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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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Early life nutritional programming of health and disease in The Gambia
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Dammann, R., Richter, A. M., Jiménez, A. P., Woods, M., Küster, M. M., & Witharana, C. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18102160 · Cited by 47
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“In this model, maternal dietary supplementation with the methylgroup donor folate during pregnancy locks the regulatory sequence of the mutant Agouti locus in a hypermethylated state and therefore suppresses phenotypic variability [ 21 ].”
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“In a mouse strain carrying the abnormal agouti gene for coat color, dams fed a diet containing four added methyl donors and cofactors, one of which was FA, delivered offspring with hypermethylation of the agouti gene and a change in coat color (87).”
BackgroundWhat’s in a name? The three genealogies of the social in social epigenetics
Louvel, S. (2020) · Social Science Information · doi:10.1177/0539018419897001 · Cited by 40
“In particular, research by Waterland and Jirtle on agouti mice pioneered nutritional epigenetics (Waterland & Jirtle, 2003).”
BackgroundMicrobiota and epigenetics: promising therapeutic approaches?
El-Sayed, A., Aleya, L., & Kamel, M. S. (2021) · Environmental Science and Pollution Research · doi:10.1007/s11356-021-15623-6 · Cited by 43
“Meanwhile, the term nutraceuticals was also developed to describe foodstuffs that provide medical/health benefits and can be used to prevent/treat certain diseases (Hwang and Lim 2015; Li 2018; Waterland and Jirtle 2003).”
BackgroundDNA Methylation Dynamics in Human Carotid Plaques After Cerebrovascular Events
Zaina, S., Gonçalves, I., Carmona, F. J., Gómez, A., Heyn, H., Mollet, I. G., Morán, S., Varol, N., & Esteller, M. (2015) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.115.305630 · Cited by 40
“The DNA methylome undergoes programmed changes during cellular differentiation, but it can also be modified by exogenous stimuli such as the diet and environmental factors, some of which coincide with known atherosclerosis risk factors.(2,3) Therefore, it has been proposed that the latter may act by imposing aberrant,…”
BackgroundGiudicelli, F., Brabant, A.-L., Grit, I., Parnet, P., & Amarger, V. (2013) · PLoS ONE · doi:10.1371/journal.pone.0068268 · Cited by 43
“Supplementation with an excess of methyl donors around conception and during gestation is known to induce hypermethylation at epi-labile loci [36,37,47] and may be involved in the protection against obesity [48].”
BackgroundThe potential role of epigenetic responses to diet in ageing
Ford, D., Ions, L. J., Alatawi, F. S., & Wakeling, L. A. (2011) · Proceedings of The Nutrition Society · doi:10.1017/s0029665111000851 · Cited by 42
Dietary folates and cancer risk in a network of case–control studies
Tavani, A., Malerba, S., Pelucchi, C., Maso, L. D., Zucchetto, A., Serraino, D., Levi, F., Montella, M., Franceschi, S., Zambon, A., et al. (2012) · Annals of Oncology · doi:10.1093/annonc/mds212 · Cited by 41
The Social as Signal in the Body of Chromatin
Landecker, H. L. (2016) · The Sociological Review · doi:10.1111/2059-7932.12014 · Cited by 41
“The viable yellow agouti mouse model was used in experiments showing that dietary supplementation for pregnant mice changed the phenotype of the offspring via the epigenetic modulation of the mutant agouti effects (Waterland and Jirtle, 2003).”
MethodMorandin, C., Brendel, V., Sundström, L., Helanterä, H., & Mikheyev, A. S. (2019) · Molecular Ecology · doi:10.1111/mec.15062 · Cited by 37
“…methylation regulates a wide range of cellular processes, such as development or disease (Jirtle & Skinner, 2007; Lister et al., 2009; Waterland & Jirtle, 2003; Wolffe & Matzke, 1999) and has been shown to affect processes such as gene expression (Keshet, Yisraeli, & Cedar, 1985; Tate & Bird,…”
BackgroundFetal programming and epigenetics
Stevenson, K., Lillycrop, K. A., & Silver, M. J. (2020) · Current Opinion in Endocrine and Metabolic Research · doi:10.1016/j.coemr.2020.07.005 · Cited by 47
Zeh, J. A., & Zeh, D. W. (2008) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1438.006 · Cited by 41
Rangel-Salazar, R., Lindholm, M., Aguilar-Salinas, C. A., Alvarado‐Caudillo, Y., Døssing, K. B. V., Esteller, M., Labourier, E., Lund, G., Nielsen, F. C., Rodríguez‐Ríos, D., et al. (2011) · BMC Genomics · doi:10.1186/1471-2164-12-582 · Cited by 40
“According to this view, environmental and nutritional risk factors might impose stable epigenetic “hits” during an individual’s lifetime that, possibly in synergy with other concomitant molecular changes, cause anti- or pro-atherogenic gene expression patterns [3,4].”
BackgroundThaler, R., Karlic, H., Rust, P., & Haslberger, A. G. (2008) · British Journal Of Nutrition · doi:10.1017/s0007114508047685 · Cited by 41
“Experiments utilising the agouti mouse model show a transgenerational alteration of the mouse phenotype by hypermethylation of the agouti gene due to methyl donor-rich diets((18)).”
