Key Points
-
Epigenetics is the study of variations in gene function (phenotypes) that are somatically heritable (and sometimes also from one generation to the next), but which are not caused by genetic alterations.
-
In plants and animals, different epigenetic modifications, including DNA methylation, can have long-term effects on gene expression.
-
The environment affects gene expression and phenotypes, both in plants and animals. Although it triggers natural developmental processes in some species, it often has deleterious effects that have consequences for development and disease.
-
Different environmental cues (such as nutrition, chemical compounds, temperature changes and other stresses) can affect phenotypes and epigenetic gene regulation in experimental model systems.
-
A growing number of human studies have demonstrated long-term effects as a consequence of diet, exposure to chemical components and other external factors. The effects are particularly apparent when exposure to the environmental factor occurs during gestation.
-
For many environmentally induced phenotypes, particularly in humans, it remains unclear to what extent epigenetic modifications could be involved. This is a challenge for future research.
-
Genetic differences between individuals influence epigenetic deregulation, and possibly also susceptibility to environmental stresses.
Abstract
Epigenetic phenomena in animals and plants are mediated by DNA methylation and stable chromatin modifications. There has been considerable interest in whether environmental factors modulate the establishment and maintenance of epigenetic modifications, and could thereby influence gene expression and phenotype. Chemical pollutants, dietary components, temperature changes and other external stresses can indeed have long-lasting effects on development, metabolism and health, sometimes even in subsequent generations. Although the underlying mechanisms remain largely unknown, particularly in humans, mechanistic insights are emerging from experimental model systems. These have implications for structuring future research and understanding disease and development.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Henikoff, S. & Shilatifard, A. Histone modification: cause or cog? Trends Genet. 27, 389–396 (2011).
Law, J. A. & Jacobsen, S. E. Establishing, maintaining and modifying DNA methylation patterns in plants and animals. Nature Rev. Genet. 11, 204–220 (2010).
Russo, V. E. A., Martienssen, R. A. & Riggs, A. D. Epigenetic Mechanisms of Gene Regulation, (Cold Spring Harbor Laboratory Press, New York, 1996).
Kota, S. K. & Feil, R. Epigenetic transitions in germ cell development and meiosis. Dev. Cell 19, 675–686 (2010).
Okano, M., Bell, D. W., Haber, D. A. & Li, E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99, 247–257 (1999).
Reik, W. Stability and flexibility of epigenetic gene regulation in mammalian development. Nature 447, 425–432 (2007).
Bjornsson, H. T. et al. Intra-individual change over time in DNA methylation with familial clustering. JAMA 299, 2877–2883 (2008).
Fraga, M. F. Genetic and epigenetic regulation of aging. Curr. Opin. Immunol. 21, 446–453 (2009).
Fraga, M. F. et al. Epigenetic differences arise during the lifetime of monozygotic twins. Proc. Natl Acad. Sci. USA 102, 10604–10609 (2005).
Wong, C. C. et al. A longitudinal study of epigenetic variation in twins. Epigenetics 5, 516–526 (2010).
Borgel, J. et al. Targets and dynamics of promoter DNA methylation during early mouse development. Nature Genet. 42, 1093–1100 (2010).
Zhou, V. W., Goren, A. & Bernstein, B. E. Charting histone modifications and the functional organization of mammalian genomes. Nature Rev. Genet. 12, 7–18 (2011).
Pauli, A., Rinn, J. L. & Schier, A. F. Non-coding RNAs as regulators of embryogenesis. Nature Rev. Genet. 12, 136–149 (2011).
Ito, H. et al. An siRNA pathway prevents transgenerational retrotransposition in plants subjected to stress. Nature 472, 115–119 (2011). This study explores the role of the siRNA pathway in preventing the transgenerational genetic effects of stress-induced alterations in plants.
Mirouze, M. & Paszkowski, J. Epigenetic contribution to stress adaptation in plants. Curr. Opin. Plant Biol. 14, 267–274 (2011).
Jirtle, R. L. & Skinner, M. K. Environmental epigenomics and disease susceptibility. Nature Rev. Genet. 8, 253–262 (2007).
Borrelli, E., Nestler, E. J., Allis, C. D. & Sassone-Corsi, P. Decoding the epigenetic language of neuronal plasticity. Neuron 60, 961–974 (2008).
