Nutrients can reverse or change epigenetic phenomena such as DNA methylation and histone modifications, thereby modifying the expression of critical genes associated with physiologic and pathologic processes, including embryonic development, aging, and carcinogenesis. It appears that nutrients and bioactive food components can influence epigenetic phenomena either by directly inhibiting enzymes that catalyze DNA methylation or histone modifications, or by altering the availability of substrates necessary for those enzymatic reactions. In this regard, nutritional epigenetics has been viewed as an attractive tool to prevent pediatric developmental diseases and cancer as well as to delay aging-associated processes. In recent years, epigenetics has become an emerging issue in a broad range of diseases such as type 2 diabetes mellitus, obesity, inflammation, and neurocognitive disorders. Although the possibility of developing a treatment or discovering preventative measures of these diseases is exciting, current knowledge in nutritional epigenetics is limited, and further studies are needed to expand the available resources and better understand the use of nutrients or bioactive food components for maintaining our health and preventing diseases through modifiable epigenetic mechanisms.
Epigenetics is an inheritable phenomenon that affects gene expression without base pair changes. Epigenetic phenomena include DNA methylation, histone modifications, and chromatin remodeling. Chromatin is quite dynamic and is much more than a neutral system for packaging and condensing genomic DNA. It is a critical player in controlling the accessibility of DNA for transcription. Modifications of chromatin structure can give rise to a variety of epigenetic effects. Due to its reversible character, epigenetics is now considered an attractive field of nutritional intervention.
Nutrients can modify physiologic and pathologic processes through epigenetic mechanisms that are critical for gene expression. Modulation of these processes through diet or specific nutrients may prevent diseases and maintain health. However, it is very hard to delineate the precise effect of nutrients or bioactive food components on each epigenetic modulation and their associations with physiologic and pathologic processes in our body, because the nutrients also interact with genes, other nutrients, and other lifestyle factors. Furthermore, each epigenetic phenomenon also interacts with the others, adding to the complexity of the system.
Epigenetics can be defined as somatically heritable states of gene expression resulting from changes in chromatin structure without alterations in the DNA sequence, including DNA methylation, histone modifications, and chromatin remodeling. Over the past decades, epigenetic studies mainly have been focused on embryonic development, aging, and cancer. Presently, epigenetics is highlighted in many other fields, such as inflammation, obesity, insulin resistance, type 2 diabetes mellitus, cardiovascular diseases, neurodegenerative diseases, and immune diseases. Because epigenetic modifications can be altered by external or internal environmental factors and have the ability to change gene expression, epigenetics is now considered an important mechanism in the unknown etiology of many diseases. Such induced epigenetic changes can be inherited during cell division, resulting in permanent maintenance of the acquired phenotype. Thus, epigenetics can provide a new framework for the search for etiological factors in environment-associated diseases as well as embryonic development and aging, which are also known to be affected by many environmental factors.
In the nutritional field, epigenetics is exceptionally important, because nutrients and bioactive food components can modify epigenetic phenomena and alter the expression of genes at the transcriptional level. Folate, vitamin B-12, methionine, choline, and betaine can affect DNA methylation and histone methylation through altering 1-carbon metabolism. Two metabolites of 1-carbon metabolism can affect methylation of DNA and histones: S-adenosylmethionine (AdoMet)5, which is a methyl donor for methylation reactions, and S-adenosylhomocysteine (AdoHcy), which is a product inhibitor of methyltransferases. Thus, theoretically, any nutrient, bioactive component, or condition that can affect AdoMet or AdoHcy levels in the tissue can alter the methylation of DNA and histones. Other water-soluble B vitamins like biotin, niacin, and pantothenic acid also play important roles in histone modifications. Biotin is a substrate of histone biotinylation. Niacin is involved in histone ADP-ribosylation as a substrate of poly(ADP-ribose) polymerase as well as histone acetylation as a substrate of Sirt1, which functions as histone deacetylase (HDAC). Pantothenic acid is a part of CoA to form acetyl-CoA, which is the source of acetyl group in histone acetylation. Bioactive food components directly affect enzymes involved in epigenetic mechanisms. For instance, genistein and tea catechin affects DNA methyltransferases (Dnmt). Resveratrol, butyrate, sulforaphane, and diallyl sulfide inhibit HDAC and curcumin inhibits histone acetyltransferases (HAT). Altered enzyme activity by these compounds may affect physiologic and pathologic processes during our lifetime by altering gene expression.
