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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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“Both animal and human studies have shown that changes in the prenatal environment can lead to variations in epigenetic profiles [8–10].”
BackgroundThe role of environmental exposures and the epigenome in health and disease
Perera, B. P. U., Faulk, C. D., Svoboda, L. K., Goodrich, J. M., & Dolinoy, D. C. (2019) · Environmental and Molecular Mutagenesis · doi:10.1002/em.22311 · Cited by 91
“…diet, BPA, lead, and other dietary agents or environmental toxicants, all of which continue to impact the offspring’s health later in the life course (Waterland and Jirtle, 2003; Dolinoy et al., 2006; Dolinoy et al., 2007; Kaminen-Ahola et al., 2010; Bernal et al., 2013; Faulk et al., 2013b).”
BackgroundInfluentialHormesis and epigenetics: Is there a link?
Vaiserman, A. M. (2011) · Ageing Research Reviews · doi:10.1016/j.arr.2011.01.004 · Cited by 91
“…shifted the distribution of coat colour of the offspring from yellow (agouti) to brown (pseudo-agouti), which is associated with a reduction in their risk of developing obesity, diabete and cancer, and a prolonged life span compared to yellow mice (Wolff et al., 1998; Waterland and Jirtle, 2003).”
BackgroundEpigenetic variation and inheritance in mammals
Rakyan, V. K., & Beck, S. (2006) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2006.09.002 · Cited by 88
Developmental processes and the induction of cardiovascular function: conceptual aspects
Hanson, M. A., & Gluckman, P. D. (2005) · The Journal of Physiology · doi:10.1113/jphysiol.2004.082339 · Cited by 87
“…low protein diet or of glucocorticoid administration during pregnancy can be seen on cardiovascular function and on glucose homeostasis in the F2 offspring, even in the absence of an additional nutritional challenge during the pregnancy of the F1 offspring (Torrens et al. 2002; Drake et al. 2005).”
BackgroundPoulin, R., & Frédéric Thomas, A. (2007) · Oikos · doi:10.1111/j.2007.0030-1299.16435.x · Cited by 90
Epigenetic Mechanisms Affecting Regulation of Energy Balance: Many Questions, Few Answers
Waterland, R. A. (2014) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-071813-105315 · Cited by 90
Velázquez, R., Ferreira, E., Winslow, W., Dave, N., Piras, I. S., Naymik, M., Huentelman, M. J., Tran, A., Caccamo, A., & Oddo, S. (2019) · Molecular Psychiatry · doi:10.1038/s41380-018-0322-z · Cited by 87
“We also found a significant genotype by diet interaction for Hcy (F(1, 20) = 6.”
BackgroundResultInfluentialEpigenetics, aging, and autoimmunity
Yung, R. L., & Grolleau‐Julius, A. (2008) · Autoimmunity · doi:10.1080/08916930802024889 · Cited by 85
“Interestingly, maternal dietary methyl-donor supplementation shifts the offsprings’ coat colour towards the brown pseudo-agouti phenotype by methylating the epigenome [40].”
BackgroundHepatitis B viral DNA is methylated in liver tissues
Vivekanandan, P., Thomas, D. L., & Torbenson, M. S. (2007) · Journal of Viral Hepatitis · doi:10.1111/j.1365-2893.2007.00905.x · Cited by 87
Boiani, M., Gentile, L., Gambles, V., Cavaleri, F. M., Redi, C. A., & Schöler, H. R. (2005) · Stem Cells · doi:10.1634/stemcells.2004-0352 · Cited by 88
Mechanisms of non-Mendelian inheritance in genetic disease
van Heyningen, V. (2004) · Human Molecular Genetics · doi:10.1093/hmg/ddh254 · Cited by 92
“Biallelic IGF2 and H19 expression is frequently seen in some human tissues, without phenotypic abnormality, and it has been recently proposed that imprinting status may be modulated by environmental and nutritional factors (83).”
BackgroundA genomic point-of-view on environmental factors influencing the human brain methylome
LaSalle, J. M. (2011) · Epigenetics · doi:10.4161/epi.6.7.16353 · Cited by 89
The complex relationship between folate/homocysteine metabolism and risk of Down syndrome
Coppedè, F. (2009) · Mutation Research/Reviews in Mutation Research · doi:10.1016/j.mrrev.2009.06.001 · Cited by 86
“Interestingly, Waterland and Jirtle [135] observed that maternal methyl donor supplementation during gestation can alter the offspring phenotype by methylating the epigenome.”