Hackman, D. A., Farah, M. J. & Meaney, M. J. Socioeconomic status and the brain: mechanistic insights from human and animal research. Nature Rev. Neurosci. 11, 651–659 (2010).
Simon, J. C., Pfrender, M. E., Tollrian, R., Tagu, D. & Colbourne, J. K. Genomics of environmentally induced phenotypes in 2 extremely plastic arthropods. J. Hered. 102, 512–525 (2011).
Kucharski, R., Maleszka, J., Foret, S. & Maleszka, R. Nutritional control of reproductive status in honeybees via DNA methylation. Science 319, 1827–1830 (2008). This study provides evidence that the nutrition-dependent phenotype determination in honey bees is highly dependent on DNA methylation.
Lyko, F. et al. The honey bee epigenomes: differential methylation of brain DNA in queens and workers. PLoS Biol. 8, e1000506 (2010).
Khosla, S., Mendiratta, G. & Brahmachari, V. Genomic imprinting in the mealybugs. Cytogenet. Genome Res. 113, 41–52 (2006).
Sanchez, L. Sciara as an experimental model for studies on the evolutionary relationships between the zygotic, maternal and environmental primary signals for sexual development. J. Genet. 89, 325–331 (2010).
Marshall Graves, J. A. Weird animal genomes and the evolution of vertebrate sex and sex chromosomes. Annu. Rev. Genet. 42, 565–586 (2008).
Chinnusamy, V. & Zhu, J. K. Epigenetic regulation of stress responses in plants. Curr. Opin. Plant Biol. 12, 133–139 (2009).
Kim, D. H., Doyle, M. R., Sung, S. & Amasino, R. M. Vernalization: winter and the timing of flowering in plants. Annu. Rev. Cell Dev. Biol. 25, 277–299 (2009).
Cubas, P., Vincent, C. & Coen, E. An epigenetic mutation responsible for natural variation in floral symmetry. Nature 401, 157–161 (1999).
Herrera, C. M. & Bazaga, P. Epigenetic differentiation and relationship to adaptive genetic divergence in discrete populations of the violet Viola cazorlensis. New Phytol. 187, 867–876 (2010).
Paun, O. et al. Stable epigenetic effects impact adaptation in allopolyploid orchids (Dactylorhiza: Orchidaceae). Mol. Biol. Evol. 27, 2465–2473 (2010).
Lira-Medeiros, C. F. et al. Epigenetic variation in mangrove plants occurring in contrasting natural environment. PLoS ONE 5, e10326 (2010).
Martin, A. et al. A transposon-induced epigenetic change leads to sex determination in melon. Nature 461, 1135–1138 (2009).
Verhoeven, K. J., Jansen, J. J., van Dijk, P. J. & Biere, A. Stress-induced DNA methylation changes and their heritability in asexual dandelions. New Phytol. 185, 1108–1118 (2010). Using genetically identical plants as experimental models, this study identified generalized stress-associated epigenetic changes and showed that they are frequently transmitted to the next generation.
Paszkowski, J. & Grossniklaus, U. Selected aspects of transgenerational epigenetic inheritance and resetting in plants. Curr. Opin. Plant Biol. 14, 195–203 (2011).
Rosenfeld, C. S. Animal models to study environmental epigenetics. Biol. Reprod. 82, 473–488 (2010).
Rakyan, V. K., Blewitt, M. E., Druker, R., Preis, J. I. & Whitelaw, E. Metastable epialleles in mammals. Trends Genet. 18, 348–351 (2002).
Daxinger, L. & Whitelaw, E. Transgenerational epigenetic inheritance: more questions than answers. Genome Res. 20, 1623–1628 (2010).
Gluckman, P. D., Hanson, M. A., Buklijas, T., Low, F. M. & Beedle, A. S. Epigenetic mechanisms that underpin metabolic and cardiovascular diseases. Nature Rev. Endocrinol. 5, 401–408 (2009).
Heijmans, B. T. et al. Persistent epigenetic differences associated with prenatal exposure to famine in humans. Proc. Natl Acad. Sci. USA 105, 17046–17049 (2008).
Tobi, E. W. et al. DNA methylation differences after exposure to prenatal famine are common and timing- and sex-specific. Hum. Mol. Genet. 18, 4046–4053 (2009).
