 710–719. [Google Scholar] [CrossRef] [PubMed]
  118. Ly, A.; Hoyt, L.; Crowell, J.; Kim, Y.I. Folate and DNA methylation. Antioxid. Redox Signal. 2012, 17, 302–326. [Google Scholar] [CrossRef] [PubMed]
  119. Crider, K.S.; Yang, T.P.; Berry, R.J.; Bailey, L.B. Folate and DNA methylation: A review of molecular mechanisms and the evidence for folate’s role. Adv. Nutr. 2012, 3, 21–38. [Google Scholar] [CrossRef] [PubMed]
  120. Sinclair, K.D.; Allegrucci, C.; Singh, R.; Gardner, D.S.; Sebastian, S.; Bispham, J.; Thurston, A.; Huntley, J.F.; Rees, W.D.; Maloney, C.A.; et al. DNA methylation, insulin resistance, and blood pressure in offspring determined by maternal periconceptional B vitamin and methionine status. Proc. Natl. Acad. Sci. USA 2007, 104, 19351–19356. [Google Scholar] [CrossRef] [PubMed]
  121. Zhou, H.R.; Zhang, F.F.; Ma, Z.Y.; Huang, H.W.; Jiang, L.; Cai, T.; Zhu, J.K.; Zhang, C.; He, X.J. Folate polyglutamylation is involved in chromatin silencing by maintaining global DNA methylation and histone H3K9 dimethylation in Arabidopsis. Plant Cell 2013, 25, 2545–2559. [Google Scholar] [CrossRef] [PubMed]
  122. Xue, J.; Zempleni, J. Epigenetic synergies between biotin and folate in the regulation of pro-inflammatory cytokines and repeats. Scand. J. Immunol. 2013, 78, 419–425. [Google Scholar] [CrossRef] [PubMed]
  123. Pogribny, I.P.; Ross, S.A.; Tryndyak, V.P.; Pogribna, M.; Poirier, L.A.; Karpinets, T.V. Histone H3 lysine 9 and H4 lysine 20 trimethylation and the expression of Suv4-20h2 and Suv-39h1 histone methyltransferases in hepatocarcinogenesis induced by methyl deficiency in rats. Carcinogenesis 2006, 27, 1180–1186. [Google Scholar] [CrossRef] [PubMed]
  124. Tryndyak, V.P.; Ross, S.A.; Beland, F.A.; Pogribny, I.P. Down-regulation of the microRNAs miR-34a, miR-127, and miR-200b in rat liver during hepatocarcinogenesis induced by a methyl-deficient diet. Mol. Carcinog. 2009, 48, 479–487. [Google Scholar] [CrossRef] [PubMed]
  125. Pogribny, I.P.; Starlard-Davenport, A.; Tryndyak, V.P.; Han, T.; Ross, S.A.; Rusyn, I.; Beland, F.A. Difference in expression of hepatic microRNAs miR-29c, miR-34a, miR-155, and miR-200b is associated with strain-specific susceptibility to dietary nonalcoholic steatohepatitis in mice. Lab. Invest. 2010, 90, 1437–1446. [Google Scholar] [CrossRef] [PubMed]
  126. Minor, E.A.; Court, B.L.; Young, J.I.; Wang, G. Ascorbate induces ten-eleven translocation (Tet) methylcytosine dioxygenase-mediated generation of 5-hydroxymethylcytosine. J. Biol. Chem. 2013, 288, 13669–13674. [Google Scholar] [CrossRef] [PubMed]
  127. Moison, C.; Senamaud-Beaufort, C.; Fourriere, L.; Champion, C.; Ceccaldi, A.; Lacomme, S.; Daunay, A.; Tost, J.; Arimondo, P.B.; Guieysse-Peugeot, A.L. DNA methylation associated with polycomb repression in retinoic acid receptor beta silencing. FASEB J. 2013, 27, 1468–1478. [Google Scholar] [CrossRef] [PubMed]
  128. Kuriyama, M.; Udagawa, A.; Yoshimoto, S.; Ichinose, M.; Sato, K.; Yamazaki, K.; Matsuno, Y.; Shiota, K.; Mori, C. DNA methylation changes during cleft palate formation induced by retinoic acid in mice. Cleft Palate Craniofac. J. 2008, 45, 545–551. [Google Scholar] [CrossRef] [PubMed]
  129. Lee, E.R.; Murdoch, F.E.; Fritsch, M.K. High histone acetylation and decreased polycomb repressive complex 2 member levels regulate gene specific transcriptional changes during early embryonic stem cell differentiation induced by retinoic acid. Stem Cells 2007, 25, 2191–2199. [Google Scholar] [CrossRef] [PubMed]
  130. Urvalek, A.M.; Gudas, L.J. Retinoic acid and histone deacetylases regulate epigenetic changes in embryonic stem cells. J. Biol. Chem. 2014, 289, 19519–19530. [Google Scholar] [CrossRef] [PubMed]
  131. Urvalek, A.; Laursen, K.B.; Gudas, L.J. The roles of retinoic acid and retinoic acid receptors in inducing epigenetic changes. Subcell. Biochem. 2014, 70, 129–149. [Google Scholar] [PubMed]
