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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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Variation in DNA Methylation in Avian Nestlings Is Largely Determined by Genetic Effects
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“…2020), the type of rearing environment (Morán et al. 2013; Venney et al. 2021), brood size (Sheldon et al. 2018; Sepers et al. 2021), parental care (Weaver et al. 2004), nutrition (Waterland and Jirtle 2003; Sandovici et al. 2011), and pollutant exposure (Laine et al. 2021; Mäkinen et al. 2022).”
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“Supplementation of maternal diet with methyl cycle donors and cofactors, including choline, folic acid and vitamin B12, increases methylation levels resulting in a coat colour shift in offspring towards the pseudo-agouti brown associated with CpG methylation, and thus silencing, of the IAP repetitive element within th…”
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Kussmann, M., Morine, M. J., Hager, J., Sonderegger, B., & Kaput, J. (2013) · Frontiers in Genetics · doi:10.3389/fgene.2013.00205 · Cited by 33
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Kumaran, K., Yajnik, P., Lubree, H., Joglekar, C. V., Bhat, D., Katre, P. A., Joshi, S. M., Ladkat, R., Fall, C. H. D., & Yajnik, C. S. (2017) · BMC Nutrition · doi:10.1186/s40795-017-0143-5 · Cited by 37
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Clark, J., Martin, E. M., Bulka, C. M., Smeester, L., Junior, H. P. D. O. S., O’Shea, T. M., & Fry, R. C. (2019) · Epigenetics · doi:10.1080/15592294.2019.1633865 · Cited by 35
You are affected by what your parents eat: Diet, epigenetics, transgeneration and intergeneration
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The link among microbiota, epigenetics, and disease development
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Nutritional Status Impacts Epigenetic Regulation in Early Embryo Development: A Scoping Review
Cai, S., Quan, S., Yang, G., Chen, M., Ye, Q., Wang, G., Yu, H., Wang, Y., Qiao, S., & Zeng, X. (2021) · Advances in Nutrition · doi:10.1093/advances/nmab038 · Cited by 36
“(164) found that exposure of agouti mice to methyl donors (such as folic acid, choline, and betaine)”
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Concordance for IBD among twins compared to ordinary siblings — A Norwegian population-based study
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On the Evolution of Mutation in Changing Environments: Recombination and Phenotypic Switching
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“They are capable of altering gene expression [Comb and Goodman, 1990; Nan et al., 1998], and can be induced in utero [Waterland and Jirtle, 2003].”
BackgroundMouse Models of Epigenetic Inheritance
Bernal, A. J., Murphy, S. K., & Jirtle, R. L. (2010) · Elsevier eBooks · doi:10.1016/b978-0-12-375709-8.00015-0 · Cited by 32
Anckaert, E., & Fair, T. (2015) · Reproduction Fertility and Development · doi:10.1071/rd14333 · Cited by 34
“Moreover, mouse studies showed that maternal dietary methyl donor levels affect DNA methylation levels in the offspring (Waterland and Jirtle 2003; Waterland et al. 2006; Sinclair et al. 2007).”
BackgroundThe integration of epigenetics and genetics in nutrition research for CVD risk factors
Ma, Y., & Ordovás, J. M. (2016) · Proceedings of The Nutrition Society · doi:10.1017/s0029665116000823 · Cited by 34
“In mice, supplementation of methyl donors during gestation was shown to have a dose–response relationship with the methylation of viable yellow agouti (A) locus and browness of coat colour in the offspring((45)).”
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BackgroundInfluentialGenome-wide impact of hydrogen peroxide on maintenance DNA methylation in replicating cells
Seddon, A. R., Liau, Y., Pace, P., Miller, A. L., Das, A. B., Kennedy, M. A., Hampton, M. B., & Stevens, A. J. (2021) · Epigenetics & Chromatin · doi:10.1186/s13072-021-00388-6 · Cited by 34
The Effects of Early Prenatal Alcohol Exposure on Epigenome and Embryonic Development
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“Avy is a widely used “biosensor” to study the effects of environmental exposures on the epigenome [55,56].”