Waterland, R. A. et al. Season of conception in rural gambia affects DNA methylation at putative human metastable epialleles. PLoS Genet. 6, e1001252 (2010). This study identifies for the first time putative metastable epialleles in humans, and shows how their methylation status is influenced by nutritional conditions during gestation.
Ferguson-Smith, A. C. Genomic imprinting: the emergence of an epigenetic paradigm. Nature Rev. Genet. 12, 565–575 (2011).
Hirasawa, R. & Feil, R. Genomic imprinting and human disease. Essays Biochem. 48, 187–200 (2010).
Khosla, S., Dean, W., Brown, D., Reik, W. & Feil, R. Culture of preimplantation mouse embryos affects fetal development and the expression of imprinted genes. Biol. Reprod. 64, 918–926 (2001).
Waterland, R. A. & Jirtle, R. L. Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Mol. Cell. Biol. 23, 5293–5300 (2003).
Sandovici, I. et al. Maternal diet and aging alter the epigenetic control of a promoter-enhancer interaction at the Hnf4a gene in rat pancreatic islets. Proc. Natl Acad. Sci. USA 108, 5449–5454 (2011).
Aagaard-Tillery, K. M. et al. Developmental origins of disease and determinants of chromatin structure: maternal diet modifies the primate fetal epigenome. J. Mol. Endocrinol. 41, 91–102 (2008).
Gallou-Kabani, C. et al. Sex- and diet-specific changes of imprinted gene expression and DNA methylation in mouse placenta under a high-fat diet. PLoS ONE 5, e14398 (2010).
Sinclair, K. D. et al. DNA methylation, insulin resistance, and blood pressure in offspring determined by maternal periconceptional B vitamin and methionine status. Proc. Natl Acad. Sci. USA 104, 19351–19356 (2007). This broad study reports epigenetic and physiological alterations in the offspring of sheep that were fed diets poor in compounds that are involved in methyl-donor pathways.
Lillycrop, K. A., Phillips, E. S., Jackson, A. A., Hanson, M. A. & Burdge, G. C. Dietary protein restriction of pregnant rats induces and folic acid supplementation prevents epigenetic modification of hepatic gene expression in the offspring. J. Nutr. 135, 1382–1386 (2005).
Carone, B. R. et al. Paternally induced transgenerational environmental reprogramming of metabolic gene expression in mammals. Cell 143, 1084–1096 (2010).
Hales, C. N. & Barker, D. J. The thrifty phenotype hypothesis. Br. Med. Bull. 60, 5–20 (2001).
Hoyo, C. et al. Methylation variation at IGF2 differentially methylated regions and maternal folic acid use before and during pregnancy. Epigenetics 6, 928–936 (2011).
Steegers-Theunissen, R. P. et al. Periconceptional maternal folic acid use of 400 microg per day is related to increased methylation of the IGF2 gene in the very young child. PLoS ONE 4, e7845 (2009).
Baccarelli, A. et al. Rapid DNA methylation changes after exposure to traffic particles. Am. J. Respir. Crit. Care Med. 179, 572–578 (2009).
Bollati, V. et al. Changes in DNA methylation patterns in subjects exposed to low-dose benzene. Cancer Res. 67, 876–880 (2007).
Calvanese, V. et al. A promoter DNA demethylation landscape of human hematopoietic differentiation. Nucleic Acids Res. 12 Sep 2011 (doi:10.1093/nar/gkr685).
Christensen, B. C. et al. Aging and environmental exposures alter tissue-specific DNA methylation dependent upon CpG island context. PLoS Genet. 5, e1000602 (2009).
Langevin, S. M. et al. The influence of aging, environmental exposures and local sequence features on the variation of DNA methylation in blood. Epigenetics 6, 908–919 (2011).
Grönniger, E. et al. Aging and chronic sun exposure cause distinct epigenetic changes in human skin. PLoS Genet. 6, e1000971 (2010). This epidemiological study explored the epigenetic effects of sun exposure on the skin and compared these observed differences with those that arose on ageing.
Belinsky, S. A. et al. Aberrant promoter methylation in bronchial epithelium and sputum from current and former smokers. Cancer Res. 62, 2370–2377 (2002). This study established for the first time the association between smoking and aberrant hypermethylation of tumour suppressor genes in non-transformed lung cells.
