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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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BackgroundThe epigenome and cancer prevention: A complex story of dietary supplementation
Lee, H., & Herceg, Z. (2012) · Cancer Letters · doi:10.1016/j.canlet.2012.01.021 · Cited by 24
“Using viable yellow agouti (Avy) mice, which harbor a transposable element in the agouti gene, it was shown that dietary methyl supplementation of a/a dams with extra folic acid, vitamin B12, choline, and betaine altered the phenotype of their Avy/a offspring via increased CpG methylation at the Avy locus [68].”
BackgroundBehavior Individuality: A Focus on Drosophila melanogaster
Mollá-Albaladejo, R., & Sánchez‐Alcañiz, J. A. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.719038 · Cited by 30
“Different factors influence epigenetic modifications such as diet, experience, characteristics of the ecosystem, lifestyle, and the physiological state of the individuals, impacting on disease outcome, social organization, and individual behavior, among others (Waterland and Jirtle, 2003; Cunliffe, 2016; Dawson et al.…”
BackgroundSeong, K., Maekawa, T., & Ishii, S. (2012) · Genes to Cells · doi:10.1111/j.1365-2443.2012.01587.x · Cited by 26
“Methyl donor supplementation of pregnant females via folic acid, vitamin B12, choline, or betaine altered the coat color in the offspring toward the repressed state (pseudoagouti) by causing hypermethylation of the Avy allele (Waterland & Jirtle 2003).”
BackgroundNature, nurture and socioeconomic policy—What can we learn from molecular genetics?
Lundborg, P., & Stenberg, A. (2010) · Economics & Human Biology · doi:10.1016/j.ehb.2010.08.002 · Cited by 29
Natural epigenetic variation in bats and its role in evolution
Liu, S., Sun, K., Jiang, T., & Feng, J. (2015) · Journal of Experimental Biology · doi:10.1242/jeb.107243 · Cited by 26
“Studies conducted with animals and plants have suggested that environmental change, such as diets and behaviours, could induce DNA methylation variance of organisms or their offspring (Crews et al., 2007; Maleszka, 2008; Waterland and Jirtle, 2003).”
BackgroundEpigenome: The Program For Human Health And Disease
Jirtle, R. L. (2009) · Epigenomics · doi:10.2217/epi.09.16 · Cited by 25
Galván, I., Inácio, Â., Romero-Haro, A., & Alonso-Alvarez, C. (2017) · Molecular Ecology · doi:10.1111/mec.13952 · Cited by 25
“…evidence of an environmental epigenetic change in genes (which may be mediated by certain transcription factors; see below) that control pigmentation in animals, although Waterland & Jirtle (2003) already showed that another pigmentation-related gene (Agouti) is epigenetically labile in mice.”
Pharmacological inhibition of EZH2 disrupts the female germline epigenome
Prokopuk, L., Hogg, K., & Western, P. S. (2018) · Clinical Epigenetics · doi:10.1186/s13148-018-0465-4 · Cited by 26
Wang, Z., Song, J., Li, Y., Dong, B., Zou, Z., & Ma, J. (2019) · Scientific Reports · doi:10.1038/s41598-019-38596-6 · Cited by 25
Genome-scale DNA methylome and transcriptome profiling of human neutrophils
Chatterjee, A., Stockwell, P. A., Rodger, E. J., & Morison, I. M. (2016) · Scientific Data · doi:10.1038/sdata.2016.19 · Cited by 25
Epigenetic Echoes: Bridging Nature, Nurture, and Healing Across Generations
Banushi, B., Collova, J. R., & Milroy, H. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26073075 · Cited by 30
“…for metastable epialleles that respond to prenatal environmental conditions (for instance, loci that show methylation changes associated with seasonal maternal nutrition in certain populations), but whether these contribute to transgenerational trauma effects is not known [155,157,163,164].”
Epigenetics: Genetics Versus Life Experiences
Elia, J., Laracy, S. D., Allen, J., Nissley‐Tsiopinis, J., & Borgmann‐Winter, K. E. (2011) · Current topics in behavioral neurosciences · doi:10.1007/7854_2011_144 · Cited by 28
“Hypomethylation of the agouti gene has also been shown to affect coat color in mice (Waterland and Jirtle 2003).”
BackgroundMaternal folate deficiency and metabolic dysfunction in offspring
McKay, J. A., & Mathers, J. C. (2015) · Proceedings of The Nutrition Society · doi:10.1017/s0029665115004280 · Cited by 25
“Maternal supplementation with folic acid, vitamin B12, choline and betaine increased CpG methylation at the A(vy) locus in the offspring and increased the proportion of leaner offspring with darker coats((19)).”
BackgroundZhang, H. P., Wang, G., Fu, J., Fan, T., Wang, Z. L., & Wang, G. (2016) · Respirology · doi:10.1111/resp.12774 · Cited by 24
Advancing and refining archaeological dental calculus research using multiomic frameworks
Wright, S., Dobney, K. M., & Weyrich, L. S. (2021) · STAR Science & Technology of Archaeological Research · doi:10.1080/20548923.2021.1882122 · Cited by 26
Korsmo, H. W., Dave, B., Trasino, S., Saxena, A., Liu, J., Caviglia, J. M., Edwards, K., Dembitzer, M., Sheeraz, S., Khaldi, S., et al. (2022) · Frontiers in Nutrition · doi:10.3389/fnut.2022.841787 · Cited by 24
Sainty, R., Silver, M. J., Prentice, A. M., & Monk, D. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2023.1212199 · Cited by 24
“The levels of micronutrients essential for the 1C cycle in diet can affect methylation levels (Waterland and Jirtle, 2003; Sinclair et al., 2007).”
BackgroundEpigenetic methylations and their connections with metabolism
Chiacchiera, F., Piunti, A., & Pasini, D. (2013) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-013-1293-5 · Cited by 25
Medical practice and community health care in the 21st Century: A time of change
Genuis, S. J. (2008) · Public Health · doi:10.1016/j.puhe.2008.04.002 · Cited by 24
Early Brain Development and Human Development
Mustard, J. F. (2010) · Cited by 24
James, P., Domínguez-Salas, P., Hennig, B. J., Moore, S. E., Prentice, A. M., & Silver, M. J. (2018) · Current Developments in Nutrition · doi:10.1093/cdn/nzy082 · Cited by 23
“This resulted in changes to offspring fur color, appetite, adiposity, and glucose tolerance (27, 35).”
BackgroundRees, W. D. (2018) · Proceedings of The Nutrition Society · doi:10.1017/s0029665118002537 · Cited by 25
“Changes in DNA methylation and gene expression in the offspring of animals fed a methyl-deficient diet were first shown in the classical studies of the Agouti mouse((88)).”
Sasco, A. J. (2007) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2007.10.015 · Cited by 24
“Such mechanisms may play a role in the occurrence of both cancer in general [46,47] and hormone-dependent cancers and other outcomes following exposure in particular to selected pesticides, even when the exposure occurs generations before [48e51], or to compounds such as phthalates [52].”
BackgroundTissue- and Sex-Specific DNA Methylation Changes in Mice Perinatally Exposed to Lead (Pb)
Wang, K., Liu, S., Svoboda, L. K., Rygiel, C. A., Neier, K. E., Jones, T. R., Colacino, J. A., Dolinoy, D. C., & Sartor, M. A. (2020) · Frontiers in Genetics · doi:10.3389/fgene.2020.00840 · Cited by 26
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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