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Transposable Elements: Targets for Early Nutritional Effects on Epigenetic Gene Regulation
Open accessAbstract
Early nutrition affects adult metabolism in humans and other mammals, potentially via persistent alterations in DNA methylation. With viable yellow agouti (A(vy)) mice, which harbor a transposable element in the agouti gene, we tested the hypothesis that the metastable methylation status of specific transposable element insertion sites renders them epigenetically labile to early methyl donor nutrition. Our results show that dietary methyl supplementation of a/a dams with extra folic acid, vitamin B(12), choline, and betaine alter the phenotype of their A(vy)/a offspring via increased CpG methylation at the A(vy) locus and that the epigenetic metastability which confers this lability is due to the A(vy) transposable element. These findings suggest that dietary supplementation, long presumed to be purely beneficial, may have unintended deleterious influences on the establishment of epigenetic gene regulation in humans.
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“In this case there is a correlation between DNA methylation at the promoter and silencing of the gene [5,6].”
From A genome-wide screen for modifiers of transgene variegation identifies genes with critical roles in development (2008) · cites this paper as [5]
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Sensing hypoxia: physiology, genetics and epigenetics
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Kadayıfçı, F. Z., Zheng, S., & Pan, Y. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19124055 · Cited by 141
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“Avy mice were used to demonstrate that maternal diet influences epigenetic states and hence phenotypes of F1 offspring through altering the probability of methylation of the Avy locus (Waterland and Jirtle 2003; Wolff et al. 1998).”
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Genetic and Epigenetic Variation, but Not Diet, Shape the Sperm Methylome
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“Other experimental animal models have shown effects of methyl-donor nutrients in the mother, like folic acid and vitamin B12, on gene methylation and the development of obesity, insulin resistance and diabetes in the offspring [24, 25].”
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“It was shown that methylation at MEs occurs stochastically but can in part be modified by maternal intake of nutrients related to one-carbon metabolism (Waterland et al., 2006; Waterland and Jirtle, 2003).”
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“Coat color in the yellow agouti mouse, which harbors a transposon in the agouti gene, was influenced by increased folate and methyl group intakes due to increased methylation of the transposable element, suggesting a possible deleterious effect on genome stability [51].”
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“This response could occur partly through epigenetic processes whereby nutritional influences affect foetal DNA(89), but low birth weight could also elicit overfeeding in mothers responding to concern about weight.”
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“color gene) and causes permanent change in coat color [24,25] thus, suggesting that prenatal and natal environmental interventions could induce epigenetic alterations with robust impact on stress-related disorders.”
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BackgroundPosition of the Academy of Nutrition and Dietetics: Nutritional Genomics
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“The addition of folic acid, vitamin B-12, choline, and betaine to the maternal diet of pregnant mice altered the wild type phenotype of yellow coat and obesity to a phenotype characterized by a less yellow coat color; pseudo-agouti; and lower prevalence of cancer, diabetes, and obesity.(37) Adding genistein at levels…”
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“However, when a pregnant A/a dam is fed a diet rich in methyl-donors, her offspring are born with increased agouti methylation, restored agouti expression, and they do not develop obesity, thus illustrating an epigenetic route for the enduring effects of maternal diet [1, 2].”
BackgroundMetabolism and Epigenetic Interplay in Cancer: Regulation and Putative Therapeutic Targets
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“The Agouti Yellow mouse model, where maternal diet alters offspring gene expression and resultant clinical phenotypes [98], offers mechanistic insight into this connection between the maternal exposome and offspring phenotype.”
BackgroundInvestigations on Transgenerational Epigenetic Response Down the Male Line in F2 Pigs
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“The Jirtle lab showed an effect of maternal diet during gestation on the agouti color phenotype in viable yellow agouti (A(vy)) mice, which was mediated through methylation of a transposable element in the A(vy) transposable element (30).”
