REVIEW URRENT C OPINION
Genetic and metabolic determinants of human epigenetic variation Paul Haggarty
Purpose of review Epigenetics has emerged in recent years as one of the most important biological mechanisms linking exposures across the life course to long-term health. This article reviews recent developments in our understanding of the metabolic and genetic determinants of epigenetic variation in human populations. Recent findings Epigenetic status is influenced by a range of environmental exposures, including diet and nutrition, social status, the early emotional environment, and infertility and its treatment. The period around conception is particularly sensitive to environmental exposures with evidence for effects on epigenetic imprinting within the offspring. Epigenetic status is also influenced by genotype, and genetic variation in methylene tetrahydrofolate reductase, and the DNA methytransferase and ten-eleven translocation methylcytosine dioxygenase proteins has been linked to the epigenetic status, biological function and disease. Summary Epigenetics is at the heart of a series of feedback loops linking the environment to the human genome in a way that allows crosstalk between the genome and the environment it exists within. It offers the potential for modification of adverse epigenetic states resulting from events/exposures at earlier life stages. We need to better understand the nutritional programming of epigenetic states, the persistence of these marks in time and their effect on biological function and health in current and future generations. Keywords DNMT, epigenetics, genotype, imprinting, nutrition, TET
INTRODUCTION Epigenetics is concerned with information in the genome in addition to that contained within the DNA base sequence. It comprises a number of mechanisms that involve modifications to DNA, histones, RNA and chromatin, with functional consequences for the human genome. It is emerging as a key mechanism through which the environment can directly influence the human genome in ways that may persist over decades, or even more than one lifetime, with significant consequences for health and well-being across the life course [1]. Epigenetic states change with age in complex ways. Epigenetic variation increases and the pattern of coherent blocks of DNA methylation breaks down with age; global methylation falls with age; gene-specific methylation may increase or decrease with age; some repeat elements decrease in methylation with age but this is not universal; methylation status of a number of imprinted regions is relatively stable across the life course [1]. These processes are influenced by both the environment www.co-clinicalnutrition.com
and genotype, and this gives rise to epigenetic variation between individuals. This variation has significant consequences for biological function, health and longevity, and it is important to understand its origin and the factors that determine it. The importance of both genetics and environment can be most clearly seen in studies in twins where monozygotic twins are epigenetically very similar during the early years of life, but differences begin to develop in childhood and accumulate over time, with the magnitude of these being dependent on age and discordance in lifestyle [2–6]. The methyl and acetyl groups that constitute the main epigenetic marks are at the heart of Rowett Institute of Nutrition & Health, University of Aberdeen, Aberdeen, Scotland, UK Correspondence to Paul Haggarty, Rowett Institute of Nutrition & Health, University of Aberdeen, Aberdeen, AB21 9SB Scotland, UK. Tel: +44 1224 438630; fax: +44 1224 684880; e-mail: [email protected] Curr Opin Clin Nutr Metab Care 2015, 18:334–338 DOI:10.1097/MCO.0000000000000194 Volume 18 Number 4 July 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Determinants of human epigenetic variation Haggarty
KEY POINTS Epigenetic status is influenced by a range of exposures across different domains: diet and nutrition, social status, the early emotional environment, infertility and its treatment. Imprinting status is important in health and disease; it is influenced by the early environment and, once set, many imprinted regions remain stable over decades, with potential implications for offspring health. Epigenetic status is influenced by genotype, in both the underlying DNA sequence being epigenetically marked and in the genes coding for the factors controlling epigenetic processes, and genetic variation in MTHFR and the DNMT and TET proteins has been linked to the epigenetic status, biological function, and disease risk. Epigenotype is influenced by genotype, but, unlike genotype, there is the potential for modification and there is evidence for the reversibility of some adverse epigenetic states. Epigenetic processes lie at the heart of a series of feedback loops whereby the environment can influence the genome and the genome can change the environment that it is exposed to through epigenetic factors in the brain influencing human behaviour, dietary choice, alcohol intake, addiction and physical activity.
nutritional metabolism and energy flux (Fig. 1), and there is evidence that the activity of these pathways influences epigenetic status. DNA methylation is controlled by the DNA methyltransferases (DNMTs), and humans have four main variants – DNMT1, DNMT3A, DNMT3B and DNMT3L. There is some overlap in function, but the main role of DNMT1 is to ensure the maintenance of existing methylation patterns, whilst DNMT3A and DNMT3B are primarily required for de-novo methylation, with DNMT3L acting as an essential co-factor, particularly in the establishment of methylation imprints in the gametes. DNMT3A, DNMT3B and DNMT3L are expressed in oocytes at the same time as imprinting methylation occurs. There are also germ cell-specific isoforms of DNMT1, suggesting that it may also have some role in supporting de-novo methylation. DNA methylation can be removed by active or passive mechanisms [8]. Active demethylation can occur through an oxidation step that converts methyl-C to hydroxymethyl-C via the ten-eleven translocation (TET) methylcytosine dioxygenase enzymes [9]. Because hydroxymethyl-C is not recognized by DNMT1, the memory imposed by methyl-C is also passively lost during cell division [8]. There is
overlap and interaction between different types of epigenetic regulation with DNA methylation status correlating with histone modification [10,11]. Propagation of epigenetic signals and their interpretation are controlled by a large machinery of methyl-binding proteins, transcription factors, insulators and so on. These include the methylbinding proteins such as methyl CpG binding protein 2 (MeCp2) [12,13] and CCCTC-binding factor (CTCF), a zinc finger protein insulator which mediates intra-chromosomal and inter-chromosomal contacts and co-ordinates DNA methylation and higher-order chromatin structure [14].