Breitling, L. P., Yang, R., Korn, B., Burwinkel, B. & Brenner, H. Tobacco-smoking-related differential DNA methylation: 27K discovery and replication. Am. J. Hum. Genet. 88, 450–457 (2011).
Dean, W. et al. Altered imprinted gene methylation and expression in completely ES cell-derived mouse fetuses: association with aberrant phenotypes. Development 125, 2273–2282 (1998).
Doherty, A. S., Mann, M. R., Tremblay, K. D., Bartolomei, M. S. & Schultz, R. M. Differential effects of culture on imprinted H19 expression in the preimplantation mouse embryo. Biol. Reprod. 62, 1526–1535 (2000).
Young, L. E. et al. Epigenetic change in IGF2R is associated with fetal overgrowth after sheep embryo culture. Nature Genet. 27, 153–154 (2001).
Pecinka, A. et al. Epigenetic regulation of repetitive elements is attenuated by prolonged heat stress in Arabidopsis. Plant Cell 22, 3118–3129 (2010).
Law, R. D. & Suttle, J. C. Chromatin remodeling in plant cell culture: patterns of DNA methylation and histone H3 and H4 acetylation vary during growth of asynchronous potato cell suspensions. Plant Physiol. Biochem. 43, 527–534 (2005).
Jullien, P. E. & Berger, F. DNA methylation reprogramming during plant sexual reproduction? Trends Genet. 26, 394–399 (2010).
Teixeira, F. K. & Colot, V. Repeat elements and the Arabidopsis DNA methylation landscape. Heredity 105, 14–23 (2010).
Yauk, C. et al. Germ-line mutations, DNA damage, and global hypermethylation in mice exposed to particulate air pollution in an urban/industrial location. Proc. Natl Acad. Sci. USA 105, 605–610 (2008).
Johannes, F. et al. Assessing the impact of transgenerational epigenetic variation on complex traits. PLoS Genet. 5, e1000530 (2009).
Richards, E. J. Natural epigenetic variation in plant species: a view from the field. Curr. Opin. Plant Biol. 14, 204–209 (2011).
Manning, K. et al. A naturally occurring epigenetic mutation in a gene encoding an SBP-box transcription factor inhibits tomato fruit ripening. Nature Genet. 38, 948–952 (2006).
Saze, H. & Kakutani, T. Heritable epigenetic mutation of a transposon-flanked Arabidopsis gene due to lack of the chromatin-remodeling factor DDM1. EMBO J. 26, 3641–3652 (2007).
Teixeira, F. K. et al. A role for RNAi in the selective correction of DNA methylation defects. Science 323, 1600–1604 (2009).
Sasaki, H. & Matsui, Y. Epigenetic events in mammalian germ-cell development: reprogramming and beyond. Nature Rev. Genet. 9, 129–140 (2008).
Schmitz, R. J. et al. Transgenerational epigenetic instability is a source of novel methylation variants. Science 334, 369–373 (2011).
Ingouff, M. et al. Zygotic resetting of the HISTONE 3 variant repertoire participates in epigenetic reprogramming in Arabidopsis. Curr. Biol. 20, 2137–2143 (2010).
Lane, N. et al. Resistance of IAPs to methylation reprogramming may provide a mechanism for epigenetic inheritance in the mouse. Genesis 35, 88–93 (2003).
Morgan, H. D., Sutherland, H. G., Martin, D. I. & Whitelaw, E. Epigenetic inheritance at the agouti locus in the mouse. Nature Genet. 23, 314–318 (1999).
Blewitt, M. E., Vickaryous, N. K., Paldi, A., Koseki, H. & Whitelaw, E. Dynamic reprogramming of DNA methylation at an epigenetically sensitive allele in mice. PLoS Genet. 2, e49 (2006).
Anway, M. D., Cupp, A. S., Uzumcu, M. & Skinner, M. K. Epigenetic transgenerational actions of endocrine disruptors and male fertility. Science 308, 1466–1469 (2005).
Stouder, C. & Paoloni-Giacobino, A. Transgenerational effects of the endocrine disruptor vinclozolin on the methylation pattern of imprinted genes in the mouse sperm. Reproduction 139, 373–379 (2010).
