Epigenetics: A New Bridge between Nutrition and Health

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.     

Nutritional Epigenomics: A Portal to Disease Prevention

Epigenetics can be defined as inheritable and reversible phenomena that affect gene expression without altering the underlying base pair sequence. Epigenomics is the study of genome-wide epigenetic modifications. Because gene expression changes are critical in both normal development and disease progression, epigenetics is widely applicable to many aspects of biological research. The influences of nutrients and bioactive food components on epigenetic phenomena such as DNA methylation and various types of histone modifications have been extensively investigated. Because an individual’s epigenetic patterns are established during early gestation and are changed and personalized by environmental factors during our lifetime, epigenetic mechanisms are quite important in the development of transgenerational and adult obesity as well as in the development of diabetes mellitus. Aging and cancer demonstrate profound genome-wide DNA methylation changes, suggesting that nutrition may affect the aging process and cancer development through epigenetic mechanisms.     

Nutritional epigenetics: impact of folate deficiency on DNA methylation and colon cancer susceptibility

The inheritance of information based on gene expression levels is known as epigenetics, as opposed to genetics, which refers to information transmitted on the basis of gene sequence. In contrast to genetic changes observed in cancer, epigenetic changes are gradual in onset and are progressive, their effects are dose-dependent and are potentially reversible. These observations present new opportunities in cancer-risk modification and prevention using dietary and lifestyle factors and potential chemopreventive drugs. In this regard, folate, a water-soluble B vitamin, has been a focus of intense interest because of an inverse association between folate status and the risk of several malignancies (in particular, colorectal cancer) and of its potential ability to modulate DNA methylation. DNA methylation is an important epigenetic determinant in gene expression, in the maintenance of DNA integrity and stability, in chromosomal modifications, and in the development of mutations. Aberrant patterns and dysregulation of DNA methylation are mechanistically related to colorectal carcinogenesis. Folate plays an essential role in one-carbon transfer involving re-methylation of homocysteine to methionine, thereby ensuring the provision of S-adenosylmethionine, the primary methyl group donor for most biological methylation reactions. The portfolio of evidence from animal, human, and in vitro studies suggests that the effects of folate deficiency and supplementation on DNA methylation are gene and site specific, and appear to depend on cell type, target organ, stage of transformation, and the degree and duration of folate depletion.     

Dietary factors and epigenetic regulation for prostate cancer prevention

The role of epigenetic alterations in various human chronic diseases has gained increasing attention and has resulted in a paradigm shift in our understanding of disease susceptibility. In the field of cancer research, e.g., genetic abnormalities/mutations historically were viewed as primary underlying causes; however, epigenetic mechanisms that alter gene expression without affecting DNA sequence are now recognized as being of equal or greater importance for oncogenesis. Methylation of DNA, modification of histones, and interfering microRNA (miRNA) collectively represent a cadre of epigenetic elements dysregulated in cancer. Targeting the epigenome with compounds that modulate DNA methylation, histone marks, and miRNA profiles represents an evolving strategy for cancer chemoprevention, and these approaches are starting to show promise in human clinical trials. Essential micronutrients such as folate, vitamin B-12, selenium, and zinc as well as the dietary phytochemicals sulforaphane, tea polyphenols, curcumin, and allyl sulfur compounds are among a growing list of agents that affect epigenetic events as novel mechanisms of chemoprevention. To illustrate these concepts, the current review highlights the interactions among nutrients, epigenetics, and prostate cancer susceptibility. In particular, we focus on epigenetic dysregulation and the impact of specific nutrients and food components on DNA methylation and histone modifications that can alter gene expression and influence prostate cancer progression.     

