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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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“Variable DNA methylation levels across individuals at the A promoter result in a variable coat colour in each mouse, in addition to other traits [73], and can also be influenced by maternal diet [74,75].”
BackgroundLee, H.-S. (2015) · Nutrients · doi:10.3390/nu7115467 · Cited by 236
“Supplementation of methyl donors including folate during pregnancy increased DNA methylation of the agouti gene in Avy offspring , leading to low agouti expression and yellow to brown coat color [8].”
BackgroundXie, Q., Bai, Q., Zou, L., Zhang, Q., Zhou, Y. G., Chang, H., Yi, L., Zhu, J., & Mi, M. (2014) · Genes Chromosomes and Cancer · doi:10.1002/gcc.22154 · Cited by 241
Epigenomic disruption: The effects of early developmental exposures
Bernal, A. J., & Jirtle, R. L. (2010) · Birth Defects Research Part A Clinical and Molecular Teratology · doi:10.1002/bdra.20685 · Cited by 244
“…characteristics: 1) they are established in a stochastic manner (Morgan and others, 1999), 2) they are potentially inherited transgenerationally (Rakyan and others, 2003), and 3) their establishment can be altered by environmental agents, such as food supplements (Waterland and Jirtle, 2003).”
BackgroundMethodInfluentialFolate: a magic bullet or a double edged sword for colorectal cancer prevention?
Kim, Y. (2006) · Gut · doi:10.1136/gut.2006.095463 · Cited by 236
Imprinting evolution and the price of silence
Murphy, S. K., & Jirtle, R. L. (2003) · BioEssays · doi:10.1002/bies.10277 · Cited by 235
Environmental epigenetics of asthma: An update
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An epigenetic perspective on the free radical theory of development
Hitchler, M. J., & Domann, F. E. (2007) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2007.06.027 · Cited by 241
“In these pioneering studies genetically identical offspring have different coat colors by changing the level of DNA methylation at the agouti locus [86-88].”
BackgroundNutritional programming of disease: unravelling the mechanism
Langley‐Evans, S. C. (2008) · Journal of Anatomy · doi:10.1111/j.1469-7580.2008.00977.x · Cited by 241
“The major interest in a role for DNA methylation in nutritional programming was largely initiated by the work of Waterland & Jirtle (2003).”
BackgroundThe early life environment and the epigenome
Szyf, M. (2009) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2009.01.009 · Cited by 238
Mechanisms of disease: the developmental origins of disease and the role of the epigenotype
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Genetic, Epigenetic, and Environmental Contributions to Neural Tube Closure
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“Interestingly, gestation appears to be particularly sensitive to environmental changes, as maternal folate intake during gestation induces differential DNA methylation and phenotypic changes in Avy offspring but not in their mothers (176).”
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“An interesting example is a study demonstrating that nutritional supplementation during gestation of yellow agouti mice affects adult metabolism and susceptibility to disease, and literally changes the color of the animals, apparently through DNA methylation ( Waterland & Jirtle, 2003 ).”
BackgroundInfluentialEpigenetics in male reproduction: effect of paternal diet on sperm quality and offspring health
Schagdarsurengin, U., & Steger, K. (2016) · Nature Reviews Urology · doi:10.1038/nrurol.2016.157 · Cited by 222
Environmental and nutritional effects on the epigenetic regulation of genes
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“Varying the mother´s diet tends to produce offspring with a wide variation in individual coat color and obese phenotype as epigenetic modifications of agouti gene were established in early development (Waterland and Jirtle 2003).”
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Plasticity, Robustness, Development and Evolution
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The Dynamic Epigenome and its Implications in Toxicology
Szyf, M. (2007) · Toxicological Sciences · doi:10.1093/toxsci/kfm177 · Cited by 227
“Exposures of the dams to high methyl content diet rich in 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 (Waterland and Jirtle, 2003).”
BackgroundReview article: Epigenetic control of fetal gene expression
Nafee, T. M., Farrell, W., Carroll, W. D., Fryer, A. A., & Ismail, K. (2007) · BJOG An International Journal of Obstetrics & Gynaecology · doi:10.1111/j.1471-0528.2007.01528.x · Cited by 224
Low folate levels may protect against colorectal cancer
Guelpen, B. R. V., Hultdin, J., Johansson, I., Hallmans, G., Stenling, R., Riboli, E., Winkvist, A., & Palmqvist, R. (2006) · Gut · doi:10.1136/gut.2005.085480 · Cited by 222
Epigenetics: molecular mechanisms and implications for disease
Handel, A. E., Ebers, G. C., & Ramagopalan, S. V. (2009) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2009.11.003 · Cited by 227
Allegrucci, C., Thurston, A., Lucas, E. S., & Young, L. E. (2005) · Reproduction · doi:10.1530/rep.1.00360 · Cited by 223
“A maternal hypermethylating diet during mouse pregnancy increased DNA methylation in repetitive sequences, promoting ectopic expression of the agouti gene (Waterland & Jirtle 2003).”
Molecular genetics of autism spectrum disorder
Veenstra-VanderWeele, J. M., & Cook, E. H. (2004) · Molecular Psychiatry · doi:10.1038/sj.mp.4001505 · Cited by 224
The fetal origins of memory: The role of dietary choline in optimal brain development
Zeisel, S. H. (2006) · The Journal of Pediatrics · doi:10.1016/j.jpeds.2006.06.065 · Cited by 221
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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