GENETIC EFFECTS ON EPIGENETIC STATUS Significant heritability of epigenetic status has been demonstrated in human twin studies [2–6]. Nontwin family studies have also highlighted familial clustering of DNA methylation and the change in methylation over time [15]. Even in imprinted genes, the methylation status is more similar between related individuals [3,4]. This similarity in genetically related individuals can result from heritable variation in the DNA sequence at the epigenetic target or in the genes that regulate epigenetic processes. There is now a good deal of evidence that the underlying DNA sequence can account for variation in patterns of methylation within the same region [16,17 ,18,19 ]. An example is the imprinting control region of H19 where methylation appears to be influenced by a local polymorphism [3]. Sequence variation in the genes coding for the enzymes of the epigenetic pathway (Fig. 1) provides another way in which epigenetic variation between individuals can result from genetic variation. There is a rapidly growing literature on the effects of genetic variation in the genes involved in the provision of methyl and acetyl groups, the genes which use these groups to epigenetically modify DNA and histones, and the genes involved in interpreting epigenetic marks. Examples include the effect of polymorphism in the genes coding for MTHFR, and the DNMT and TET proteins [20–26]. Interestingly, these effects do not simply result in general increases or decreases in global methylation. Polymorphisms in MTHFR that have been shown to influence some methylation states may not affect important imprinted genes [27 ]. Such differential specificity within the genome is more likely to influence biological function than a general scaling up or down of all gene expression. The biological significance of genetic variation within the genes of the epigenetic pathway is evidenced by the growing literature, linking &&
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Genes and cell metabolism
Chromatin structure HISTONE HMT
DNA
TET
Methyl
HAT
Methyl HDAC
Alcohol
Acetyl
ADH
DNMT
MBPs
ALDH
MeCP2
ADH
Polyphenols
CTCF
Acetyl donors
Acetyl
Methylation
Methyl
Fat synthesis
SAM
ALDH
Acetyl CoA
Alcohol
TCA
CBS
SAH
Homocysteine Fatty acids
Pyruvate
Methionine
Amino acids
MTR
B12
TCN2
MTRR
THF Macronutrient metabolism genes 5,10 meth THF Fat
Carbohydrate
5 meth THF
Protein MTHFR
FIGURE 1. Metabolic and genetic factors with the potential to influence epigenetic status. Acetyl denotes the acetyl groups, and Methyl the methyl groups. ADH, alcohol dehydrogenase; ALDH, acetaldehyde dehydrogenase; CBS, cystathionine beta synthase; CTCF, CCCTC-binding factor; DNMT, DNA methyl transferases; HAT, histone acetylases; HDAC, histone deacetylases; HMT, histone methyltransferases; MBP, methyl binding proteins; MeCP2, methyl CpG binding protein 2; MTHFR, methylene tetrahydrofolate reductase; MTR, methionine synthase; MTRR, methionine synthase reductase; SAH; S-adenosylhomocysteine; SAM, S-adenosylmethionine; TCA, tricarboxylic acid; TCN2, transcobalamin; TET, ten-eleven translocation; THF, tetrahydrofolate. Reproduced with permission from [7].
these to biological function and disease outcomes [20,21,24,28,29,30 ]. &
ENVIRONMENTAL EFFECTS ON EPIGENETIC STATUS The methyl groups which epigenetically modify DNA and histones are produced by the methylation pathway – involving nutrients such as the B vitamins and methionine – whilst histone acetylation uses acetyl groups produced in the metabolism of carbohydrate, fat and some amino acids (Fig. 1). It is therefore not surprising that diet, nutrition and alcohol intake influence epigenetic status, and there are numerous reports of effects on DNA methylation of alcohol, the B vitamins, protein, micronutrients, functional food components and general nutritional status (see, for example, review [31]). An area where there has been much recent interest has been in the effect of fatty acids on epigenetic status [32,33,34 ]. The redox metabolite nicotinamide adenine dinucleotide (NAD) is central to metabolism, but it is also a cofactor for the sirtuins (a group of protein deacetylases), and it has been suggested that this could provide a mechanism for &
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the epigenetic sensing of metabolic flux [35]. The epigenome is also responsive to a wide range of nondietary factors including socioeconomic status [36,37], smoking [38] and even the early emotional environment [39]. The sensitivity of the human epigenome to environmental influences is not uniform across the life course. The period at the start of life is characterized by intense epigenetic activity, with significant epigenetic changes occurring in the early embryo and even the gametes before fertilization [40]. The imprinted genes in particular are methylated during this period, but there is variation between individuals in the level of imprinting methylation [27 ], and this variation – how it comes about and what it signifies – is of considerable interest. There are reports of effects of maternal nutrient intake during pregnancy, affecting human offspring epigenetic status [3,26,27 ,41–43]. The ultimate donor for methylation reactions is S-adenosyl methionine, which is produced by the folate-methylation cycle, and it has been reported that the use of folic acid use in pregnancy alters the level of methylation within the imprinted genes IGF2 and PEG3, and the repeat element Long &
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Determinants of human epigenetic variation Haggarty
Interspersed Nuclear Element 1, in the offspring [27 ]. Interestingly, the effect was of opposite sign in the two imprinted genes, suggesting that it may be naive to assume that this is a simple substrate limitation effect or that the supply of nutrients involved in the methylation cycle will affect all genes equally. Imprinting status is thought to be important in health and disease [44 ], and early effects on imprinting could have significant consequences for health as, once set, many imprinted regions remain stable over decades [45]. Loss of imprinting is a hallmark of cancer and human imprinting syndromes, where the normal process of imprinting is disrupted, result in a wide range of mental and physical phenotypes including behaviour change, low intelligence, overeating, obesity, diabetes and cancer [44 ,46–48]. Most of the pregnancy studies have investigated nutrient exposure in mothers, but trans-generational epigenetic programming is also relevant to fathers, and the nutrients they consume during the epigenetic programming of the sperm that provide one half of the DNA of the offspring [49]. The importance of the early environment is not limited to nutrition as infertility and its treatment have also been related to offspring epigenetic status [50,51 ]. &
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CONCLUSION Epigenetics has emerged in recent years as one of the most promising biological explanations linking exposures across the life course to long-term health. Epigenotype is influenced by genotype, but, unlike genotype, there is the potential for modification of adverse epigenetic states resulting from events/ exposures at earlier life stages. Infusion of methionine in animal models has been reported to reverse the effect of maternal behaviour on epigenetic changes in the stress response pathway in the brain [52]. Whilst chronic methionine administration reverses the changes in brain DNA methylation and DNMT3b expression associated with cocaine addiction [53]. We need to better understand the nutritional programming of epigenetic states, the persistence of these marks in time and their effect on biological function and the response to diet. Epigenetic processes provide a mechanism for sensing the environment at the level of the genome and programming the way the genome then responds to the environment over different timescales (from minutes to more than one lifetime). The human diet has undergone profound changes over recent generations and this trend is likely to accelerate. It is important to understand the epigenetic consequences of such rapid changes and how these might affect the health of current and future generations.