Epigenetic Aspects of Fertilization and Preimplantation Development in Mammals: Lessons from the Mouse

During gametogenesis, the parental genomes are separated and are epigenetically marked by modifications that will direct the expression profile of genes necessary for meiosis as well as for the formation of the oocyte and sperm cell. Immediately after sperm-egg fusion, the parental haploid genomes show great epigenetic asymmetry with differences in the levels of DNA methylation and histone tail modifications. The epigenetic program acquired during oogenesis and spermatogenesis must be reset for the zygote to successfully proceed through preimplantation development and this occurs as the two genomes approach each other in preparation for karyogamy. During preimplantation development, the embryo is vested with the responsibility of maintaining the primary imprints. In addition, female embryos must silence one of the X-chromosomes in order to transcribe equal levels of X-linked genes as their male counterparts. This review is intended as a survey of the epigenetic modifications and mechanisms present in zygotes and preimplantation mouse embryos, namely DNA methylation, histone modifications, dosage compensation, genomic imprinting, and regulation by non-coding RNAs.     

Session 2: Personalised nutrition. Epigenomics: a basis for understanding individual differences?

Epigenetics encompasses changes to marks on the genome that are copied from one cell generation to the next, which may alter gene expression but which do not involve changes in the primary DNA sequence. These marks include DNA methylation (methylation of cytosines within CpG dinucleotides) and post-translational modifications (acetylation, methylation, phosphorylation and ubiquitination) of the histone tails protruding from nucleosome cores. The sum of genome-wide epigenetic patterns is known as the epigenome. It is hypothesised that altered epigenetic marking is a means through which evidence of environmental exposures (including nutritional status and dietary exposure) is received and recorded by the genome. At least some of these epigenetic marks are remembered through multiple cell generations and their effects may be revealed in altered gene expression and cell function. Altered epigenetic marking allows plasticity of phenotype in a fixed genotype. Despite their identical genotypes, monozygotic twins show increasing epigenetic diversity with age and with divergent lifestyles. Differences in epigenetic markings may explain some inter-individual variation in disease risk and in response to nutritional interventions.     

Early Life Nutrition,Epigenetics and Programming of Later Life Disease

The global pandemic of obesity and type 2 diabetes is often causally linked to marked changes in diet and lifestyle; namely marked increases in dietary intakes of high energy diets and concomitant reductions in physical activity levels. However, less attention has been paid to the role of developmental plasticity and alterations in phenotypic outcomes resulting from altered environmental conditions during the early life period. Human and experimental animal studies have highlighted the link between alterations in the early life environment and increased risk of obesity and metabolic disorders in later life. This link is conceptualised as the developmental programming hypothesis whereby environmental influences during critical periods of developmental plasticity can elicit lifelong effects on the health and well-being of the offspring. In particular, the nutritional environment in which the fetus or infant develops influences the risk of metabolic disorders in offspring. The late onset of such diseases in response to earlier transient experiences has led to the suggestion that developmental programming may have an epigenetic component, as epigenetic marks such as DNA methylation or histone tail modifications could provide a persistent memory of earlier nutritional states. Moreover, evidence exists, at least from animal models, that such epigenetic programming should be viewed as a transgenerational phenomenon. However, the mechanisms by which early environmental insults can have long-term effects on offspring are relatively unclear. Thus far, these mechanisms include permanent structural changes to the organ caused by suboptimal levels of an important factor during a critical developmental period, changes in gene expression caused by epigenetic modifications (including DNA methylation, histone modification, and microRNA) and permanent changes in cellular ageing. A better understanding of the epigenetic basis of developmental programming and how these effects may be transmitted across generations is essential for the implementation of initiatives aimed at curbing the current obesity and diabetes crisis.     

Impact of Phytochemicals and Dietary Patterns on Epigenome and Cancer

Cancer remains one of the leading causes of death around the world. Initially it is recognized as a genetic disease, but now it is known to involve epigenetic abnormalities along with genetic alterations. Epigenetics refers to heritable changes that are not encoded in the DNA sequence itself, but play an important role in the control of gene expression. It includes changes in DNA methylation, histone modifications, and RNA interference. Although it is heritable, environmental factors such as diet could directly influence epigenetic mechanisms in humans. This article will focus on the role of dietary patterns and phytochemicals that have been demonstrated to influence the epigenome and more precisely histone and non-histone proteins modulation by acetylation that helps to induce apoptosis and phosphorylation inhibition, which counteracts with cells proliferation. Recent developments discussed here enhance our understanding of how dietary intervention could be beneficial in preventing or treating cancer and improving health outcomes.     