BackgroundMiller, J. W., Garrod, M. G., Allen, L. H., Haan, M. N., & Green, R. (2009) · American Journal of Clinical Nutrition · doi:10.3945/ajcn.2009.27514 · Cited by 121
A genomic atlas of systemic interindividual epigenetic variation in humans
Gunasekara, C., Scott, C. A., Laritsky, E., Baker, M. S., MacKay, H., Duryea, J., Kessler, N. J., Hellenthal, G., Wood, A. C., Hodges, K. R., et al. (2019) · Genome biology · doi:10.1186/s13059-019-1708-1 · Cited by 119
“In mouse and human studies, epigenetically metastable loci are characterized by stochastic interindividual variation in epigenotype that is established in the early embryo [5] and influenced by periconceptional environment [7, 8, 37, 38].”
BackgroundVelázquez, R., Ash, J. A., Powers, B. E., Kelley, C. M., Strawderman, M. S., Luscher, Z. I., Ginsberg, S. D., Mufson, E. J., & Strupp, B. J. (2013) · Neurobiology of Disease · doi:10.1016/j.nbd.2013.04.016 · Cited by 124
Ashe, A., Morgan, D. K., Whitelaw, N. C., Bruxner, T. J., Vickaryous, N. K., Cox, L. L., Butterfield, N. C., Wicking, C., Blewitt, M. E., Wilkins, S. J., et al. (2008) · Genome Biology · doi:10.1186/gb-2008-9-12-r182 · Cited by 117
“In this case there is a correlation between DNA methylation at the promoter and silencing of the gene [5,6].”
BackgroundGenetic and epigenetic influence on the response to environmental particulate matter
Ji, H., & Hershey, G. K. K. (2011) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2011.11.008 · Cited by 124
Models of Intergenerational and Transgenerational Transmission of Risk for Psychopathology in Mice
Klengel, T., Dias, B. G., & Ressler, K. J. (2015) · Neuropsychopharmacology · doi:10.1038/npp.2015.249 · Cited by 125
Epigenetic supersimilarity of monozygotic twin pairs
Baak, T. E. V., Coarfa, C., Dugué, P., Fiorito, G., Laritsky, E., Baker, M. S., Kessler, N. J., Dong, J., Duryea, J., Silver, M. J., et al. (2018) · Genome biology · doi:10.1186/s13059-017-1374-0 · Cited by 114
“Mouse [10, 11, 26] and human studies [13, 14, 27, 28]”
Hirst, M., & Marra, M. A. (2008) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2008.09.011 · Cited by 120
Shaping adult phenotypes through early life environments
Weaver, I. C. G. (2009) · Birth Defects Research Part C Embryo Today Reviews · doi:10.1002/bdrc.20164 · Cited by 121
Forty mouse strain survey of body composition
Reed, D. R., Bachmanov, A. A., & Tordoff, M. G. (2007) · Physiology & Behavior · doi:10.1016/j.physbeh.2007.03.026 · Cited by 117
“The discovery of epigenetic effects for traits like coat color, obesity and body size has challenged traditional approaches used to assess genetic and non-genetic effects [34].”
Metabolic crosstalk between choline/1-carbon metabolism and energy homeostasis
Zeisel, S. H. (2012) · Clinical Chemistry and Laboratory Medicine (CCLM) · doi:10.1515/cclm-2012-0518 · Cited by 119
“Methyl-folate can deliver methyl-groups thereby sparing choline for use in PC synthesis; betaine can deliver methyl-groups thereby sparing folate for use in DNA synthesis.”
BackgroundInfluentialFreeman, D. J. (2009) · Seminars in Fetal and Neonatal Medicine · doi:10.1016/j.siny.2009.09.001 · Cited by 119
Dnmt1 Expression in Pre- and Postimplantation Embryogenesis and the Maintenance of IAP Silencing
Gaudet, F., Rideout, W. M., Meissner, A., Dausman, J. A., Leonhardt, H., & Jaenisch, R. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.4.1640-1648.2004 · Cited by 121
“ing effects in adulthood or in the next generation, such as the determination of coat color of A mice or the kinked-tail phenotype of Axin mice (29, 42, 44).”