The Deep Epigenetic Impact of Nutrition
- The sight of seeing a predictive outcome analysis for the development of a disease process from a genetic test has many people scared out of their socks. In many cases, some people have no interest in looking at the data at all. But of course, these individuals are still under the premise that their inherited gene sequence means certain diseases are inevitable. Nothing can be further from the truth.
- Epigenetics demonstrates that gene expression is influenced heavily by lifestyle factors, such as diet, how well your body can adapt to stress and its environment, as well as how well your body can detoxify chemicals and toxic metals. Of course, if you have inherent genetic weaknesses, you consume a standard American diet and are filled with toxic mercury from dental amalgams, then the health outcome of the situation is headed down hill.
- Even if you have mutated genes that alter the function of important biochemical pathways of your body, such as in methylation pathways, there are ways to bypass the issues. Gene-specific nutrient therapy, referred to as Nutrigenomics and a strong, individualized whole food diet, can prevent your genetic weaknesses from expressing certain diseases.
- What’s more, is that the study of the epigenome demonstrates that changes in DNA and histones can be passed down from parent to child. And yet, the underlying genetic sequence remains unchanged. This means that a bad diet and exposure to lots of toxins will not only affect your health, but can affect the health of your children and even their future generations.
Effects of nutrients on DNA methylation.
DNA methylation, which modifies a cytosine base at the CpG dinucleotide residues with methyl groups, is catalyzed by Dnmt and regulates gene expression patterns by altering chromatin structures. Currently, 5 different Dnmt are known: Dnmt1, Dnmt2, Dnmt 3a, Dnmt3b and DnmtL. Dnmt1 is a maintenance Dnmt and Dnmt 3a, 3b, and L are de novo Dnmt. The function of Dnmt2 is not yet clear. By affecting these Dnmt during our lifetime, nutrients and bioactive food components can change global DNA methylation, which is associated with chromosomal integrity, as well as gene-specific promoter DNA methylation, which is closely associated with gene expression. Furthermore, these Dnmts work together with enzymes that catalyze other epigenetic phenomena, and changes in the activity of these enzymes may be involved in the development of various diseases.
Compared with DNA methylation reactions, the DNA demethylation process has not been well delineated. However, the DNA demethylation mechanism is currently highlighted, because DNA demethylation is important in cellular processes during embryonic development and stem cell differentiation. Several candidate mechanism are suggested: 1) base excision repair initiated by 5-methylcytosine DNA glycosylase; 2) base excision repair initiated by coupled activities of 5-mC deaminase that converts 5-mC to T, and G/T mismatch DNA glycosylase that corrects the G/T mismatch; 3) nucleotide excision repair that removes methylated CpG dinucleotides; 4) oxidative removal of the methyl group; and 5) hydrolytic removal of the methyl group. Most recently, hydroxymethyl cytosine was found. The conversion of 5-methylcytosine to 5-hydroxymethylcytosine (5hmC) in mammalian DNA is mediated by methylcytosine oxygenase TET1 (3). In addition, 5hmC might be produced by the addition of formaldehyde to cytosines in DNA by Dnmt proteins (4). It appears that 5hmC might serve biologically important roles by itself, or it might serve as an intermediate in DNA demethylation. It was also suggested that a reversible enzymatic reaction catalyzed by Dnmt proteins can produce unmodified cytosine from 5hmC, supporting that 5hmC might be an intermediate in direct DNA demethylation. Because 5hmC is present in mammalian DNA at a significant level in a tissue-specific manner, further studies are needed to delineate the role of 5hmC, especially in aging and cancer, both of which demonstrate DNA hypomethylation.
Folate, a water-soluble B vitamin, has been extensively studied for its effect on DNA methylation, because folate carries a methyl group and ultimately delivers that methyl group for the synthesis of AdoMet, the unique methyl donor for DNA methylation reactions. However, folate is not the sole determinant of DNA methylation, because other methyl donor nutrients such as methionine, choline, betaine, and vitamin B-12 as well as other environmental factors can also change DNA methylation status. In a recent animal study, dietary folate levels were positively correlated with both genomic and p16 promoter DNA methylation status, along with an altered p16 gene expression level in aged mouse colon. This result is consistent with a human study that T lymphocytes showed DNA demethylation and overexpression of genes associated with autoimmunity after the age of 50 y when T lymphocytes from healthy adults 22–81 y old were cultured with a low-folate and -methionine medium. The effects were reproduced by Dnmt1 knockdowns in T lymphocytes from young participants. Because it is known that Dnmt1 expression is decreased by aging, we can speculate that age-dependent decreases in Dnmt levels and low dietary methyl donor nutrients synergistically alter the DNA methylation status and DNA methylation-mediated gene expression.