饮食限制延缓衰老的表观遗传学机制

目的 近年来兴起的表观遗传学被认为在饮食影响健康、延缓衰老中发挥重要的作用。本文旨在从表观遗传学视角分析饮食限制延缓衰老的机制,为临床上抗衰老及其防治相关疾病提供理论参考。方法 系统综述了表观遗传学与衰老的关系,及饮食限制延缓衰老的表观遗传调控方式。结果 饮食限制通过DNA甲基化、组蛋白修饰、非编码RNA调控和染色质重塑等表观遗传修饰调节基因表达,进而影响衰老及其相关疾病的发生发展。结论 饮食限制是一种有效的可操作的环境因素,可通过调节表观遗传修饰进而延缓衰老,保持健康。     

Environmental chemical exposures and human epigenetics

Every year more than 13 million deaths worldwide are due to environmental pollutants, and approximately 24% of diseases are caused by environmental exposures that might be averted through preventive measures. Rapidly growing evidence has linked environmental pollutants with epigenetic variations, including changes in DNA methylation, histone modifications and microRNAs. Environ mental chemicals and epigenetic changes All of these mechanisms are likely to play important roles in disease aetiology, and their modifications due to environmental pollutants might provide further understanding of disease aetiology, as well as biomarkers reflecting exposures to environmental pollutants and/or predicting the risk of future disease. We summarize the findings on epigenetic alterations related to environmental chemical exposures, and propose mechanisms of action by means of which the exposures may cause such epigenetic changes. We discuss opportunities, challenges and future directions for future epidemiology research in environmental epigenomics. Future investigations are needed to solve methodological and practical challenges, including uncertainties about stability over time of epigenomic changes induced by the environment, tissue specificity of epigenetic alterations, validation of laboratory methods, and adaptation of bioinformatic and biostatistical methods to high-throughput epigenomics. In addition, there are numerous reports of epigenetic modifications arising following exposure to environmental toxicants, but most have not been directly linked to disease endpoints. To complete our discussion, we also briefly summarize the diseases that have been linked to environmental chemicals-related epigenetic changes.     

Olive Oil Improves While Trans Fatty Acids Further Aggravate the Hypomethylation of LINE-1 Retrotransposon DNA in an Environmental Carcinogen Model

DNA methylation is an epigenetic mechanism that is crucial for mammalian development and genomic stability. Aberrant DNA methylation changes have been detected not only in malignant tumor tissues; the decrease of global DNA methylation levels is also characteristic for aging. The consumption of extra virgin olive oil (EVOO) as part of a balanced diet shows preventive effects against age-related diseases and cancer. On the other hand, consuming trans fatty acids (TFA) increases the risk of cardiovascular diseases as well as cancer. The aim of the study was to investigate the LINE-1 retrotransposon (L1-RTP) DNA methylation pattern in liver, kidney, and spleen of mice as a marker of genetic instability. For that, mice were fed with EVOO or TFA and were pretreated with environmental carcinogen 7,12-dimethylbenz[a]anthracene (DMBA)—a harmful substance known to cause L1-RTP DNA hypomethylation. Our results show that DMBA and its combination with TFA caused significant L1-RTP DNA hypomethylation compared to the control group via inhibition of DNA methyltransferase (DNMT) enzymes. EVOO had the opposite effect by significantly decreasing DMBA and DMBA + TFA-induced hypomethylation, thereby counteracting their effects.     