Guerrero-Bosagna, C., Settles, M., Lucker, B. & Skinner, M. K. Epigenetic transgenerational actions of vinclozolin on promoter regions of the sperm epigenome. PLoS ONE 5, e13100 (2010).
Stouder, C. & Paoloni-Giacobino, A. Specific transgenerational imprinting effects of the endocrine disruptor methoxychlor on male gametes. Reproduction 141, 207–216 (2011).
Brykczynska, U. et al. Repressive and active histone methylation mark distinct promoters in human and mouse spermatozoa. Nature Struct. Mol. Biol. 17, 679–687 (2010).
Hammoud, S. S. et al. Distinctive chromatin in human sperm packages genes for embryo development. Nature 460, 473–478 (2009).
Greer, E. L. et al. Transgenerational epigenetic inheritance of longevity in Caenorhabditis elegans. Nature 479, 365–371 (2011).
Kumar, S. V. & Wigge, P. A. H2A.Z-containing nucleosomes mediate the thermosensory response in Arabidopsis. Cell 140, 136–147 (2010).
De Lucia, F., Crevillen, P., Jones, A. M., Greb, T. & Dean, C. A PHD-polycomb repressive complex 2 triggers the epigenetic silencing of FLC during vernalization. Proc. Natl Acad. Sci. USA 105, 16831–16836 (2008).
Swiezewski, S., Liu, F., Magusin, A. & Dean, C. Cold-induced silencing by long antisense transcripts of an Arabidopsis Polycomb target. Nature 462, 799–802 (2009).
Seong, K. H., Li, D., Shimizu, H., Nakamura, R. & Ishii, S. Inheritance of stress-induced, ATF-2-dependent epigenetic change. Cell 145, 1049–1061 (2011). This study describes an epigenetic, environmentally triggered phenotype in fruit flies that can be transgenerationally transmitted.
Cavalli, G. & Paro, R. The Drosophila Fab-7 chromosomal element conveys epigenetic inheritance during mitosis and meiosis. Cell 93, 505–518 (1998).
Chandler, V. L. Paramutation's properties and puzzles. Science 330, 628–629 (2010).
Jia, S., Noma, K. & Grewal, S. I. RNAi-independent heterochromatin nucleation by the stress-activated ATF/CREB family proteins. Science 304, 1971–1976 (2004).
Wolff, G. L., Kodell, R. L., Moore, S. R. & Cooney, C. A. Maternal epigenetics and methyl supplements affect agouti gene expression in Avy/a mice. FASEB J. 12, 949–957 (1998).
Kaminen-Ahola, N. et al. Maternal ethanol consumption alters the epigenotype and the phenotype of offspring in a mouse model. PLoS Genet. 6, e1000811 (2010).
Dolinoy, D. C., Weidman, J. R., Waterland, R. A. & Jirtle, R. L. Maternal genistein alters coat color and protects Avy mouse offspring from obesity by modifying the fetal epigenome. Environ. Health Perspect. 114, 567–572 (2006).
Ross, S. A. & Milner, J. A. Epigenetic modulation and cancer: effect of metabolic syndrome? Am. J. Clin. Nutr. 86, s872–s877 (2007).
Dolinoy, D. C., Huang, D. & Jirtle, R. L. Maternal nutrient supplementation counteracts bisphenol A-induced DNA hypomethylation in early development. Proc. Natl Acad. Sci. USA 104, 13056–13061 (2007). This work shows that nutritional interventions during gestation can counteract some deleterious epigenetic effects that are induced by specific endocrine disruptors during embryonic development.
Weinhouse, C. et al. An expression microarray approach for the identification of metastable epialleles in the mouse genome. Epigenetics 6, 1105–1113 (2011).
Dashwood, R. H. & Ho, E. Dietary histone deacetylase inhibitors: from cells to mice to man. Semin. Cancer Biol. 17, 363–369 (2007).
Zhou, W. et al. Requirement of RIZ1 for cancer prevention by methyl-balanced diet. PLoS ONE 3, e3390 (2008).
Imai, S., Armstrong, C. M., Kaeberlein, M. & Guarente, L. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature 403, 795–800 (2000).
Vaquero, A. et al. Human SirT1 interacts with histone H1 and promotes formation of facultative heterochromatin. Mol. Cell 16, 93–105 (2004).