Epigenetic status is influenced by both the environment and the genotype (in the local DNA sequence being epigenetically marked and in the genes coding for the factors controlling epigenetic processes). But the emerging picture is even more complicated and more interesting than this. Nutrients can directly affect the epigenetic machinery [54,55 ], whilst genetic variation in the pathways that control epigenetics can influence nutritional status [56,57 ]. Most surprising of all is the possibility that the genome may affect the environment that it is exposed to through epigenetic factors in the brain influencing human behaviour, dietary choice, alcohol intake, addiction and physical activity [1]. The process of epigenetics is at the heart of a series of feedback loops linking the environment to the human genome in a way that allows crosstalk between the genome and the environment it exists in. We are only beginning to understand the implications of this new paradigm for human biology and human health. &&
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Acknowledgements The author gratefully acknowledges the support of the Scottish Government. Financial support and sponsorship The study was supported by Scottish Government. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Haggarty P, Ferguson-Smith AC. Life course epigenetics and healthy ageing. In: Kuh D, Cooper R, Hardy R, Richards M, Ben-Shlomo Y, editors. A life course approach to healthy ageing, 1st ed London: Oxford University Press; 2014. pp. 198–212. 2. Ollikainen M, Smith KR, Joo EJ, et al. DNA methylation analysis of multiple tissues from newborn twins reveals both genetic and intrauterine components to variation in the human neonatal epigenome. Hum Mol Genet 2010; 19:4176–4188. 3. Coolen MW, Statham AL, Qu W, et al. Impact of the genome on the epigenome is manifested in DNA methylation patterns of imprinted regions in monozygotic and dizygotic twins. PLoS One 2011; 6:e25590. 4. Ollikainen M, Craig JM. Epigenetic discordance at imprinting control regions in twins. Epigenomics 2011; 3:295–306. 5. Martino D, Loke YJ, Gordon L, et al. Longitudinal, genome-scale analysis of DNA methylation in twins from birth to 18 months of age reveals rapid epigenetic change in early life and pair-specific effects of discordance. Genome Biol 2013; 14:R42. 6. Levesque ML, Casey KF, Szyf M, et al. Genome-wide DNA methylation variability in adolescent monozygotic twins followed since birth. Epigenetics 2014; 9:1410–1421. 7. Haggarty P. Nutrition and the epigenome. Prog Mol Biol Translat Sci 2012; 108:427–466. 8. Hackett JA, Surani MA. DNA methylation dynamics during the mammalian life cycle. Philos Trans R Soc Lond B Biol Sci 2013; 368:20110328.
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Genes and cell metabolism 9. Branco MR, Ficz G, Reik W. Uncovering the role of 5-hydroxymethylcytosine in the epigenome. Nat Rev Genet 2012; 13:7–13. 10. Guo X, Wang L, Li J, et al. Structural insight into autoinhibition and histone H3induced activation of DNMT3A. Nature 2015; 517:640–644. 11. Zhang W, Spector TD, Deloukas P, et al. Predicting genome-wide DNA methylation using methylation marks, genomic position, and DNA regulatory elements. Genome Biol 2015; 16:14. 12. Kernohan KD, Jiang Y, Tremblay DC, et al. ATRX partners with cohesin and MeCP2 and contributes to developmental silencing of imprinted genes in the brain. Dev Cell 2010; 18:191–202. 13. Muotri AR, Marchetto MC, Coufal NG, et al. L1 retrotransposition in neurons is modulated by MeCP2. Nature 2010; 468:443–446. 14. Phillips JE, Corces VG. CTCF: master weaver of the genome. Cell 2009; 137:1194–1211. 15. Bjornsson HT, Sigurdsson MI, Fallin MD, et al. Intra-individual change over time in DNA methylation with familial clustering. J Am Med Assoc 2008; 299:2877–2883. 16. Lienert F, Wirbelauer C, Som I, et al. Identification of genetic elements that autonomously determine DNA methylation states. Nat Genet 2011; 43:1091–1097. 17. McVicker G, van de Geijn B, Degner JF, et al. Identification of genetic && variants that affect histone modifications in human cells. Science 2013; 342:747–749. This study reports hundreds of loci, genome-wide, that affect histone modification or RNA polymerase II (Pol II) occupancy with the same variant being associated with changes in multiple histone marks and Pol II, as well as in deoxyribonuclease I sensitivity and nucleosome positioning. 18. Kilpinen H, Waszak SM, Gschwind AR, et al. Coordinated effects of sequence variation on DNA binding, chromatin structure, and transcription. Science 2013; 342:744–747. 19. Schubeler D. Function and information content of DNA methylation. Nature & 2015; 517:321–326. A good recent review of the importance of DNA methylation, including a discussion of the links with genotype. 20. Haggarty P, Hoad G, Horgan GW, Campbell DM. DNA methyltransferase candidate polymorphisms, imprinting methylation, and birth outcome. PLoS One 2013; 8:e68896. 21. Haggarty P, Hoad G, Harris SE, et al. Human intelligence and polymorphisms in the DNA methyltransferase genes involved in epigenetic marking. PLoS One 2010; 5:e11329. 22. de VS, Wouters KA, Gottschalk RW, et al. Dietary methyl donors, methyl metabolizing enzymes, and epigenetic regulators: diet-gene interactions and promoter CpG island hypermethylation in colorectal cancer. Cancer Causes Control 2011; 22:1–12. 23. Lin J, Zeng RM, Li RN, Cao WH. Aberrant DNA methylation of the P16, MGMT, and hMLH1 genes in combination with the methylenetetrahydrofolate reductase C677T genetic polymorphism and folate intake in gastric cancer. Genet Mol Res 2014; 13:2060–2068. 24. Liao XX, Zhan ZX, Luo YY, et al. Association study between SNP rs150689919 in the DNA demethylation gene, TET1, and Parkinson’s disease in Chinese Han population. BMC Neurol 2013; 13:196. 25. Rotondo JC, Selvatici R, Di DM, et al. Methylation loss at H19 imprinted gene correlates with methylenetetrahydrofolate reductase gene promoter hypermethylation in semen samples from infertile males. Epigenetics 2013; 8:990– 997. 26. McKay JA, Groom A, Potter C, et al. Genetic and nongenetic influences during pregnancy on infant global and site specific DNA methylation: role for folate gene variants and vitamin B12. PLoS One 2012; 7:e33290. 27. Haggarty P, Hoad G, Campbell DM, et al. Folate in pregnancy and imprinted & gene and repeat element methylation in the offspring. Am J Clin Nutr 2013; 97:94–99. A large-scale study in human pregnancy of the effects of folate intake and status on offspring methylation within the imprinted genes and repeat elements and the lack of effect of common variants within the folate-methylation cycle. 28. Ley TJ, Ding L, Walter MJ, et al. DNMT3A mutations in acute myeloid leukemia. N Engl J Med 2010; 363:2424–2433. 29. Saradalekshmi KR, Neetha NV, Sathyan S, et al. DNA methyl transferase (DNMT) gene polymorphisms could be a primary event in epigenetic susceptibility to schizophrenia. PLoS One 2014; 9:e98182. 30. Song F, Amos CI, Lee JE, et al. Identification of a melanoma susceptibility & locus and somatic mutation in TET2. Carcinogenesis 2014; 35:2097–2101. This study used GWAS to identify a link between melanoma and genetic variation in the TET2 gene on chromosome 4q24. 31. Haggarty P. Epigenetic consequences of a changing human diet. Proc Nutr Soc 2013; 72:363–371. 32. Hoile SP, Clarke-Harris R, Huang RC, et al. Supplementation with N-3 longchain polyunsaturated fatty acids or olive oil in men and women with renal disease induces differential changes in the DNA methylation of FADS2 and ELOVL5 in peripheral blood mononuclear cells. PLoS One 2014; 9:e109896. 33. Gillberg L, Jacobsen SC, Ronn T, et al. 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.