In the cystathionine beta-synthase knockout mouse,elevations in total plasma homocysteine increase tissue S-adenosylhomocysteine,but responses of S-adenosylmethionine and DNA methylation are tissue specific

The cystathionine beta-synthase knockout mouse provides a unique opportunity to study biochemical consequences of a defective cystathionine beta-synthase enzyme. The present study was undertaken to assess the effect of elevated plasma total homocysteine caused by cystathionine beta-synthase deficiency on one-carbon metabolism in 10 homozygous mutant mice and 10 age- and sex-matched wild-type mice. Plasma total homocysteine levels, S-adenosylmethionine and S-adenosylhomocysteine concentrations in liver, kidney and brain were measured by HPLC. Tissue DNA methylation status was measured by in vitro DNA methyl acceptance. Plasma total homocysteine concentration in food-deprived homozygous mutant mice (271.1 +/- 61.5 micro mol/L) was markedly higher than in wild-type mice (7.4 +/- 2.9 micro mol/L) (P < 0.001). In liver only, S-adenosylmethionine concentrations were higher in the homozygous mutant mice (35.6 +/- 5.9 nmol/g) than in wild type mice (19.1 +/- 6.1 nmol/g) (P < 0.001) and tended to be lower in kidney (P = 0.07). In contrast, S-adenosylhomocysteine concentrations were significantly higher in homozygous mutant mice compared with wild-type mice in all tissues studied. Genomic DNA methylation status in homozygous mutant compared with wild-type mice was lower in liver (P = 0.037) and tended to be lower in kidney (P = 0.077) but did not differ in brain (P = 0.46). The results of this study are consistent with the predicted role of cystathionine beta-synthase in the regulation of plasma total homocysteine levels and tissue S-adenosylhomocysteine levels. However, the fact that the absence of the enzyme had differential effects on S-adenosylmethionine concentrations and DNA methylation status in different tissues suggests that regulation of biological methylation is a complex tissue-specific phenomenon.     

Influence of Genetics on Disease Susceptibility and Progression

For many chronic diseases, the influence of genetics is complex and phenotypes do not conform to simple Mendelian patterns of inheritance. Discussed here are two types of genetic influences on healthy aging. The first involves variation in the gene sequence itself and how this may influence disease susceptibility, progression, and severity, interacting with other recognized risk factors. The second involves epigenetic regulatory mechanisms that may potentially provide insight into how environmental influences affect the expressed genome, thus improving our understanding of the genetic mechanisms underlying multifactorial diseases. The interleukin-1 family of cytokines can be used to illustrate how genetic sequence variation may affect such diseases. This cytokine family plays a key role in mediating inflammation, which is now understood to be a central component of a growing number of chronic diseases. Recent work has revealed many sequence variations in the regulatory DNA of genes encoding important members of the interleukin-1 family, and these variations are associated with differential effects on the inflammatory response. The interactions of environmental factors with both DNA sequence variations and epigenetic modifications are likely to determine the phenotypes of multifactorial diseases of aging as well as the phenotype of healthy aging.     

Epigenetics and maternal nutrition: nature v. nurture

Under- and over-nutrition during pregnancy has been linked to the later development of diseases such as diabetes and obesity. Epigenetic modifications may be one mechanism by which exposure to an altered intrauterine milieu or metabolic perturbation may influence the phenotype of the organism much later in life. Epigenetic modifications of the genome provide a mechanism that allows the stable propagation of gene expression from one generation of cells to the next. This review highlights our current knowledge of epigenetic gene regulation and the evidence that chromatin remodelling and histone modifications play key roles in adipogenesis and the development of obesity. Epigenetic modifications affecting processes important to glucose regulation and insulin secretion have been described in the pancreatic β-cells and muscle of the intrauterine growth-retarded offspring, characteristics essential to the pathophysiology of type-2 diabetes. Epigenetic regulation of gene expression contributes to both adipocyte determination and differentiation in in vitro models. The contributions of histone acetylation, histone methylation and DNA methylation to the process of adipogenesis in vivo remain to be evaluated.     