It appears that folate is essential for DNA methylation reprogramming during the early embryonic period. Because folate deficiency in early pregnancy is associated with an increased risk of neural tube defects, aberrant reprogramming of DNA methylation by low dietary folate has been suggested as a candidate mechanism. Steegers-Theunissen et al. investigated whether periconceptional maternal folic acid supplementation affects methylation at the differentially methylated region (DMR) of the insulin-like growth factor 2 gene (IGF2) in 120 children aged 17 mo. Eight-six mothers of these children had used folic acid periconceptionally but 34 mothers had not. IGF2 is an imprinting gene in which the methylated allele at DMR (imprinted allele) is repressed. Abnormal derepression of imprinted alleles (loss of imprinting) has been suggested to cause pediatric developmental diseases or cancer in later life. Children of mothers who used folic acid had a 4.5% higher methylation of the IGF2 DMR than children who were not exposed to maternal folic acid supplementation (P = 0.014). This result indicates that periconceptional folic acid supplementation is associated with imprinting status of IGF2 in the child, which may affect intrauterine programming of growth and development with consequences for health and disease throughout life. In an animal study using mature female sheep, restriction of folate, vitamin B-12, and methionine from the periconceptional diet induced obesity in adult offspring as well as altered immune responses to an antigenic challenge. In these adult offspring, methylation status of 4% of 1400 CpG islands was altered. This study indicates that dietary methyl nutrients during the periconceptional period can change DNA methylation patterns in offspring and it may modify adult health-related phenotypes.
Animal studies also suggest that dietary folate during the postweaning period also affects DNA methylation status in a way that may modify disease susceptibility in later life. Kotsopoulos et al. reported that a low-folate diet provided from the postweaning period to puberty increased genomic DNA methylation by 34–48% (P < 0.04) in rat liver that persisted into adulthood. An animal study also indicated that a postweaning diet can affect imprinting status at the IGF2 locus.
Vitamin B-12, a water-soluble B vitamin and essential cofactor of methionine synthase in 1-carbon metabolism, has been known to affect genomic DNA methylation. Most recently, Uekawa et al. demonstrated that severe vitamin B-12 deficiency induces promoter hypomethylation of the cystathionine β-synthase gene and represses this gene transcription in rats, even though supplementation with methionine, the precursor of AdoMet and product of methionine synthase, could not reverse this effect. Choline is a methyl donor nutrient and maternal choline availability is essential for fetal neurogenesis such as hippocampal development as well as memory function throughout life. In a mouse study, choline deprivation during the embryonic period caused hypermethylation of a specific CpG site within the calbindin 1 (Calb1) gene, which is important in hippocampus development, along with increased expression of Calb1 . This study indicates that choline deficiency during the embryonic period could change DNA methylation and thereby alter fetal brain development.
Effects of bioactive food components on DNA methylation.
- A growing body of evidence suggests that certain bioactive food components, including tea polyphenols, genistein from soybean, or isothiocyanates from plant foods, might inhibit the development of cancer by reducing DNA hypermethylation status in critical genes associated with cancer, such as p16 or retinoic acid receptor beta (RARβ). The effects of dietary polyphenols appear to be either through their direct inhibition by interaction with the catalytic site of the Dnmt1 molecule or their influence on methylation status indirectly through metabolic effects associated with energy metabolism.
- In a human study, healthy premenopausal women demonstrated that a daily supplementation with isoflavones induced dose-specific changes in RARβ2 and cyclin D2 (CCND2) gene methylation from the intraductal specimens, which are correlated with serum genistein levels. In a cultured cell study, genistein alone showed a significant antileukemic activity against murine cells, and this effect was enhanced when used in combination with 5-aza-2′-deoxycytidine, a potent inhibitor of Dnmt and an effective agent for the treatment of leukemia. These results suggest that genistein may have the potential to increase the clinical efficacy of 5-aza-2′-deoxycytidine for the treatment of cancer through its inhibitory effect on DNA methylation. Treatment with genistein could be more physiologic than that with potent cancer chemotherapeutic agents.
- On the other hand, transgenerational studies using CD-1 mice demonstrated that neonatal exposure to genistein can induce uterine adenocarcinoma, which is associated with abnormal hypomethylation of CpG islands in the nucleosomal binding protein 1 (Nsbp1) gene throughout life. The Nsbp1 is purported to be involved in chromatin remodeling and transcriptional activation. This study indicates that the reprogramming of uterine Nsbp1 expression by neonatal genistein exposure could be mediated by DNA methylation.