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34. Hall E, Volkov P, Dayeh T, et al. Effects of palmitate on genome-wide mRNA expression and DNA methylation patterns in human pancreatic islets. BMC Med 2014; 12:103. A study demonstrating the way in which palmitic acid influences epigenetic state and gene expression in human pancreatic islets with possible implications for impaired insulin secretion and T2D. 35. Baur JA, Ungvari Z, Minor RK, et al. Are sirtuins viable targets for improving healthspan and lifespan? Nat Rev Drug Discov 2012; 11:443–461. 36. McGuinness D, McGlynn LM, Johnson PC, et al. Socio-economic status is associated with epigenetic differences in the pSoBid cohort. Int J Epidemiol 2012; 41:151–160. 37. Borghol N, Suderman M, McArdle W, et al. Associations with early-life socioeconomic position in adult DNA methylation. Int J Epidemiol 2012; 41:62–74. 38. Scoccianti C, Ricceri F, Ferrari P, et al. Methylation patterns in sentinel genes in peripheral blood cells of heavy smokers: Influence of cruciferous vegetables in an intervention study. Epigenetics 2011; 6:1114–1119. 39. Zhang TY, Meaney MJ. Epigenetics and the environmental regulation of the genome and its function. Annu Rev Psychol 2010; 61:439–443. 40. Lane M, Robker RL, Robertson SA. Parenting from before conception. Science 2014; 345:756–760. 41. Boeke CE, Baccarelli A, Kleinman KP, et al. Gestational intake of methyl donors and global LINE-1 DNA methylation in maternal and cord blood: prospective results from a folate-replete population. Epigenetics 2012; 7:253–260. 42. Soubry A, Schildkraut JM, Murtha A, et al. Paternal obesity is associated with IGF2 hypomethylation in newborns: results from a Newborn Epigenetics Study (NEST) cohort. BMC Med 2013; 11:29. 43. Lee HS, Barraza-Villarreal A, Biessy C, et al. Dietary supplementation with polyunsaturated fatty acid during pregnancy modulates DNA methylation at IGF2/H19 imprinted genes and growth of infants. Physiol Genomics 2014; 46:851–857. 44. Peters J. The role of genomic imprinting in biology and disease: an expanding & view. Nat Rev Genet 2014; 15:517–530. A good recent review of the importance of imprinting. 45. Woodfine K, Huddleston JE, Murrell A. Quantitative analysis of DNA methylation at all human imprinted regions reveals preservation of epigenetic stability in adult somatic tissue. Epigenet Chromatin 2011; 4:1. 46. Azzi S, Abi HW, Netchine I. Beckwith-Wiedemann and Russell-Silver syndromes: from new molecular insights to the comprehension of imprinting regulation. Curr Opin Endocrinol Diabetes Obes 2014; 21:30–38. 47. Rocha CF, Paiva CL. Prader-Willi-like phenotypes: a systematic review of their chromosomal abnormalities. Genet Mol Res 2014; 13:2290–2298. 48. Bird LM. Angelman syndrome: review of clinical and molecular aspects. Appl Clin Genet 2014; 7:93–104. 49. Ferguson-Smith AC, Patti ME. You are what your dad ate. Cell Metab 2011; 13:115–117. 50. Lazaraviciute G, Kauser M, Bhattacharya S, et al. A systematic review and meta-analysis of DNA methylation levels and imprinting disorders in children conceived by IVF/ICSI compared with children conceived spontaneously. Hum Reprod Update 2014; 20:840–852. 51. Whitelaw N, Bhattacharya S, Hoad G, et al. Epigenetic status in the offspring & of spontaneous and assisted conception. Hum Reprod 2014; 29:1452– 1458. An example from outside the field of nutrition investigating imprinted gene methylation in the offspring following infertility treatment and whether the effects are due to treatment or linked to infertility. 52. Weaver IC, Champagne FA, Brown SE, et al. Reversal of maternal programming of stress responses in adult offspring through methyl supplementation: altering epigenetic marking later in life. J Neurosci 2005; 25:11045–11054. 53. Tian W, Zhao M, Li M, et al. Reversal of cocaine-conditioned place preference through methyl supplementation in mice: altering global DNA methylation in the prefrontal cortex. PLoS One 2012; 7:e33435. 54. Zhang Y, Wang X, Han L, et al. Green tea polyphenol EGCG reverse cisplatin resistance of A549/DDP cell line through candidate genes demethylation. Biomed Pharmacother 2015; 69:285–290. 55. Blaschke K, Ebata KT, Karimi MM, et al. Vitamin C induces Tet-dependent && DNA demethylation and a blastocyst-like state in ES cells. Nature 2013; 500:222–226. An important study demonstrating a direct effect of nutrition on TET dependent DNA methylation. There are many examples of such effects on the DNMTs but the importance of TET in influencing epigenetic status emerged relatively recently and this is one of the first examples of an interaction with nutrition. 56. Cabo R, Hernes S, Slettan A, et al. Effect of genetic polymorphisms involved in folate metabolism on the concentration of serum folate and plasma total homocysteine (p-tHcy) in healthy subjects after short-term folic acid supplementation: a randomized, double blind, crossover study. Genes Nutr 2015; 10:456. 57. Tsang BL, Devine OJ, Cordero AM, et al. Assessing the association between && the methylenetetrahydrofolate reductase (MTHFR) 677C>T polymorphism and blood folate concentrations: a systematic review and meta-analysis of trials and observational studies. Am J Clin Nutr 2015. [Epub ahead of print] A study demonstrating a biologically significant effect of MTHFR C677T genotype on red blood cell folate concentrations. This is an example of the complicated ways in which genotype interacts with nutrition to potentially influence epigenetic state. &
Volume 18 Number 4 July 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Genetic and metabolic determinants of human epigenetic variation Paul Haggarty