  132. Schenk, T.; Chen, W.C.; Gollner, S.; Howell, L.; Jin, L.; Hebestreit, K.; Klein, H.U.; Popescu, A.C.; Burnett, A.; Mills, K.; et al. Inhibition of the lsd1 (KDM1A) demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia. Nat. Med. 2012, 18, 605–611. [Google Scholar] [CrossRef] [PubMed]
  133. Das, S.; Foley, N.; Bryan, K.; Watters, K.M.; Bray, I.; Murphy, D.M.; Buckley, P.G.; Stallings, R.L. MicroRNA mediates DNA demethylation events triggered by retinoic acid during neuroblastoma cell differentiation. Cancer Res. 2010, 70, 7874–7881. [Google Scholar] [CrossRef] [PubMed]
  134. Hassan, Y.I.; Zempleni, J. Epigenetic regulation of chromatin structure and gene function by biotin. J. Nutr. 2006, 136, 1763–1765. [Google Scholar] [PubMed]
  135. Huang, Y.; Khor, T.O.; Shu, L.; Saw, C.L.; Wu, T.Y.; Suh, N.; Yang, C.S.; Kong, A.N. A gamma-tocopherol-rich mixture of tocopherols maintains Nrf2 expression in prostate tumors of TRAMP mice via epigenetic inhibition of CpG methylation. J. Nutr. 2012, 142, 818–823. [Google Scholar] [CrossRef] [PubMed]
  136. Cornwell, D.G.; Ma, J. Studies in vitamin E: Biochemistry and molecular biology of tocopherol quinones. Vitam. Horm. 2007, 76, 99–134. [Google Scholar] [PubMed]
  137. Bobrowska-Korczak, B.; Skrajnowska, D.; Tokarz, A. Effect of zinc and copper supplementation on the prognostic value of urinary 5-methyl-2’-deoxycytidine in DMBA-induced carcinogenesis in rats. Cancer Biomark. 2013, 13, 403–410. [Google Scholar] [PubMed]
  138. Wang, L.; Bammler, T.K.; Beyer, R.P.; Gallagher, E.P. Copper-induced deregulation of microRNA expression in the zebrafish olfactory system. Environ. Sci. Technol. 2013, 47, 7466–7474. [Google Scholar] [PubMed]
  139. Yang, G.; Zhu, Y.; Dong, X.; Duan, Z.; Niu, X.; Wei, J. TLT2-ICAM1-Gadd45alpha axis mediates the epigenetic effect of selenium on DNA methylation and gene expression in Keshan disease. Biol. Trace Elem. Res. 2014, 159, 69–80. [Google Scholar] [CrossRef] [PubMed]
  140. Metes-Kosik, N.; Luptak, I.; Dibello, P.M.; Handy, D.E.; Tang, S.S.; Zhi, H.; Qin, F.; Jacobsen, D.W.; Loscalzo, J.; Joseph, J. Both selenium deficiency and modest selenium supplementation lead to myocardial fibrosis in mice via effects on redox-methylation balance. Mol. Nutr. Food Res. 2012, 56, 1812–1824. [Google Scholar] [CrossRef] [PubMed]
  141. Szarc vel Szic, K.; Ndlovu, M.N.; Haegeman, G.; Vanden Berghe, W. Nature or nurture: Let food be your epigenetic medicine in chronic inflammatory disorders. Biochem. Pharmacol. 2010, 80, 1816–1832. [Google Scholar] [CrossRef] [PubMed]
  142. Khan, S.I.; Aumsuwan, P.; Khan, I.A.; Walker, L.A.; Dasmahapatra, A.K. Epigenetic events associated with breast cancer and their prevention by dietary components targeting the epigenome. Chem. Res. Toxicol. 2012, 25, 61–73. [Google Scholar] [CrossRef] [PubMed]
  143. Vanden Berghe, W. Epigenetic impact of dietary polyphenols in cancer chemoprevention: Lifelong remodeling of our epigenomes. Pharmacol. Res. 2012, 65, 565–576. [Google Scholar] [CrossRef] [PubMed]
  144. Ong, T.P.; Moreno, F.S.; Ross, S.A. Targeting the epigenome with bioactive food components for cancer prevention. J. Nutrigenet. Nutr. 2011, 4, 275–292. [Google Scholar] [CrossRef]

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Chango, A.; Pogribny, I.P. Considering Maternal Dietary Modulators for Epigenetic Regulation and Programming of the Fetal Epigenome. Nutrients 2015, 7, 2748-2770. https://0-doi-org.brum.beds.ac.uk/10.3390/nu7042748

AMA Style

Chango A, Pogribny IP. Considering Maternal Dietary Modulators for Epigenetic Regulation and Programming of the Fetal Epigenome. Nutrients. 2015; 7(4):2748-2770. https://0-doi-org.brum.beds.ac.uk/10.3390/nu7042748

Chicago/Turabian Style

Chango, Abalo, and Igor P. Pogribny. 2015. "Considering Maternal Dietary Modulators for Epigenetic Regulation and Programming of the Fetal Epigenome" Nutrients 7, no. 4: 2748-2770. https://0-doi-org.brum.beds.ac.uk/10.3390/nu7042748

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