Nutrition and epigenetics: An emerging field

Epigenetics refers to heritable changes to gene expression encoded not by differences in the genetic sequence but by other chemical modifications to chromatin, such as methylation of the DNA backbone, or acetylation and methylation of the histone core. The total set of such epigenetic marks can be referred to as the epigenome, but unlike the genome, epigenetic marks differ between tissues and are modified by metabolic conditions and environmental exposures throughout life. In humans and animal models, key metabolic pathways, such as those of energy metabolism and obesity, are believed to be partly regulated by epigenetic mechanisms and to be subject to metabolic and nutritional modification in utero and throughout life. There is growing interest in the possibility that extremes of energy or micronutrient availability may modulate the epigenome and hence modify the development and disease susceptibility of individuals. Particular interest is evident for methyl donors, including folic acid, which might directly modify DNA methylation in humans.     

Vitamin D as a Nutri-Epigenetic Factor in Autoimmunity—A Review of Current Research and Reports on Vitamin D Deficiency in Autoimmune Diseases

Epigenetics is a series of alterations regulating gene expression without disrupting the DNA sequence of bases. These regulatory mechanisms can result in embryogenesis, cellular differentiation, X-chromosome inactivation, and DNA-protein interactions. The main epigenetic mechanisms considered to play a major role in both health and disease are DNA methylation, histone modifications, and profiling of non-coding RNA. When the fragile balance between these simultaneously occurring phenomena is disrupted, the risk of pathology increases. Thus, the factors that determine proper epigenetic modeling are defined and those with disruptive influence are sought. Several such factors with proven negative effects have already been described. Diet and nutritional substances have recently been one of the most interesting targets of exploration for epigenetic modeling in disease states, including autoimmunity. The preventive role of proper nutrition and maintaining sufficient vitamin D concentration in maternal blood during pregnancy, as well as in the early years of life, is emphasized. Opportunities are also being investigated for affecting the course of the disease by exploring nutriepigenetics. The authors aim to review the literature presenting vitamin D as one of the important nutrients potentially modeling the course of disease in selected autoimmune disorders.     

Biomarkers of nutrient exposure and status in one-carbon (methyl) metabolism

One-carbon metabolism is a network of interrelated biochemical reactions that involve the transfer of one-carbon groups from one compound to another. The coenzymes necessary for several of these reactions include the B-vitamins, folate, vitamin B-12, vitamin B-6 and riboflavin (vitamin B-2), whereas important intermediary compounds in this schema include methionine and choline. There has been renewed interest in one-carbon metabolism during the past several years, engendered by recent insights that indicate that modest dietary inadequacies of the abovementioned nutrients, of a degree insufficient to cause classical deficiency syndromes, can still contribute to important diseases such as neural tube defects, cardiovascular disease and cancer. Traditional means of assessing nutrient exposure with food frequency questionnaires, and nutrient status with plasma and urine vitamin assays, has some genuine validity and utility. Assessing the concentration of appropriate intermediary compounds, such as plasma homocysteine for folate and methylmalonic acid for vitamin B-12, provides further insights because they appear to add a degree of sensitivity that does not exist with the more traditional assays. There may also be value in developing measures that integrate the status of all these nutrients and express it as a functional "methylation capacity" of the individual. Plasma or tissue concentrations of S-adenosylmethionine and S-adenosylhomocysteine, and genomic DNA methylation are two potential candidates in this regard although much work is yet to be done to define the nature of these relationships.     

肺癌表遗传学研究进展

表遗传学机制在肺癌的形成中占据重要地位,包括DNA的甲基化和组蛋白修饰,肺癌中与癌形成有关基因的失活多与异常甲基化有关,并且组蛋白修饰和甲基化紧密联系着。表遗传学改变多发生在肺癌早期,使得它成为肺癌化学预防的优良指标,了解肺癌表遗传现象的机制及其与传统遗传学的相互作用关系将有利于发现安全、高效的化学预防药物。