BackgroundLy, A., Hoyt, L., Crowell, J., & Kim, Y. (2012) · Antioxidants and Redox Signaling · doi:10.1089/ars.2012.4554 · Cited by 116
“Studies using viable yellow agouti mice have unequivocally demonstrated that maternal dietary methyl group supplementation containing FA can permanently alter the phenotypic coat color of the offspring via increased CpG methylation in the promoter region of the agouti gene (174, 178).”
Towards incorporating epigenetic mechanisms into carcinogen identification and evaluation
Herceg, Z., Lambert, M.-P., van Veldhoven, K., Demetriou, C. A., Vineis, P., Smith, M. T., Straíf, K., & Wild, C. P. (2013) · Carcinogenesis · doi:10.1093/carcin/bgt212 · Cited by 117
The developmental environment, epigenetic biomarkers and long-term health
Godfrey, K. M., Costello, P. M., & Lillycrop, K. A. (2015) · Journal of Developmental Origins of Health and Disease · doi:10.1017/s204017441500121x · Cited by 122
“Differences in the mother’s intake of dietary methyl donors and co-factors (including folic acid, vitamin B12, betaine and choline) were shown to alter DNA methylation of the Agouti gene and induce differences in the coat colour of the offspring.(40,41) Studies in other animal models have also shown that perturbations…”
BackgroundMcGee, M., Bainbridge, S. A., & Fontaine‐Bisson, B. (2018) · Nutrition Reviews · doi:10.1093/nutrit/nuy006 · Cited by 119
Schneider, E., Pliushch, G., Hajj, N. E., Galetzka, D., Puhl, A. G., Schorsch, M., Frauenknecht, K. B. M., Riepert, T., Tresch, A., Müller, A. M., et al. (2010) · Nucleic Acids Research · doi:10.1093/nar/gkq126 · Cited by 122
Boeke, C. E., Baccarelli, A., Kleinman, K., Burris, H. H., Litonjua, A. A., Rifas‐Shiman, S. L., Tarantini, L., & Gillman, M. W. (2012) · Epigenetics · doi:10.4161/epi.7.3.19082 · Cited by 115
Single Molecule Epigenetic Analysis in a Nanofluidic Channel
Cipriany, B. R., Zhao, R., Murphy, P. J., Levy, S. L., Tan, C. P., Craighead, H. G., & Soloway, P. D. (2010) · Analytical Chemistry · doi:10.1021/ac9028642 · Cited by 112
Faulk, C. D., Barks, A. K., Liu, K., Goodrich, J. M., & Dolinoy, D. C. (2013) · Epigenomics · doi:10.2217/epi.13.49 · Cited by 114
Quantitative epigenetics and evolution
Banta, J. A., & Richards, C. L. (2018) · Heredity · doi:10.1038/s41437-018-0114-x · Cited by 116
Vanhees, K., Vonhögen, I. G. C., van Schooten, F., & Godschalk, R. (2013) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-013-1427-9 · Cited by 121
“Although dietary methyl-donor supplementation of female mice before and during gestation affected the methylation status of transposable repetitive elements upstream of the transcription start site in the Agouti gene in heterozygous A offspring mice [50] and successive generations of A mice placed on a diet supplement…”
BackgroundCancer Susceptibility: Epigenetic Manifestation of Environmental Exposures
Weidman, J. R., Dolinoy, D. C., Murphy, S. K., & Jirtle, R. L. (2007) · The Cancer Journal · doi:10.1097/ppo.0b013e31803c71f2 · Cited by 119
Neural tube defect genes and maternal diabetes during pregnancy
Salbaum, J. M., & Kappen, C. (2010) · Birth Defects Research Part A Clinical and Molecular Teratology · doi:10.1002/bdra.20680 · Cited by 112
“With the recent finding that epigenetic modifications may be subject to dietary modulation (Waterland and Jirtle, 2003; Davison et al., 2009; Wellen et al., 2009), this opens new avenues for strategies that are aimed at preventing NTDs by targeting epigenetic mechanisms.”