Effects of diet on DNA methylation.
- In rats moderate maternal dietary protein restriction is known to alter phenotypes in the offspring, which manifests as hypertension, dyslipidemia, and impaired glucose metabolism. However, these abnormalities can be reversed by folate supplementation. It has been shown that the induction of an altered phenotype by a maternal protein restriction diet during pregnancy involves changes in DNA methylation and histone modifications in specific genes, including the glucocorticoid receptor (GR) (33% lower; P < 0.001) and PPARα (26% lower; P < 0.05) in the liver of juvenile and adult offspring.
- The honeybee model clearly demonstrated the epigenetic effects of diet on the phenotype, because honeybees grow to be either queens or workers depending on whether they are fed royal jelly or beebread. The different honeybee phenotype has been suggested to occur through epigenetic changes in DNA methylation patterns induced by the different types of honey. More recent studies found that ∼35% of the annotated honeybee genes are expected to be methylated at the CpG dinucleotides by a highly conserved DNA methylation system, suggesting that honeybees use DNA methylation to control the levels of activity of the genes that might be needed for conserved core biological processes
- An animal study using the obese Berlin fat mouse inbred line and the lean C57BL/6NCrl line of Mus musculus examined the methylation status and expression levels of the melanocortin-4 receptor (Mc4r) gene, which plays an important role in body weight regulation, in response to a standard and a high-fat diet. With the standard diet, the methylation status did not differ between the lines. With the high-fat diet, methylation of the CpGs near the transcription start site was decreased in both lines. The results suggest that a high-fat diet might affect the methylation status of the Mc4r gene. The Mc4r gene expression, however, was only marginally increased in the obese mouse line, whereas there was no change in the lean mouse line
- Alcohol profoundly affects 1-carbon metabolism by limiting methyl transfer reactions. Recently, Kaminen-Ahola et al. conducted an animal study using a model of gestational alcohol exposure. They observed changes in the expression of an epigenetically sensitive allele, Agouti viable yellow (Avy), in the offspring after maternal ad libitum ingestion of 10% (v:v) ethanol between gestational d 0.5 and 8.5. Maternal ethanol ingestion increased the probability of transcriptional silencing at this locus, resulting in more mice with an agouti-colored coat. This transcriptional silencing correlated with hypermethylation at Avy. In the ethanol-exposed group, 11% of the CpG dinucleotides were methylated compared with 2% in the control group. This demonstrates that ethanol can affect adult phenotype by altering the epigenotype of the early embryo.
The Future of Epigenetics
- As knowledge of the epigenome grows, we continue to learn more about how the substances we consume and the social situations we inhabit influence the way our genes are expressed. Scientists are already rethinking the way organisms evolve and how traits are passed on from parent to offspring. But at what point will this knowledge begin to change the way we live? At what point will we be able to take a pill and block or unblock the right combination of genes to improve our quality of life?
- While turning off aging and fine-tuning the human genome are pretty awe-inspiring possibilities, epigeneticists are far more interested in discovering ways to treat epigenetic diseases. As some cancers occur due to the deactivation of tumor-suppressing genes, researchers have worked to develop medications that reactivate them. The drug azacitidine, for instance, treats leukemia in this manner. Finding just the right parts of the epigenome to treat, however, can be like finding a needle in a haystack. And once researchers find the areas they want to affect, epigenetic drugs aren’t all that specific. They might succeed in blocking or unblocking the genes they wanted to treat, but also affect other genes, resulting in potentially dangerous side effects.
- Following the completion of the Human Genome Project, the Human Epigenome Project is currently striving to map the scope of changes that can occur between genome and phenotype. Once finished, however, an epigenomic map could also prove useful in determining which individuals are at risk for certain diseases and encouraging the kind of lifestyle changes that can prevent the wrong genes from switching on or off.
- More than future medicines are at stake, however. Epigenetic discoveries also force doctors to reexamine existing drugs. Even azacitidine, the first FDA-approved epigenomic drug, was used previously to treat bone-marrow stem cell disorders. It was only after the discovery of its epigenetic effects that doctors explored its uses in other areas.
- Stem cells are also of key interest to epigeneticists. By studying the epigenetic changes that determine how cells develop, it may eventually become possible to dictate what tissue type a stem cell will develop into. For more information on the implications of this, read How Stem Cells Work.
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