Purpose of review Epigenetics has emerged in recent years as one of the most important biological mechanisms linking exposures across the life course to long-term health. This article reviews recent developments in our understanding of the metabolic and genetic determinants of epigenetic variation in human populations. Recent findings Epigenetic status is influenced by a range of environmental exposures, including diet and nutrition, social status, the early emotional environment, and infertility and its treatment. The period around conception is particularly sensitive to environmental exposures with evidence for effects on epigenetic imprinting within the offspring. Epigenetic status is also influenced by genotype, and genetic variation in methylene tetrahydrofolate reductase, and the DNA methytransferase and ten-eleven translocation methylcytosine dioxygenase proteins has been linked to the epigenetic status, biological function and disease. Summary Epigenetics is at the heart of a series of feedback loops linking the environment to the human genome in a way that allows crosstalk between the genome and the environment it exists within. It offers the potential for modification of adverse epigenetic states resulting from events/exposures at earlier life stages. We need to better understand the nutritional programming of epigenetic states, the persistence of these marks in time and their effect on biological function and health in current and future generations. Keywords DNMT, epigenetics, genotype, imprinting, nutrition, TET
INTRODUCTION Epigenetics is concerned with information in the genome in addition to that contained within the DNA base sequence. It comprises a number of mechanisms that involve modifications to DNA, histones, RNA and chromatin, with functional consequences for the human genome. It is emerging as a key mechanism through which the environment can directly influence the human genome in ways that may persist over decades, or even more than one lifetime, with significant consequences for health and well-being across the life course [1]. Epigenetic states change with age in complex ways. Epigenetic variation increases and the pattern of coherent blocks of DNA methylation breaks down with age; global methylation falls with age; gene-specific methylation may increase or decrease with age; some repeat elements decrease in methylation with age but this is not universal; methylation status of a number of imprinted regions is relatively stable across the life course [1]. These processes are influenced by both the environment www.co-clinicalnutrition.com
and genotype, and this gives rise to epigenetic variation between individuals. This variation has significant consequences for biological function, health and longevity, and it is important to understand its origin and the factors that determine it. The importance of both genetics and environment can be most clearly seen in studies in twins where monozygotic twins are epigenetically very similar during the early years of life, but differences begin to develop in childhood and accumulate over time, with the magnitude of these being dependent on age and discordance in lifestyle [2–6]. The methyl and acetyl groups that constitute the main epigenetic marks are at the heart of Rowett Institute of Nutrition & Health, University of Aberdeen, Aberdeen, Scotland, UK Correspondence to Paul Haggarty, Rowett Institute of Nutrition & Health, University of Aberdeen, Aberdeen, AB21 9SB Scotland, UK. Tel: +44 1224 438630; fax: +44 1224 684880; e-mail: [email protected] Curr Opin Clin Nutr Metab Care 2015, 18:334–338 DOI:10.1097/MCO.0000000000000194 Volume 18 Number 4 July 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Determinants of human epigenetic variation Haggarty
KEY POINTS Epigenetic status is influenced by a range of exposures across different domains: diet and nutrition, social status, the early emotional environment, infertility and its treatment. Imprinting status is important in health and disease; it is influenced by the early environment and, once set, many imprinted regions remain stable over decades, with potential implications for offspring health. Epigenetic status is influenced by genotype, in both the underlying DNA sequence being epigenetically marked and in the genes coding for the factors controlling epigenetic processes, and genetic variation in MTHFR and the DNMT and TET proteins has been linked to the epigenetic status, biological function, and disease risk. Epigenotype is influenced by genotype, but, unlike genotype, there is the potential for modification and there is evidence for the reversibility of some adverse epigenetic states. Epigenetic processes lie at the heart of a series of feedback loops whereby the environment can influence the genome and the genome can change the environment that it is exposed to through epigenetic factors in the brain influencing human behaviour, dietary choice, alcohol intake, addiction and physical activity.
nutritional metabolism and energy flux (Fig. 1), and there is evidence that the activity of these pathways influences epigenetic status. DNA methylation is controlled by the DNA methyltransferases (DNMTs), and humans have four main variants – DNMT1, DNMT3A, DNMT3B and DNMT3L. There is some overlap in function, but the main role of DNMT1 is to ensure the maintenance of existing methylation patterns, whilst DNMT3A and DNMT3B are primarily required for de-novo methylation, with DNMT3L acting as an essential co-factor, particularly in the establishment of methylation imprints in the gametes. DNMT3A, DNMT3B and DNMT3L are expressed in oocytes at the same time as imprinting methylation occurs. There are also germ cell-specific isoforms of DNMT1, suggesting that it may also have some role in supporting de-novo methylation. DNA methylation can be removed by active or passive mechanisms [8]. Active demethylation can occur through an oxidation step that converts methyl-C to hydroxymethyl-C via the ten-eleven translocation (TET) methylcytosine dioxygenase enzymes [9]. Because hydroxymethyl-C is not recognized by DNMT1, the memory imposed by methyl-C is also passively lost during cell division [8]. There is
overlap and interaction between different types of epigenetic regulation with DNA methylation status correlating with histone modification [10,11]. Propagation of epigenetic signals and their interpretation are controlled by a large machinery of methyl-binding proteins, transcription factors, insulators and so on. These include the methylbinding proteins such as methyl CpG binding protein 2 (MeCp2) [12,13] and CCCTC-binding factor (CTCF), a zinc finger protein insulator which mediates intra-chromosomal and inter-chromosomal contacts and co-ordinates DNA methylation and higher-order chromatin structure [14].
