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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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“…the gametic overall methylation patterns, and a number of cytosine methylation patterns in gametes are found to be heritable (Rakyan et al., 2003; Waterland and Jirtle, 2003; Cropley et al., 2006; Chong et al., 2007; Borgel et al., 2010; Smallwood et al., 2011; Jiang et al., 2013; Wang et al.,…”
Fenech, M. F. (2005) · Mutagenesis · doi:10.1093/mutage/gei040 · Cited by 159
“Recent experiments in yellow agouti [A(vy)] mice, which harbour a transposable element in the agouti gene, suggest that dietary methyl supplementation of dams with extra folic acid, vitamin B12, choline and betaine alter the phenotype of their A(vy)/a offspring via increased CpG methylation at the A(vy) locus, and tha…”
BackgroundDavison, J. M., Mellott, T. J., Kovacheva, V., & Blusztajn, J. K. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m807651200 · Cited by 158
Conching, A., & Thayer, Z. M. (2019) · Social Science & Medicine · doi:10.1016/j.socscimed.2019.04.001 · Cited by 187
Impact of transposable elements on the evolution of mammalian gene regulation
Medstrand, P., van de Lagemaat, L. N., Dunn, C. A., Landry, J., Svenback, D., & Mager, D. L. (2005) · Cytogenetic and Genome Research · doi:10.1159/000084966 · Cited by 159
“Support for this theory was gained recently when it was shown that different dietary methyl supplementation given to pregnant mice resulted in differential methylation status of the agouti IAP LTR loci in the offspring which correlated with agouti phenotype (Waterland and Jirtle, 2003).”
BackgroundHealth and the Economy in the United States from 1750 to the Present
Costa, D. L. (2015) · Journal of Economic Literature · doi:10.1257/jel.53.3.503 · Cited by 163
“Waterland and Jirtle (2003) showed that supplementing the diets of Agouti mice dams with folic acid, vitamin B12, betaine, and choline permanently affected the offspring’s DNA methylation at epigenetically susceptible loci.”
BackgroundShafei, A., Ramzy, M. M., Hegazy, A. I., Husseny, A. K., EL-hadary, U. G., Taha, M. M., & Mosa, A. A. (2018) · Gene · doi:10.1016/j.gene.2018.01.016 · Cited by 163
Prenatal Arsenic Exposure and DNA Methylation in Maternal and Umbilical Cord Blood Leukocytes
Kile, M. L., Baccarelli, A., Hoffman, E. B., Tarantini, L., Quamruzzaman, Q., Rahman, M., Mahiuddin, G., Mostofa, G., Hsueh, Y., Wright, R. O., et al. (2012) · Environmental Health Perspectives · doi:10.1289/ehp.1104173 · Cited by 155
Epigenetic inheritance in mammals: Evidence for the impact of adverse environmental effects
Franklin, T. B., & Mansuy, I. M. (2009) · Neurobiology of Disease · doi:10.1016/j.nbd.2009.11.012 · Cited by 153
“Administration of a methyl-rich diet to pregnant female mice increases the level of DNA methylation at the A vy and Axin Fu genes in the offspring and induces the associated variability in phenotype (Waterland et al., 2006; Waterland and Jirtle, 2003).”
Nutrition and human health from a sex–gender perspective
Marino, M., Masella, R., Bulzomi, P., Campesi, I., Malorni, W., & Franconi, F. (2011) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2011.02.001 · Cited by 159
McKay, J. A., Groom, A., Potter, C., Coneyworth, L. J., Ford, D., Mathers, J. C., & Relton, C. L. (2012) · PLoS ONE · doi:10.1371/journal.pone.0033290 · Cited by 161
“The influence of maternal one-carbon metabolism on methylation status in the offspring has been well documented in animal models [25–32] but as yet there are few studies demonstrating the effect of this maternal factor on infant DNA methylation in humans [33].”