BackgroundProvençal, N., Suderman, M. J., Guillemin, C., Vitaro, F., Côté, S. M., Hallett, M., Tremblay, R. E., & Szyf, M. (2014) · PLoS ONE · doi:10.1371/journal.pone.0089839 · Cited by 85
“There is a growing body of evidence suggesting that in addition to the innate endogenous processes sculpting the DNA methylation pattern during gestation, the DNA methylation pattern is responsive to external environmental exposures including the social environment during both intra-uterine development and after birth…”
BackgroundDNA Methylation Signature of Childhood Chronic Physical Aggression in T Cells of Both Men and Women
Guillemin, C., Provençal, N., Suderman, M. J., Côté, S. M., Vitaro, F., Hallett, M. T., Tremblay, R. E., & Szyf, M. (2014) · PLoS ONE · doi:10.1371/journal.pone.0086822 · Cited by 84
Johnson, W., Penke, L., & Spinath, F. M. (2011) · European Journal of Personality · doi:10.1002/per.836 · Cited by 106
Advances in pharmacogenomics and individualized drug therapy: exciting challenges that lie ahead
Nebert, D. W., & Vesell, E. S. (2004) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2004.07.031 · Cited by 84
Patti, M. (2013) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-013-1298-0 · Cited by 85
“Specifically, supplementation with methyl donors, including folic acid, vitamin B12, choline, and betaine, increased methylation, silenced the A locus, and darkened coat color [53].”
Ash, J. A., Velázquez, R., Kelley, C. M., Powers, B. E., Ginsberg, S. D., Mufson, E. J., & Strupp, B. J. (2014) · Neurobiology of Disease · doi:10.1016/j.nbd.2014.06.001 · Cited by 88
“Second, these effects may be related to epigeneticmodificationswith lasting effects on gene expression, secondary to choline's role as a methyl donor (Niculescu et al., 2004, 2006; Waterland and Jirtle, 2003; Zeisel, 2009).”
Long-lasting and transgenerational effects of an environmental enrichment on memory formation
Arai, J. A., & Feig, L. A. (2010) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2010.11.003 · Cited by 87
“Interestingly, maternal diet influences the epigenetic status of F1 offspring through the alteration of methylation of the AVY locus in utero [41,42].”
BackgroundThe emerging role of epigenetic mechanisms in the etiology of neural tube defects
Greene, N. D. E., Stanier, P., & Moore, G. E. (2011) · Epigenetics · doi:10.4161/epi.6.7.16400 · Cited by 88
Human metastable epiallele candidates link to common disorders
Harris, R. A., Nagy‐Szakal, D., & Kellermayer, R. (2013) · Epigenetics · doi:10.4161/epi.23438 · Cited by 84
Burdge, G. C., Lillycrop, K. A., & Jackson, A. A. (2008) · British Journal Of Nutrition · doi:10.1017/s0007114508145883 · Cited by 87
“Promoter methylation is important for asymmetrical silencing of imprinted genes((92)) and retrotransposons((93,94)).”
Fu, V. X., Dobosy, J. R., Desotelle, J. A., Almassi, N., Ewald, J. A., Srinivasan, R., Berres, M. E., Svaren, J. P., Weindruch, R. H., & Jarrard, D. F. (2008) · Cancer Research · doi:10.1158/0008-5472.can-08-1714 · Cited by 85
“Several factors implicated in aging may play a role in this LOI including oxidative stress, diet, hormones, and environmental toxicants (7, 8, 28).”
Sie, K. K. Y., Medline, A., van Weel, J., Sohn, K., Choi, S., Croxford, R., & Kim, Y. (2011) · Gut · doi:10.1136/gut.2011.238782 · Cited by 85
Martos, S. N., Tang, W., & Wang, Z. (2015) · Progress in Biophysics and Molecular Biology · doi:10.1016/j.pbiomolbio.2015.02.011 · Cited by 84
“Gestational methyl supplementation-induced phenotypic changes correlated with the degree of CpG methylation at the IAP insertion site (Waterland and Jirtle, 2003).”
BackgroundTran, P. V., Kennedy, B. C., Pisansky, M. T., Won, K., Gewirtz, J. C., Simmons, R. A., & Georgieff, M. (2016) · Journal of Nutrition · doi:10.3945/jn.115.227561 · Cited by 84
“One potential mechanism is stable epigenetic modifications across the genome (31, 62, 63).”
BackgroundCandler, T. P., Kühnen, P., Prentice, A. M., & Silver, M. J. (2019) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2019.100773 · Cited by 86
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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