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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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Epigenetics at the Epicenter of Modern Medicine
Feinberg, A. P. (2008) · JAMA · doi:10.1001/jama.299.11.1345 · Cited by 424
Epigenetics across the human lifespan
Kanherkar, R. R., Bhatia-Dey, N., & Csoka, A. B. (2014) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2014.00049 · Cited by 407
“Studies in genomic imprinting have revealed how DNA methylation patterns are influenced by diet, and how epigenomic sensitivity to environmental cues and specifically diet can be used to influence disease susceptibility (Waterland and Jirtle, 2003; Carone et al., 2010; Jennings and Willis, 2014).”
BackgroundMethyl donor supplementation prevents transgenerational amplification of obesity
Waterland, R. A., Travisano, M., Tahiliani, K. G., Rached, M.-T., & Mirza, S. (2008) · International Journal of Obesity · doi:10.1038/ijo.2008.100 · Cited by 418
How nutrition and the maternal microbiota shape the neonatal immune system
Macpherson, A. J., de Agüero, M. G., & Ganal-Vonarburg, S. C. (2017) · Nature Reviews Immunology · doi:10.1038/nri.2017.58 · Cited by 378
Intergenerational consequences of fetal programming by in utero exposure to glucocorticoids in rats
Drake, A. J., Walker, B. R., & Seckl, J. R. (2004) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00106.2004 · Cited by 407
DNA methylation contributes to natural human variation
Heyn, H., Moran, S., Hernando-Herraez, I., Sayols, S., Gomez, A., Sandoval, J., Monk, D., Hata, K., Marques-Bonet, T., Wang, L., et al. (2013) · Genome Research · doi:10.1101/gr.154187.112 · Cited by 408
Epigenetics and cardiovascular disease
Ordovás, J. M., & Smith, C. E. (2010) · Nature Reviews Cardiology · doi:10.1038/nrcardio.2010.104 · Cited by 413
“This notion is supported by studies in experimental models that have shown the dramatic influence of maternal diet during pregnancy on the pattern of DNA methylation of specific genes, which resulted in permanent phenotypic changes such as coat color, body weight, and blood pressure”
ResultRelationship Between Methylome and Transcriptome in Patients With Nonalcoholic Fatty Liver Disease
Murphy, S. K., Yang, H., Moylan, C. A., Pang, H., Dellinger, A., Abdelmalek, M. F., Garrett, M. E., Ashley–Koch, A., Suzuki, A., Tillmann, H. L., et al. (2013) · Gastroenterology · doi:10.1053/j.gastro.2013.07.047 · Cited by 391
Clare, C., Brassington, A. H., Kwong, W. Y., & Sinclair, K. D. (2018) · Annual Review of Animal Biosciences · doi:10.1146/annurev-animal-020518-115206 · Cited by 423
Germ-line epigenetic modification of the murine A vy allele by nutritional supplementation
Cropley, J. E., Suter, C. M., Beckman, K. B., & Martin, D. I. K. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0607090103 · Cited by 403
Moffitt, T. E., Caspi, A., & Rutter, M. (2006) · Perspectives on Psychological Science · doi:10.1111/j.1745-6916.2006.00002.x · Cited by 389
“This article aims to address this uncertainty.”
Baker, J. L., Michaelsen, K. F., Rasmussen, K. M., & Sørensen, T. I. A. (2004) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/80.6.1579 · Cited by 389
Evolution and molecular mechanisms of adaptive developmental plasticity
Beldade, P., Mateus, A. R., & Keller, R. A. (2011) · Molecular Ecology · doi:10.1111/j.1365-294x.2011.05016.x · Cited by 398
“These include other regulatory mechanisms, involving players such as regulatory microRNAs and post-translation modification of regulatory proteins (Weake & Workman 2010), as well as mechanisms of signal reception and signal 2011 Blackwell Publishing Ltd transduction (see discussions in Aubin-Horth…”
BackgroundFaulk, C., & Dolinoy, D. C. (2011) · Epigenetics · doi:10.4161/epi.6.7.16209 · Cited by 386
“For mice, in utero supplementation with methyl donor rich diets increases methylation and suppresses transcription of the Runx3 gene in lung tissue(11) and permanently shifts the coat color pattern of mice carrying the Agouti viable yellow allele.(12) Dietary phytoestrogens interact with the methyl donor pathway to si…”
BackgroundNelissen, E. C. M., van Montfoort, A. P. A., Dumoulin, J. C. M., & Evers, J. L. H. (2010) · Human Reproduction Update · doi:10.1093/humupd/dmq052 · Cited by 400
“A well-known example is the effect of maternal diet on coat colour and obesity in A vy /a mice offspring (Waterland and Jirtle, 2003).”