BackgroundGenome-Scale Dna Methylation Analysis
Fouse, S. D., Nagarajan, R. P., & Costello, J. (2010) · Epigenomics · doi:10.2217/epi.09.35 · Cited by 154
Gene expression in the placenta: maternal stress and epigenetic responses
Gheorghe, C. P., Goyal, R., Mittal, A., & Longo, L. D. (2009) · The International Journal of Developmental Biology · doi:10.1387/ijdb.082770cg · Cited by 156
“In other studies in mice, the chow was supplemented with methyl supplements (Weaver et al., 2005; Wolff et al., 1998) or folic acid (Wehby & Murray, 2008), vitamin B-12, choline, and betaine to enhance metabolism of cellular methyl donors (S-adenosylmethionine) (Waterland & Jirtle, 2003).”
Immunologic endocrine disorders
Michels, A. W., & Eisenbarth, G. S. (2010) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2009.09.053 · Cited by 153
“Hypermethylation has been associated with dietary supplements (18), and there is discordance of methylation between monozygotic twins increasing with age (19).”
BackgroundTobi, E. W., Slagboom, P. E., van Dongen, J., Kremer, D., Stein, A. D., Putter, H., Heijmans, B. T., & Lumey, L. H. (2012) · PLoS ONE · doi:10.1371/journal.pone.0037933 · Cited by 153
“However, the subtle nature of the DNA methylation differences on a population level may also be inherent to the noise in the epigenetic response to environmental exposures [46].”
BackgroundSchaible, T. D., Harris, R. A., Dowd, S. E., Smith, C. W., & Kellermayer, R. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr044 · Cited by 150
“Importantly, methyl donors in the seminal nutritional studies were betaine, choline, vitamin B12 and folic acid (11,13).”
BackgroundThe interaction of genetic and environmental factors in the etiology of hypertension
Kuneš, J., & Zicha, J. (2009) · Physiological Research · doi:10.33549/physiolres.931913 · Cited by 151
Epigenetics and parental effects
Kappeler, L., & Meaney, M. J. (2010) · BioEssays · doi:10.1002/bies.201000015 · Cited by 159
Epigenetic mechanisms and the development of asthma
Yang, I. V., & Schwartz, D. A. (2012) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2012.07.052 · Cited by 154
“Randy Jirtle’s seminal experiments showed that a maternal diet supplemented with methyl donors (folic acid, vitamin B12, choline, and betaine) shifts coat color distribution of progeny toward the brown pseudoagouti phenotype and that this shift in coat color resulted from an increase in DNA methylation in a retrotrans…”
Chronic gastritis in the hypochlorhydric gastrin-deficient mouse progresses to adenocarcinoma
Zavros, Y. L., Eaton, K. A., Kang, W., Rathinavelu, S., Katukuri, V. K., Kao, J. Y., Samuelson, L. C., & Merchant, J. L. (2005) · Oncogene · doi:10.1038/sj.onc.1208407 · Cited by 149
Fetal Alcohol Spectrum Disorders: The Epigenetic Perspective1
Haycock, P. (2009) · Biology of Reproduction · doi:10.1095/biolreprod.108.074690 · Cited by 153
“, folic acid, vitamin B 12 , choline, and betaine) [27, 28], ethanol [29], endocrine disruptors [30, 31], in vitro culture techniques [32], 2,3,7,8tetrachlorodibenzo-p-dioxin (TCDD) [33], and maternal care [34].”
Domínguez-Salas, P., Moore, S. E., Cole, D., da Costa, K.-A., Cox, S. E., Dyer, R., Fulford, A. J. C., Innis, S. M., Waterland, R. A., Zeisel, S. H., et al. (2013) · American Journal of Clinical Nutrition · doi:10.3945/ajcn.112.048462 · Cited by 148
“Animal studies have shown that periconceptional supplementation/ restriction of the maternal diet with betaine, choline, folic acid, methionine, or vitamin B-12 can affect the establishment of DNA methylation patterns, altering gene expression and phenotype of the offspring (7, 8).”
Background
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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