Peng, L. et al. SIRT1 Deacetylates the DNA methyltransferase 1 (DNMT1) protein and alters its activities. Mol. Cell. Biol. 31, 4720–4734 (2011).
Vaquero, A. & Reinberg, D. Calorie restriction and the exercise of chromatin. Genes Dev. 23, 1849–1869 (2009).
Bosch-Presegue, L. et al. Stabilization of Suv39H1 by SirT1 is part of oxidative stress response and ensures genome protection. Mol. Cell 42, 210–223 (2011).
Rodgers, J. T. et al. Nutrient control of glucose homeostasis through a complex of PGC-1α and SIRT1. Nature 434, 113–118 (2005).
Beher, D. et al. Resveratrol is not a direct activator of SIRT1 enzyme activity. Chem. Biol. Drug Des. 74, 619–624 (2009).
Kaeberlein, M. et al. Substrate-specific activation of sirtuins by resveratrol. J. Biol. Chem. 280, 17038–17045 (2005).
El-Maarri, O. et al. Gender specific differences in levels of DNA methylation at selected loci from human total blood: a tendency toward higher methylation levels in males. Hum. Genet. 122, 505–514 (2007).
Waxman, D. J. & O'Connor, C. Growth hormone regulation of sex-dependent liver gene expression. Mol. Endocrinol. 20, 2613–2629 (2006).
Kaminsky, Z. A. et al. DNA methylation profiles in monozygotic and dizygotic twins. Nature Genet. 41, 240–245 (2009).
Ollikainen, M. et al. DNA methylation analysis of multiple tissues from newborn twins reveals both genetic and intrauterine components to variation in the human neonatal epigenome. Hum. Mol. Genet. 19, 4176–4188 (2010).
Gertz, J. et al. Analysis of DNA methylation in a three-generation family reveals widespread genetic influence on epigenetic regulation. PLoS Genet. 7, e1002228 (2011).
Hellman, A. & Chess, A. Extensive sequence-influenced DNA methylation polymorphism in the human genome. Epigenetics Chromatin 3, 11 (2010).
Kerkel, K. et al. Genomic surveys by methylation-sensitive SNP analysis identify sequence-dependent allele-specific DNA methylation. Nature Genet. 40, 904–908 (2008).
Murrell, A. et al. An association between variants in the IGF2 gene and Beckwith-Wiedemann syndrome: interaction between genotype and epigenotype. Hum. Mol. Genet. 13, 247–255 (2004).
Schilling, E., El Chartouni, C. & Rehli, M. Allele-specific DNA methylation in mouse strains is mainly determined by cis-acting sequences. Genome Res. 19, 2028–2035 (2009).
Rakyan, V. K. et al. Human aging-associated DNA hypermethylation occurs preferentially at bivalent chromatin domains. Genome Res. 20, 434–439 (2010).
Teschendorff, A. E. et al. Age-dependent DNA methylation of genes that are suppressed in stem cells is a hallmark of cancer. Genome Res. 20, 440–446 (2010).
Heijmans, B. T., Kremer, D., Tobi, E. W., Boomsma, D. I. & Slagboom, P. E. Heritable rather than age-related environmental and stochastic factors dominate variation in DNA methylation of the human IGF2/H19 locus. Hum. Mol. Genet. 16, 547–554 (2007).
Henckel, A. et al. Histone methylation is mechanistically linked to DNA methylation at imprinting control regions in mammals. Hum. Mol. Genet. 18, 3375–3383 (2009).
Feng, S., Jacobsen, S. E. & Reik, W. Epigenetic reprogramming in plant and animal development. Science 330, 622–627 (2010).
Biniszkiewicz, D. et al. Dnmt1 overexpression causes genomic hypermethylation, loss of imprinting, and embryonic lethality. Mol. Cell. Biol. 22, 2124–2135 (2002).
Weaver, J. R. et al. Domain-specific response of imprinted genes to reduced DNMT1. Mol. Cell. Biol. 30, 3916–3928 (2010).
Marini, N. J. et al. The prevalence of folate-remedial MTHFR enzyme variants in humans. Proc. Natl Acad. Sci. USA 105, 8055–8060 (2008).
