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 mice carrying the Avy allele, there is a correlation between DNA methylation at the promoter and silencing of the gene.
“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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Epigenetic gene regulation: Linking early developmental environment to adult disease
Dolinoy, D. C., Weidman, J. R., & Jirtle, R. L. (2006) · Reproductive Toxicology · doi:10.1016/j.reprotox.2006.08.012 · Cited by 494 · see citing works
“Maternal dietary supplementation with methyl donors such as folic acid, choline, and betaine [ 34 ] or the phytoestrogen, genistein [32], shifts the coat color of the offspring from yellow to brown, and reduces the incidence of obesity, diabetes, and cancer.”
BackgroundMethodInfluentialCancer chemoprevention by dietary polyphenols: Promising role for epigenetics
Link, A., Balaguer, F., & Goel, A. (2010) · Biochemical Pharmacology · doi:10.1016/j.bcp.2010.06.036 · Cited by 500 · see citing works
“A higher proportion of offspring with wild type coat color were obtained from supplemented dams, which was consistent with higher levels of DNA methylation of the agouti gene [59,60].”
ResultFood as exposure: Nutritional epigenetics and the new metabolism
Landecker, H. L. (2011) · BioSocieties · doi:10.1057/biosoc.2011.1 · Cited by 498 · see citing works
“…with or stripped of ‘nutrients likely to enrich the pool of methyl donors and vitamin cofactors required for methylation’ such as folic acid, betaine, choline, methionine, given to pregnant mice, lead to offspring that are thinner and browner (Waterland and Jirtle, 2003; Rosenfeld, 2010, p. 478).”
BackgroundMaternal methyl supplements increase offspring DNA methylation at <i>Axin fused</i>
Waterland, R. A., Dolinoy, D. C., Lin, J., Smith, C. A., Shi, X., & Tahiliani, K. G. (2006) · genesis · doi:10.1002/dvg.20230 · Cited by 480 · see citing works
“Bisulfite modification was performed as previously described (Waterland and Jirtle, 2003), except that deamination was carried out at 558C for 3 h instead of 4 h. Bisulfite-modified genomic DNA from AxinFu/þ animals (2 ll) was PCR-amplified in 50-ll reactions with Platinum Taq DNA polymerase…”
BackgroundMethodInfluentialGluckman, P. D., Hanson, M. A., Spencer, H. G., & Bateson, P. (2005) · Proceedings of the Royal Society B: Biological Sciences · doi:10.1098/rspb.2004.3001 · Cited by 479 · see citing works
“For instance, manipulation of maternal dietary methyl group provision in agouti mice around conception alters the degree of DNA methylation at the agouti locus in the pre-implantation embryo and the colour of the subsequently developing coat (Wolff et al. 1998; Waterland & Jirtle 2003).”
BackgroundSun, Y. V., & Hu, Y.-J. (2016) · Advances in Genetics · doi:10.1016/bs.adgen.2015.11.004 · Cited by 459 · see citing works
“…environmental (e.g. smoking (Breitling, Yang, Korn, Burwinkel, & Brenner, 2011; Shenker et al.; Sun, 2014; Sun, Smith, et al., 2013), poor nutrition(Waterland & Jirtle, 2003), genetic factors (Sun, 2014; D. Zhang et al., 2010), and age – all well known risk factors human diseases (Bocklandt et…”
Essex, M. J., Thomas Boyce, W., Hertzman, C., Lam, L. L., Armstrong, J. M., Neumann, S. M. A., & Kobor, M. S. (2013) · Child Development · doi:10.1111/j.1467-8624.2011.01641.x · Cited by 462 · see citing works
The Fetal Matrix: Evolution, Development and Disease
Gluckman, P., & Hanson, M. (2004) · doi:10.1017/cbo9781139106955 · Cited by 460 · see citing works
Epigenetic Transgenerational Actions of Endocrine Disruptors
Anway, M. D., & Skinner, M. K. (2006) · Endocrinology · doi:10.1210/en.2005-1058 · Cited by 455 · see citing works
Season of Conception in Rural Gambia Affects DNA Methylation at Putative Human Metastable Epialleles
Waterland, R. A., Kellermayer, R., Laritsky, E., Rayco‐Solon, P., Harris, R. A., Travisano, M., Zhang, W., Torskaya, M. S., Zhang, J., Shen, L., et al. (2010) · PLoS Genetics · doi:10.1371/journal.pgen.1001252 · Cited by 454 · see citing works
“We devised a human genome-scale screening approach based on a definitive characteristic of murine MEs: systemic interindividual variation in DNA methylation [11,12].”