BackgroundGene Coexpression Networks in Human Brain Identify Epigenetic Modifications in Alcohol Dependence
Ponomarev, I., Wang, S., Zhang, L., Harris, R. A., & Mayfield, R. D. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.3136-11.2012 · Cited by 387
“Many TEs have retained functional promoters, and the effects of TEs on expression of adjacent individual genes have been well documented (Waterland and Jirtle, 2003).”
BackgroundInfluentialNon‐genomic transgenerational inheritance of disease risk
Gluckman, P. D., Hanson, M. A., & Beedle, A. S. (2007) · BioEssays · doi:10.1002/bies.20522 · Cited by 384
“Importantly, the level of DNA methylation of the epialleles in the F1 generation, and the resulting phenotype, can be altered by the F0 maternal environment as reflected by dietary manipulation((53,54)) or, for agouti, endocrine exposure.”
BackgroundSteegers-Theunissen, R. P. M., Twigt, J., Pestinger, V., & Sinclair, K. D. (2013) · Human Reproduction Update · doi:10.1093/humupd/dmt041 · Cited by 378
“Working with the viable yellow agouti ( A vy ) mouse , Waterland and Jirtle ( 2003 ) demonstrated that dietary supplementation with methionine , folate , B12 , choline and betaine throughout gestation and lactation increased CpG methylation at the agouti locus , thereby recapitulating the mottled…”
BackgroundEpigenetics and cancer: towards an evaluation of the impact of environmental and dietary factors
Herceg, Z. (2007) · Mutagenesis · doi:10.1093/mutage/gel068 · Cited by 378
“This idea is supported by a study demonstrating that dietary methyl supplementation during early embryonic development in mice increases methylation levels at specific genes resulting in permanent changes in gene expression (128).”
BackgroundNutrition, epigenetics, and developmental plasticity: implications for understanding human disease
Burdge, G. C., & Lillycrop, K. A. (2010) · Annual Review of Nutrition · doi:10.1146/annurev.nutr.012809.104751 · Cited by 372
Maternal High-Fat Diet Effects on Third-Generation Female Body Size via the Paternal Lineage
Dunn, G. A., & Bale, T. L. (2011) · Endocrinology · doi:10.1210/en.2010-1461 · Cited by 381
Jiang, Y.-H., Bressler, J., & Beaudet, A. L. (2004) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev.genom.5.061903.180014 · Cited by 371
“This is likely to be the first of many examples in humans and other mammals to support a mechanistic link between diet and epigenetic processes (Wolff et al. 1998; Waterland and Jirtle 2003).”
BackgroundEpigenetics and Human DiseasePreprint
Zoghbi, H. Y., & Beaudet, A. L. (2016) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a019497 · Cited by 373
Fitzgerald, K. N., Hodges, R., Hanes, D., Stack, E., Cheishvili, D., Szyf, M., Henkel, J., Twedt, M. W., Giannopoulou, D., Herdell, J., et al. (2021) · Aging · doi:10.18632/aging.202913 · Cited by 361
“The power of nutrition to bring about transformative phenotypic changes has held up over the intervening years, most strongly in animal studies, but also in some limited human trials [33].”
BackgroundA paternal environmental legacy: Evidence for epigenetic inheritance through the male germ line
Soubry, A., Hoyo, C., Jirtle, R. L., & Murphy, S. K. (2014) · BioEssays · doi:10.1002/bies.201300113 · Cited by 373
“Following a landmark study by Waterland and Jirtle [8] using the agouti viable yellow (Avy) mouse model, the biological mechanisms underlying these associations in humans are now proposed to involve alterations in the epigenome, including DNA methylation, histone modifications, and transcription of non-coding RNAs.”
BackgroundMethodInfluential
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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