Juriloff, D. M., Harris, M. J., Mager, D. L., & Gagnier, L. (2014) · Birth Defects Research Part A Clinical and Molecular Teratology · doi:10.1002/bdra.23320 · Cited by 40
Toffoli, L. V., Rodrigues, G. M., de Oliveira, J. F., Silva, A. S., Moreira, E. G., Pelosi, G. G., & Gomes, M. V. (2014) · Behavioural Brain Research · doi:10.1016/j.bbr.2014.02.031 · Cited by 42
Weinhouse, C., Anderson, O. S., Jones, T. R., Kim, J. H., Liberman, S. A., Nahar, M. S., Rozek, L. S., Jirtle, R. L., & Dolinoy, D. C. (2011) · Epigenetics · doi:10.4161/epi.6.9.17103 · Cited by 41
“Interestingly, A methylation profiles are similar within tissues derived from the three germ layers (brain representing ectodermal; kidney representing mesodermal; and liver representing endodermal origin); thus, metastable epiallele epigenetic profiles are likely set prior to germ layer differentiation.(7-9) To aid i…”
BackgroundWhy Are Genetics Important for Nutrition? Lessons from Epigenetic Research
Ruemmele, F. M., & Garnier‐Lengliné, H. (2012) · Annals of Nutrition and Metabolism · doi:10.1159/000337363 · Cited by 40
Mahmood, S., Smiraglia, D. J., Srinivasan, M., & Patel, M. S. (2013) · Journal of Developmental Origins of Health and Disease · doi:10.1017/s2040174413000238 · Cited by 44
“Supplementation of the maternal diet with methyl donors in the agouti mouse has been shown to shift the coat color of the offspring from yellow (agouti) to brown (pseudoagouti) with protection from the obesity phenotype.(34,35) In order to determine whether DNA methylation plays a role in the observed altered expressi…”
BackgroundDNA methylation program during development
Zhou, F. (2012) · Frontiers in Biology · doi:10.1007/s11515-012-9246-1 · Cited by 40
“(Waterland and Jirtle, 2003; Dolinoy et al., 2006).”
BackgroundNovel Epigenetic Biomarkers Mediating Bisphenol A Exposure and Metabolic Phenotypes in Female Mice
Anderson, O. S., Kim, J. H., Peterson, K. E., Sánchez, B. N., Sant, K. E., Sartor, M. A., Weinhouse, C., & Dolinoy, D. C. (2016) · Endocrinology · doi:10.1210/en.2016-1441 · Cited by 40
“Because of the plasticity of the epigenome (30), such strategies”
BackgroundBakulski, K. M., Dou, J., Thompson, R. C., Lee, C., Middleton, L. Y. M., Perera, B. P. U., Ferris, S. P., Jones, T. R., Neier, K. E., Zhou, X. Y., et al. (2020) · Toxicological Sciences · doi:10.1093/toxsci/kfaa069 · Cited by 42
“This results in forced heterozygosity on an invariant genetic background which is approximately 93% identical to the C57BL/6J strain (Waterland and Jirtle, 2003; Weinhouse et al., 2014).”
ResultZighelboim, I., Goodfellow, P. J., Schmidt, A. P., Walls, K. C., Mallon, M. A., Mutch, D. G., Yan, P. S., Huang, T. H. ‐., & Powell, M. A. (2007) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-06-2367 · Cited by 40
Genome-wide association studies in economics and entrepreneurship research: promises and limitations
Koellinger, P., van der Loos, M. J. H. M., Groenen, P. J. F., Thurik, R., Rivadeneira, F., van Rooij, F. J. A., Uitterlinden, A. G., & Albert Hofman, D. (2010) · Small Business Economics · doi:10.1007/s11187-010-9286-3 · Cited by 41
“For example, an experiment on agouti mice, which are yellow, fat, and susceptible to life-shortening diseases like cancer and diabetes, found that a change in diet of mother mice could have far-reaching consequences for their offspring (Waterland and Jirtle 2003).”
BackgroundPhylogenetic Footprint Analysis of IGF2 in Extant MammalsPreprint
Weidman, J. R., Murphy, S. K., Nolan, C. M., Dietrich, F. S., & Jirtle, R. L. (2004) · Genome Research · doi:10.1101/gr.2774804 · Cited by 40
“Sodium bisulfite modification of both opossum and platypus kidney and liver DNA was performed as previously described (Waterland and Jirtle 2003).”
MethodGrytten, J. I., Skau, I., & Sørensen, R. J. (2014) · Social Science & Medicine · doi:10.1016/j.socscimed.2014.01.008 · Cited by 39
“According to this hypothesis, negative environmental factors at a critical phase in the development of the fetus can influence the fetus’s genes causing a permanent change in the structure and function of the organs (Waterland & Jirtle, 2003, 2004).”
BackgroundFacioscapulohumeral Muscular Dystrophy As a Model for Epigenetic Regulation and Disease
Himeda, C. L., Jones, T. I., & Jones, P. L. (2014) · Antioxidants and Redox Signaling · doi:10.1089/ars.2014.6090 · Cited by 37
“Indeed, environmental factors have been shown to drive major epigenetic changes, as in the case of fetal alcohol syndrome, in which alcohol alters developmental patterns of DNA methylation (126), and maternal diet, which can affect the methylation and expression status of a metastable epiallele in mice (166).”
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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