GENETIC EFFECTS ON EPIGENETIC STATUS Significant heritability of epigenetic status has been demonstrated in human twin studies [2–6]. Nontwin family studies have also highlighted familial clustering of DNA methylation and the change in methylation over time [15]. Even in imprinted genes, the methylation status is more similar between related individuals [3,4]. This similarity in genetically related individuals can result from heritable variation in the DNA sequence at the epigenetic target or in the genes that regulate epigenetic processes. There is now a good deal of evidence that the underlying DNA sequence can account for variation in patterns of methylation within the same region [16,17 ,18,19 ]. An example is the imprinting control region of H19 where methylation appears to be influenced by a local polymorphism [3]. Sequence variation in the genes coding for the enzymes of the epigenetic pathway (Fig. 1) provides another way in which epigenetic variation between individuals can result from genetic variation. There is a rapidly growing literature on the effects of genetic variation in the genes involved in the provision of methyl and acetyl groups, the genes which use these groups to epigenetically modify DNA and histones, and the genes involved in interpreting epigenetic marks. Examples include the effect of polymorphism in the genes coding for MTHFR, and the DNMT and TET proteins [20–26]. Interestingly, these effects do not simply result in general increases or decreases in global methylation. Polymorphisms in MTHFR that have been shown to influence some methylation states may not affect important imprinted genes [27 ]. Such differential specificity within the genome is more likely to influence biological function than a general scaling up or down of all gene expression. The biological significance of genetic variation within the genes of the epigenetic pathway is evidenced by the growing literature, linking &&
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Genes and cell metabolism
Chromatin structure HISTONE HMT
DNA
TET
Methyl
HAT
Methyl HDAC
Alcohol
Acetyl
ADH
DNMT
MBPs
ALDH
MeCP2
ADH
Polyphenols
CTCF
Acetyl donors
Acetyl
Methylation
Methyl
Fat synthesis
SAM
ALDH
Acetyl CoA
Alcohol
TCA
CBS
SAH
Homocysteine Fatty acids
Pyruvate
Methionine
Amino acids
MTR
B12
TCN2
MTRR
THF Macronutrient metabolism genes 5,10 meth THF Fat
Carbohydrate
5 meth THF
Protein MTHFR
FIGURE 1. Metabolic and genetic factors with the potential to influence epigenetic status. Acetyl denotes the acetyl groups, and Methyl the methyl groups. ADH, alcohol dehydrogenase; ALDH, acetaldehyde dehydrogenase; CBS, cystathionine beta synthase; CTCF, CCCTC-binding factor; DNMT, DNA methyl transferases; HAT, histone acetylases; HDAC, histone deacetylases; HMT, histone methyltransferases; MBP, methyl binding proteins; MeCP2, methyl CpG binding protein 2; MTHFR, methylene tetrahydrofolate reductase; MTR, methionine synthase; MTRR, methionine synthase reductase; SAH; S-adenosylhomocysteine; SAM, S-adenosylmethionine; TCA, tricarboxylic acid; TCN2, transcobalamin; TET, ten-eleven translocation; THF, tetrahydrofolate. Reproduced with permission from [7].
these to biological function and disease outcomes [20,21,24,28,29,30 ]. &
ENVIRONMENTAL EFFECTS ON EPIGENETIC STATUS The methyl groups which epigenetically modify DNA and histones are produced by the methylation pathway – involving nutrients such as the B vitamins and methionine – whilst histone acetylation uses acetyl groups produced in the metabolism of carbohydrate, fat and some amino acids (Fig. 1). It is therefore not surprising that diet, nutrition and alcohol intake influence epigenetic status, and there are numerous reports of effects on DNA methylation of alcohol, the B vitamins, protein, micronutrients, functional food components and general nutritional status (see, for example, review [31]). An area where there has been much recent interest has been in the effect of fatty acids on epigenetic status [32,33,34 ]. The redox metabolite nicotinamide adenine dinucleotide (NAD) is central to metabolism, but it is also a cofactor for the sirtuins (a group of protein deacetylases), and it has been suggested that this could provide a mechanism for &
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the epigenetic sensing of metabolic flux [35]. The epigenome is also responsive to a wide range of nondietary factors including socioeconomic status [36,37], smoking [38] and even the early emotional environment [39]. The sensitivity of the human epigenome to environmental influences is not uniform across the life course. The period at the start of life is characterized by intense epigenetic activity, with significant epigenetic changes occurring in the early embryo and even the gametes before fertilization [40]. The imprinted genes in particular are methylated during this period, but there is variation between individuals in the level of imprinting methylation [27 ], and this variation – how it comes about and what it signifies – is of considerable interest. There are reports of effects of maternal nutrient intake during pregnancy, affecting human offspring epigenetic status [3,26,27 ,41–43]. The ultimate donor for methylation reactions is S-adenosyl methionine, which is produced by the folate-methylation cycle, and it has been reported that the use of folic acid use in pregnancy alters the level of methylation within the imprinted genes IGF2 and PEG3, and the repeat element Long &
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Determinants of human epigenetic variation Haggarty
Interspersed Nuclear Element 1, in the offspring [27 ]. Interestingly, the effect was of opposite sign in the two imprinted genes, suggesting that it may be naive to assume that this is a simple substrate limitation effect or that the supply of nutrients involved in the methylation cycle will affect all genes equally. Imprinting status is thought to be important in health and disease [44 ], and early effects on imprinting could have significant consequences for health as, once set, many imprinted regions remain stable over decades [45]. Loss of imprinting is a hallmark of cancer and human imprinting syndromes, where the normal process of imprinting is disrupted, result in a wide range of mental and physical phenotypes including behaviour change, low intelligence, overeating, obesity, diabetes and cancer [44 ,46–48]. Most of the pregnancy studies have investigated nutrient exposure in mothers, but trans-generational epigenetic programming is also relevant to fathers, and the nutrients they consume during the epigenetic programming of the sperm that provide one half of the DNA of the offspring [49]. The importance of the early environment is not limited to nutrition as infertility and its treatment have also been related to offspring epigenetic status [50,51 ]. &
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CONCLUSION Epigenetics has emerged in recent years as one of the most promising biological explanations linking exposures across the life course to long-term health. Epigenotype is influenced by genotype, but, unlike genotype, there is the potential for modification of adverse epigenetic states resulting from events/ exposures at earlier life stages. Infusion of methionine in animal models has been reported to reverse the effect of maternal behaviour on epigenetic changes in the stress response pathway in the brain [52]. Whilst chronic methionine administration reverses the changes in brain DNA methylation and DNMT3b expression associated with cocaine addiction [53]. We need to better understand the nutritional programming of epigenetic states, the persistence of these marks in time and their effect on biological function and the response to diet. Epigenetic processes provide a mechanism for sensing the environment at the level of the genome and programming the way the genome then responds to the environment over different timescales (from minutes to more than one lifetime). The human diet has undergone profound changes over recent generations and this trend is likely to accelerate. It is important to understand the epigenetic consequences of such rapid changes and how these might affect the health of current and future generations.
