Introduction
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.
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.
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) (1). 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.
Current status of knowledge
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.
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.
Effects of nutrients on DNA methylation.
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.
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. (7).
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 (9).
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) (14). 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 [reviewed in (15)].
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.
Histone modification
Nucleosome and chromatin structure.
A nucleosome, which consists of 146 bp DNA and an octamer of histone proteins (histone 2A, histone 2B, histone 3, and histone 4), is a building block of chromatin, which can regulate transcriptional processes through postsynthetic modifications of DNA and the histone (Fig. 1). In contrast to DNA that is modified only by methylation, histones can be modified by methylation, acetylation, phosphorylation, biotinylation, ubiquitination, sumoylation, and ADP-ribosylation.
Histone acetylation.
Histone acetylation is one of the most extensively studied histone modifications.
Calorie restriction reduces the expression of inflammatory genes such as NF-κB, AP1, COX-2, and iNOS. NF-κB is known to be activated by histone acetylation. p300 HAT acetylates the p50 subunit of NF-κB, thereby increasing NF-κB binding and NF-κB mediated transactivation. Further, caloric restriction reduces the expression of Sirt1, a major mediator of calorie restriction (36), which functions as a HDAC (37) and regulates p300 HAT (38). Sirt1 is also a regulator of histone methyltransferases (39).
Resveratrol, a bioactive component in grape skins and novel potent activator of Sirt1, has an antiinflammatory effect against colitis and colitis-associated colon cancer (40,41). The antiinflammatory effect of resveratrol is conveyed through the inhibitory effects of iNOS, COX-2, and NF-κB (42–44). It has been suggested that histone acetylation by activated NF-κB can be repressed by resveratrol. Butyrate, a SCFA that enters into the active site of the HDAC enzymes and inhibits the activity, enhances derivation of induced pluripotent stem cells by increasing histone H3 acetylation and DNA demethylation. Butyrate stimulation may provide an effective method for reprogramming various human adult somatic cells (45).
Histone methylation.
Compared with histone acetylation, the effects of nutrients or bioactive components on histone methylation have not yet been extensively studied, even though cancer and aging demonstrated substantial changes in histone methylation.
Histone biotinylation.
Biotin, an essential water-soluble B vitamin, has been known to modify tails of histone H2A, H3, and H4 through a covalent attachment of biotin to specific lysine residues catalyzed by the enzymes biotinidase and holocarboxylase synthase. Biotinylations at histone H4 lysine 8 and lysine 12 have been associated with heterochromatin structures, gene silencing, mitotic condensation of chromatin, and DNA repair (53,54).
Chromatin remodeling
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MicroRNA
MicroRNA is a new class of noncoding, endogenous, small RNA that regulates gene expression by translational repression, representing a new important class of regulatory molecules. MicroRNA can play important roles in controlling DNA methylation and histone modifications, creating a highly controlled feedback mechanism.
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Referência :
(1) Adv Nutr. 2010 Nov;1(1):8-16.