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“Inadequate maternal one-carbon donor intake during critical periods of early embryonic development has been linked to lower DNA methylation at the agouti locus [83], predisposing to adult obesity, diabetes, and cancer [84].”
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Market-Velker, B. A., Denomme, M. M., & Mann, M. R. W. (2012) · Methods in molecular biology · doi:10.1007/978-1-61779-971-6_23 · Cited by 33
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Yuasa, Y. (2010) · Advances in genetics · doi:10.1016/b978-0-12-380864-6.00007-9 · Cited by 32
Epigenetics and Obesity: A Relationship Waiting to Be Explained
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“In Agouti viable yellow (Avy) mice, increased intake of methyl donors and folic acid induced a graded switch in coat color by inducing increased methylation of a retrotransposon containing a cryptic promoter located proximal to the Agouti gene [11].”
Chromatin Modifications Associated With Diabetes and Obesity
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Weinhouse, C., Bergin, I. L., Harris, C., & Dolinoy, D. C. (2015) · Epigenetics · doi:10.1080/15592294.2015.1107694 · Cited by 33
“Mouse and human liver samples Mice were obtained from a colony generated by backcrossing C3H/HeJ mice carrying the viable yellow Agouti (A) allele with C57BL/6J mice, followed by >200 generations of sibling mating.(39) The A strain is isogenic(39) and has been empirically confirmed to be genetically 93% C57BL/6J.”
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“The archetypal example of the promise of epigenetic modification is the agouti mouse experiments by Jirtle and Waterland (Waterland and Jirtle, 2003).”
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“In the Avy mice, supplementation of methyl donors including folate during pregnancy increased DNA methylation of the agouti gene in the Avy offspring leading to a decrease in agouti expression and browning of the coat color [14,20].”
BackgroundDennis, C., Marini, F. C., Dick, J. A., Atkinson, S. A., Barrett, J., Bell, R. C., Bérard, A., Berger, H. M., Brown, H. K., Constantin, E., et al. (2021) · BMJ Open · doi:10.1136/bmjopen-2020-046311 · Cited by 35
Haggarty, P. (2012) · Progress in molecular biology and translational science · doi:10.1016/b978-0-12-398397-8.00016-2 · Cited by 32
“Classes of transposons include the long interspersed nuclear elements (LINE1), the intracisternal A particle, the short interspersed transposable nuclear elements (SINE), and the Alu family of human SINE elements.(24,25) Some transposon classes are able to move around the genome and have the potential to cause abnorma…”
BackgroundMaternal Prenatal Nutrition and Health in Grandchildren and Subsequent Generations
Susser, E., Kirkbride, J. B., Heijmans, B. T., Kresovich, J. K., Lumey, L. H., & Stein, A. D. (2010) · Annual Review of Anthropology · doi:10.1146/annurev-anthro-081309-145645 · Cited by 31
Effects of cobalt/vitamin B12 status in ewes on ovum development and lamb viability at birth
Mitchell, L. M., Robinson, J. J., Watt, R. G., McEvoy, T. G., Ashworth, C. J., Rooke, J. A., & Dwyer, C. M. (2007) · Reproduction Fertility and Development · doi:10.1071/rd07012 · Cited by 32
“In investigations, albeit involving laboratory species, supplementation of the maternal diet with methyl donors and cofactors such as vitamin B12, folate, choline and betaine has been shown to affect gene expression in the offspring, with implications for their long-term health and viability (Cooney et al. 2002; Water…”
BackgroundSaravanan, P., & Yajnik, C. S. (2010) · The British Journal of Diabetes · doi:10.1177/1474651409358015 · Cited by 32
Maternal folate status and obesity/insulin resistance in the offspring: a systematic review
Xie, R.-H., Liu, Y.-J., Retnakaran, R. R., MacFarlane, A. J., Hamilton, J., Smith, G. N., WALKER, M. C., & Wen, S. W. (2015) · International Journal of Obesity · doi:10.1038/ijo.2015.189 · Cited by 32
Nutritional Epigenetic Regulators in the Field of Cancer
Schnekenburger, M., & Diederich, M. F. (2015) · Elsevier eBooks · doi:10.1016/b978-0-12-800206-3.00018-5 · Cited by 35
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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