Epigenetic status is influenced by both the environment and the genotype (in the local DNA sequence being epigenetically marked and in the genes coding for the factors controlling epigenetic processes). But the emerging picture is even more complicated and more interesting than this. Nutrients can directly affect the epigenetic machinery [54,55 ], whilst genetic variation in the pathways that control epigenetics can influence nutritional status [56,57 ]. Most surprising of all is the possibility that the genome may affect the environment that it is exposed to through epigenetic factors in the brain influencing human behaviour, dietary choice, alcohol intake, addiction and physical activity [1]. The process of epigenetics is at the heart of a series of feedback loops linking the environment to the human genome in a way that allows crosstalk between the genome and the environment it exists in. We are only beginning to understand the implications of this new paradigm for human biology and human health. &&
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Acknowledgements The author gratefully acknowledges the support of the Scottish Government. Financial support and sponsorship The study was supported by Scottish Government. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Haggarty P, Ferguson-Smith AC. Life course epigenetics and healthy ageing. In: Kuh D, Cooper R, Hardy R, Richards M, Ben-Shlomo Y, editors. A life course approach to healthy ageing, 1st ed London: Oxford University Press; 2014. pp. 198–212. 2. Ollikainen M, Smith KR, Joo EJ, et al. DNA methylation analysis of multiple tissues from newborn twins reveals both genetic and intrauterine components to variation in the human neonatal epigenome. Hum Mol Genet 2010; 19:4176–4188. 3. Coolen MW, Statham AL, Qu W, et al. Impact of the genome on the epigenome is manifested in DNA methylation patterns of imprinted regions in monozygotic and dizygotic twins. PLoS One 2011; 6:e25590. 4. Ollikainen M, Craig JM. Epigenetic discordance at imprinting control regions in twins. Epigenomics 2011; 3:295–306. 5. Martino D, Loke YJ, Gordon L, et al. Longitudinal, genome-scale analysis of DNA methylation in twins from birth to 18 months of age reveals rapid epigenetic change in early life and pair-specific effects of discordance. Genome Biol 2013; 14:R42. 6. Levesque ML, Casey KF, Szyf M, et al. Genome-wide DNA methylation variability in adolescent monozygotic twins followed since birth. Epigenetics 2014; 9:1410–1421. 7. Haggarty P. Nutrition and the epigenome. Prog Mol Biol Translat Sci 2012; 108:427–466. 8. Hackett JA, Surani MA. DNA methylation dynamics during the mammalian life cycle. Philos Trans R Soc Lond B Biol Sci 2013; 368:20110328.
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Genes and cell metabolism 9. Branco MR, Ficz G, Reik W. Uncovering the role of 5-hydroxymethylcytosine in the epigenome. Nat Rev Genet 2012; 13:7–13. 10. Guo X, Wang L, Li J, et al. Structural insight into autoinhibition and histone H3induced activation of DNMT3A. Nature 2015; 517:640–644. 11. Zhang W, Spector TD, Deloukas P, et al. Predicting genome-wide DNA methylation using methylation marks, genomic position, and DNA regulatory elements. Genome Biol 2015; 16:14. 12. Kernohan KD, Jiang Y, Tremblay DC, et al. ATRX partners with cohesin and MeCP2 and contributes to developmental silencing of imprinted genes in the brain. Dev Cell 2010; 18:191–202. 13. Muotri AR, Marchetto MC, Coufal NG, et al. L1 retrotransposition in neurons is modulated by MeCP2. Nature 2010; 468:443–446. 14. Phillips JE, Corces VG. CTCF: master weaver of the genome. Cell 2009; 137:1194–1211. 15. Bjornsson HT, Sigurdsson MI, Fallin MD, et al. Intra-individual change over time in DNA methylation with familial clustering. J Am Med Assoc 2008; 299:2877–2883. 16. Lienert F, Wirbelauer C, Som I, et al. Identification of genetic elements that autonomously determine DNA methylation states. Nat Genet 2011; 43:1091–1097. 17. McVicker G, van de Geijn B, Degner JF, et al. Identification of genetic && variants that affect histone modifications in human cells. Science 2013; 342:747–749. This study reports hundreds of loci, genome-wide, that affect histone modification or RNA polymerase II (Pol II) occupancy with the same variant being associated with changes in multiple histone marks and Pol II, as well as in deoxyribonuclease I sensitivity and nucleosome positioning. 18. Kilpinen H, Waszak SM, Gschwind AR, et al. Coordinated effects of sequence variation on DNA binding, chromatin structure, and transcription. Science 2013; 342:744–747. 19. Schubeler D. Function and information content of DNA methylation. Nature & 2015; 517:321–326. A good recent review of the importance of DNA methylation, including a discussion of the links with genotype. 20. Haggarty P, Hoad G, Horgan GW, Campbell DM. DNA methyltransferase candidate polymorphisms, imprinting methylation, and birth outcome. PLoS One 2013; 8:e68896. 21. Haggarty P, Hoad G, Harris SE, et al. Human intelligence and polymorphisms in the DNA methyltransferase genes involved in epigenetic marking. PLoS One 2010; 5:e11329. 22. de VS, Wouters KA, Gottschalk RW, et al. Dietary methyl donors, methyl metabolizing enzymes, and epigenetic regulators: diet-gene interactions and promoter CpG island hypermethylation in colorectal cancer. Cancer Causes Control 2011; 22:1–12. 23. Lin J, Zeng RM, Li RN, Cao WH. Aberrant DNA methylation of the P16, MGMT, and hMLH1 genes in combination with the methylenetetrahydrofolate reductase C677T genetic polymorphism and folate intake in gastric cancer. Genet Mol Res 2014; 13:2060–2068. 24. Liao XX, Zhan ZX, Luo YY, et al. Association study between SNP rs150689919 in the DNA demethylation gene, TET1, and Parkinson’s disease in Chinese Han population. BMC Neurol 2013; 13:196. 25. Rotondo JC, Selvatici R, Di DM, et al. Methylation loss at H19 imprinted gene correlates with methylenetetrahydrofolate reductase gene promoter hypermethylation in semen samples from infertile males. Epigenetics 2013; 8:990– 997. 26. McKay JA, Groom A, Potter C, et al. Genetic and nongenetic influences during pregnancy on infant global and site specific DNA methylation: role for folate gene variants and vitamin B12. PLoS One 2012; 7:e33290. 27. Haggarty P, Hoad G, Campbell DM, et al. Folate in pregnancy and imprinted & gene and repeat element methylation in the offspring. Am J Clin Nutr 2013; 97:94–99. A large-scale study in human pregnancy of the effects of folate intake and status on offspring methylation within the imprinted genes and repeat elements and the lack of effect of common variants within the folate-methylation cycle. 28. Ley TJ, Ding L, Walter MJ, et al. DNMT3A mutations in acute myeloid leukemia. N Engl J Med 2010; 363:2424–2433. 29. Saradalekshmi KR, Neetha NV, Sathyan S, et al. DNA methyl transferase (DNMT) gene polymorphisms could be a primary event in epigenetic susceptibility to schizophrenia. PLoS One 2014; 9:e98182. 30. Song F, Amos CI, Lee JE, et al. Identification of a melanoma susceptibility & locus and somatic mutation in TET2. Carcinogenesis 2014; 35:2097–2101. This study used GWAS to identify a link between melanoma and genetic variation in the TET2 gene on chromosome 4q24. 31. Haggarty P. Epigenetic consequences of a changing human diet. Proc Nutr Soc 2013; 72:363–371. 32. Hoile SP, Clarke-Harris R, Huang RC, et al. Supplementation with N-3 longchain polyunsaturated fatty acids or olive oil in men and women with renal disease induces differential changes in the DNA methylation of FADS2 and ELOVL5 in peripheral blood mononuclear cells. PLoS One 2014; 9:e109896. 33. Gillberg L, Jacobsen SC, Ronn T, et al. 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.