BackgroundMethyl nutrients, DNA methylation, and cardiovascular disease
Glier, M. B., Green, T., & Devlin, A. M. (2013) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.201200636 · Cited by 114
“However, epigenomic marks are also responsive to environmental shifts, like changes in nutritional status [2], and as such, are attractive diet-related targets for the prevention and treatment of CVD.”
BackgroundDupras, C., Saulnier, K. M., & Joly, Y. (2019) · Social Studies of Science · doi:10.1177/0306312719866007 · Cited by 113
“We considered the publication of two seminal scientific articles, one in the field of ‘nutritional epigenetics’ (Waterland and Jirtle, 2003) and the other in ‘social epigenetics’ (Weaver et al.”
BackgroundMethodNair, S. G., Adams-Deutsch, T., Epstein, D. H., & Shaham, Y. (2009) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2009.05.003 · Cited by 112
Epigenetic epidemiology: Promises for public health research
Bakulski, K. M., & Fallin, M. D. (2014) · Environmental and Molecular Mutagenesis · doi:10.1002/em.21850 · Cited by 113
Epigenetic biomarkers of colorectal cancer: Focus on DNA methylation
Coppedè, F. (2011) · Cancer Letters · doi:10.1016/j.canlet.2011.12.030 · Cited by 111
“Several researchers have clearly demonstrated that, at least in mice, supplementing amother’s nutritionally adequate dietwith extra folic acid, vitamin B12, choline, and betaine can permanently affect the offspring’s DNA methylation at epigenetically susceptible loci, thusmodifying the phenotype, development and healt…”
BackgroundAnimal Models to Study Environmental Epigenetics1
Rosenfeld, C. S. (2009) · Biology of Reproduction · doi:10.1095/biolreprod.109.080952 · Cited by 116
“Agouti viable yellow (A) mice Maternal diet enriched in genistein or methyl supplements resulted in increased number of brown, healthy offspring correlated with methylation of the IAP site embedded within the A gene [8, 10, 14].”
BackgroundMethod
Metadata
- Authors
- Waterland, R. A., & Jirtle, R. L.
- Affiliations
- Duke Medical Center (US)
- Corresponding author
- Jirtle, Randy L.
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2003-08-01
- Volume
- 23
- Issue
- 15
- Pages
- 5293-5300
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC165709
- OpenAlex
- W2100489386
- Cited by
- 2,019
- References
- 35
- Citations by year
- 2026: 30 · 2025: 47 · 2024: 54 · 2023: 37 · 2022: 82 · 2021: 68 · 2020: 38 · 2019: 75 · 2018: 76 · 2017: 88 · 2016: 93 · 2015: 110 · 2014: 143 · 2013: 130 · 2012: 144
- FWCI
- 22.68
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (R01CA025951, CA25951)
- National Institute of Environmental Health Sciences (ES08823, R01ES008823)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Birth, Development, and Health
- Health Sciences › Nursing › Nutrition and Dietetics › Folate and B Vitamins Research
- Keywords
- transposable elements, DNA methylation, epigenetic inheritance, early life nutrition, methyl donor supplementation, folic acid, vitamin B12, choline, betaine, agouti gene, CpG methylation, maternal diet, offspring phenotype
- MeSH terms
- Alleles, Animals, Betaine, Choline, DNA Transposable Elements, Exons, Folic Acid, Gene Expression Regulation, Mice, Inbred C3H, Mice, Inbred C57BL, Models, Genetic, Molecular Sequence Data, Nutritional Physiological Phenomena, Phenotype, Sulfites, Vitamin B 12, Polymerase Chain Reaction, Sequence Analysis, DNA, CpG Islands, DNA Methylation, Dietary Supplements, Mice
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