MethodAn integrated epigenetic and genetic approach to common human disease
BJORNSSON, H. (2004) · Trends in Genetics · doi:10.1016/j.tig.2004.06.009 · Cited by 448 · see citing works
Jansson, T., & Powell, T. L. (2007) · Clinical Science · doi:10.1042/cs20060339 · Cited by 542 · see citing works
Plagemann, A., Harder, T., Brunn, M., Harder, A., Roepke, K., Wittrock‐Staar, M., Ziska, T., Schellong, K., Rodekamp, E., Melchior, K., et al. (2009) · The Journal of Physiology · doi:10.1113/jphysiol.2009.176156 · Cited by 439 · see citing works
“…in none of the most prominent studies on DNA methylation in models of perinatal programming was the specific type of cells from which the DNA probes came considered (Waterland & Jirtle, 2003; Weaver et al. 2004; Bogdarina et al. 2007; Park et al. 2008; Lillycrop et al. 2008; McGowan et al. 2009).”
BackgroundAging and epigenetic drift: a vicious cycle
Issa, J.-P. (2014) · Journal of Clinical Investigation · doi:10.1172/jci69735 · Cited by 419 · see citing works
“Indeed, gestational exposure to high levels of folate and vitamin B12 can increase locusspecific DNA methylation patterns in newborn mice (66), and population variation at specific sites in newborns has been linked to month of conception in a study that shows marked seasonal variation in dietary habits (67).”
Phenotypic differences in genetically identical organisms: the epigenetic perspective.
Wong, A., Gottesman, I., & Petronis, A. (2005) · Human Molecular Genetics · doi:10.1093/hmg/ddi116 · Cited by 438 · see citing works
Drake, A. J., & Walker, B. (2004) · Journal of Endocrinology · doi:10.1677/joe.0.1800001 · Cited by 430 · see citing works
In utero supplementation with methyl donors enhances allergic airway disease in mice
Hollingsworth, J. W., Maruoka, S., Boon, K., Garantziotis, S., Li, Z., Tomfohr, J. K., Bailey, N., Potts, E. N., Whitehead, G. S., Brass, D. M., et al. (2016) · Journal of Clinical Investigation · doi:10.1172/jci87742 · Cited by 424 · see citing works
RetractedPaternally induced transgenerational inheritance of susceptibility to diabetes in mammals
Wei, Y., Yang, C.-R., Wei, Y.-P., Zhao, Z.-A., Hou, Y., Schatten, H., & Sun, Q.-Y. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1321195111 · Cited by 423 · see citing works
“As cytosine methylation is a widespread DNA modification that carries heritable information between generations (6, 18), we therefore turned to genome-wide studies to search for differentially methylated loci between control and prediabetic offspring.”
BackgroundFolate and colorectal cancer: An evidence‐based critical review
Kim, Y. (2007) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.200600191 · Cited by 422 · see citing works
Associations with early-life socio-economic position in adult DNA methylation
Borghol, N., Suderman, M. J., McArdle, W. L., Racine, A., Hallett, M. T., Pembrey, M. E., Hertzman, C., Power, C., & Moshe Szyf, A. (2011) · International Journal of Epidemiology · doi:10.1093/ije/dyr147 · Cited by 415 · see citing works
Epigenetics at the Epicenter of Modern Medicine
Feinberg, A. P. (2008) · JAMA · doi:10.1001/jama.299.11.1345 · Cited by 414 · see citing works
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 · see citing works
“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 414 · see citing works
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 · see citing works
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 409 · see citing works
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 · see citing works
Epigenetics and cardiovascular disease
Ordovás, J. M., & Smith, C. E. (2010) · Nature Reviews Cardiology · doi:10.1038/nrcardio.2010.104 · Cited by 402 · see citing works
“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 · see citing works
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 399 · see citing works
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 396 · see citing works
Moffitt, T. E., Caspi, A., & Rutter, M. (2006) · Perspectives on Psychological Science · doi:10.1111/j.1745-6916.2006.00002.x · Cited by 389 · see citing works
“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 · see citing works
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 388 · see citing works
“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 · see citing works
“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 385 · see citing works
“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 377 · see citing works
“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 381 · see citing works
“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 · see citing works
“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 371 · see citing works
“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).”
BackgroundMaternal 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 372 · see citing works
Nutrition, 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 · see citing works
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 365 · see citing works
“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 361 · see citing works
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 · see citing works
“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 354 · see citing works
“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
- 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 › Medicine › Rheumatology › 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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