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34. Hall E, Volkov P, Dayeh T, et al. Effects of palmitate on genome-wide mRNA expression and DNA methylation patterns in human pancreatic islets. BMC Med 2014; 12:103. A study demonstrating the way in which palmitic acid influences epigenetic state and gene expression in human pancreatic islets with possible implications for impaired insulin secretion and T2D. 35. Baur JA, Ungvari Z, Minor RK, et al. Are sirtuins viable targets for improving healthspan and lifespan? Nat Rev Drug Discov 2012; 11:443–461. 36. McGuinness D, McGlynn LM, Johnson PC, et al. Socio-economic status is associated with epigenetic differences in the pSoBid cohort. Int J Epidemiol 2012; 41:151–160. 37. Borghol N, Suderman M, McArdle W, et al. Associations with early-life socioeconomic position in adult DNA methylation. Int J Epidemiol 2012; 41:62–74. 38. Scoccianti C, Ricceri F, Ferrari P, et al. Methylation patterns in sentinel genes in peripheral blood cells of heavy smokers: Influence of cruciferous vegetables in an intervention study. Epigenetics 2011; 6:1114–1119. 39. Zhang TY, Meaney MJ. Epigenetics and the environmental regulation of the genome and its function. Annu Rev Psychol 2010; 61:439–443. 40. Lane M, Robker RL, Robertson SA. Parenting from before conception. Science 2014; 345:756–760. 41. Boeke CE, Baccarelli A, Kleinman KP, et al. Gestational intake of methyl donors and global LINE-1 DNA methylation in maternal and cord blood: prospective results from a folate-replete population. Epigenetics 2012; 7:253–260. 42. Soubry A, Schildkraut JM, Murtha A, et al. Paternal obesity is associated with IGF2 hypomethylation in newborns: results from a Newborn Epigenetics Study (NEST) cohort. BMC Med 2013; 11:29. 43. Lee HS, Barraza-Villarreal A, Biessy C, et al. Dietary supplementation with polyunsaturated fatty acid during pregnancy modulates DNA methylation at IGF2/H19 imprinted genes and growth of infants. Physiol Genomics 2014; 46:851–857. 44. Peters J. The role of genomic imprinting in biology and disease: an expanding & view. Nat Rev Genet 2014; 15:517–530. A good recent review of the importance of imprinting. 45. Woodfine K, Huddleston JE, Murrell A. Quantitative analysis of DNA methylation at all human imprinted regions reveals preservation of epigenetic stability in adult somatic tissue. Epigenet Chromatin 2011; 4:1. 46. Azzi S, Abi HW, Netchine I. Beckwith-Wiedemann and Russell-Silver syndromes: from new molecular insights to the comprehension of imprinting regulation. Curr Opin Endocrinol Diabetes Obes 2014; 21:30–38. 47. Rocha CF, Paiva CL. Prader-Willi-like phenotypes: a systematic review of their chromosomal abnormalities. Genet Mol Res 2014; 13:2290–2298. 48. Bird LM. Angelman syndrome: review of clinical and molecular aspects. Appl Clin Genet 2014; 7:93–104. 49. Ferguson-Smith AC, Patti ME. You are what your dad ate. Cell Metab 2011; 13:115–117. 50. Lazaraviciute G, Kauser M, Bhattacharya S, et al. A systematic review and meta-analysis of DNA methylation levels and imprinting disorders in children conceived by IVF/ICSI compared with children conceived spontaneously. Hum Reprod Update 2014; 20:840–852. 51. Whitelaw N, Bhattacharya S, Hoad G, et al. Epigenetic status in the offspring & of spontaneous and assisted conception. Hum Reprod 2014; 29:1452– 1458. An example from outside the field of nutrition investigating imprinted gene methylation in the offspring following infertility treatment and whether the effects are due to treatment or linked to infertility. 52. Weaver IC, Champagne FA, Brown SE, et al. Reversal of maternal programming of stress responses in adult offspring through methyl supplementation: altering epigenetic marking later in life. J Neurosci 2005; 25:11045–11054. 53. Tian W, Zhao M, Li M, et al. Reversal of cocaine-conditioned place preference through methyl supplementation in mice: altering global DNA methylation in the prefrontal cortex. PLoS One 2012; 7:e33435. 54. Zhang Y, Wang X, Han L, et al. Green tea polyphenol EGCG reverse cisplatin resistance of A549/DDP cell line through candidate genes demethylation. Biomed Pharmacother 2015; 69:285–290. 55. Blaschke K, Ebata KT, Karimi MM, et al. Vitamin C induces Tet-dependent && DNA demethylation and a blastocyst-like state in ES cells. Nature 2013; 500:222–226. An important study demonstrating a direct effect of nutrition on TET dependent DNA methylation. There are many examples of such effects on the DNMTs but the importance of TET in influencing epigenetic status emerged relatively recently and this is one of the first examples of an interaction with nutrition. 56. Cabo R, Hernes S, Slettan A, et al. Effect of genetic polymorphisms involved in folate metabolism on the concentration of serum folate and plasma total homocysteine (p-tHcy) in healthy subjects after short-term folic acid supplementation: a randomized, double blind, crossover study. Genes Nutr 2015; 10:456. 57. Tsang BL, Devine OJ, Cordero AM, et al. Assessing the association between && the methylenetetrahydrofolate reductase (MTHFR) 677C>T polymorphism and blood folate concentrations: a systematic review and meta-analysis of trials and observational studies. Am J Clin Nutr 2015. [Epub ahead of print] A study demonstrating a biologically significant effect of MTHFR C677T genotype on red blood cell folate concentrations. This is an example of the complicated ways in which genotype interacts with nutrition to potentially influence epigenetic state. &
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