Baranzini, S. E. et al. Genome, epigenome and RNA sequences of monozygotic twins discordant for multiple sclerosis. Nature 464, 1351–1356 (2010).
Javierre, B. M. et al. Changes in the pattern of DNA methylation associate with twin discordance in systemic lupus erythematosus. Genome Res. 20, 170–179 (2010).
Schneider, E. et al. Spatial, temporal and interindividual epigenetic variation of functionally important DNA methylation patterns. Nucleic Acids Res. 38, 3880–3890 (2010).
McLaren, A. Too late for the midwife toad: stress, variability and Hsp90. Trends Genet. 15, 169–171 (1999).
Park, P. J. ChIP-seq: advantages and challenges of a maturing technology. Nature Rev. Genet. 10, 669–680 (2009).
Pepke, S., Wold, B. & Mortazavi, A. Computation for ChIP-seq and RNA-seq studies. Nature Methods 6, S22–S32 (2009).
Baylin, S. B. & Jones, P. A. A decade of exploring the cancer epigenome — biological and translational implications. Nature Rev. Cancer 11, 726–734 (2011).
Marfil, C. F., Camadro, E. L. & Masuelli, R. W. Phenotypic instability and epigenetic variability in a diploid potato of hybrid origin, Solanum ruiz-lealii. BMC Plant Biol. 9, 21 (2009).
Ravelli, G. P., Stein, Z. A. & Susser, M. W. Obesity in young men after famine exposure in utero and early infancy. N. Engl. J. Med. 295, 349–353 (1976). This is one of the first reports in humans showing the possible long-term effects of prenatal and early-life nutrition on adult health and disease.
Dunger, D. B. et al. Association of the INS VNTR with size at birth. Nature Genet. 19, 98–100 (1998).
Baccarelli, A. et al. Neonatal thyroid function in Seveso 25 years after maternal exposure to dioxin. PLoS Med. 5, e161 (2008).
Bhargava, S. K. et al. Relation of serial changes in childhood body-mass index to impaired glucose tolerance in young adulthood. N. Engl. J. Med. 350, 865–875 (2004).
Sung, S. & Amasino, R. M. Vernalization in Arabidopsis thaliana is mediated by the PHD finger protein VIN3. Nature 427, 159–164 (2004).
Yen, T. T., Gill, A. M., Frigeri, L. G., Barsh, G. S. & Wolff, G. L. Obesity, diabetes, and neoplasia in yellow Avy/- mice: ectopic expression of the agouti gene. FASEB J. 8, 479–488 (1994).
Michaud, E. J. et al. Differential expression of a new dominant agouti allele Aiapy is correlated with methylation state and is influenced by parental lineage. Genes Dev. 8, 1463–1472 (1994).
Hussain, M. et al. Tobacco smoke induces polycomb-mediated repression of Dickkopf-1 in lung cancer cells. Cancer Res. 69, 3570–3578 (2009).
Sato, K. et al. Neonatal exposure to diethylstilbestrol alters expression of DNA methyltransferases and methylation of genomic DNA in the mouse uterus. Endocr. J. 56, 131–139 (2009).
Volle, D. H. et al. The orphan nuclear receptor small heterodimer partner mediates male infertility induced by diethylstilbestrol in mice. J. Clin. Invest. 119, 3752–3764 (2009).
Calvanese, V., Lara, E., Kahn, A. & Fraga, M. F. The role of epigenetics in aging and age-related diseases. Ageing Res. Rev. 8, 268–276 (2009).
Baccarelli, A. & Bollati, V. Epigenetics and environmental chemicals. Curr. Opin. Pediatr. 21, 243–251 (2009).
Umemura, S. et al. Aberrant promoter hypermethylation in serum DNA from patients with silicosis. Carcinogenesis 29, 1845–1849 (2008).
Acknowledgements
We thank F. Berger, M. Constância, the reviewers and all members of our teams for helpful comments and discussions. We apologize to our colleagues whose research we were unable to review owing to the focus on selected model systems, and because of space limitations. M.F.F. is grant supported by the Spanish Ministry of Health (PS09/02454) and the 'Obra Social Cajastur'. R.F. acknowledges grant funding from the 'Institut National du Cancer', the 'Ligue Contre le Cancer', the 'Agence Nationale de la Recherche' and the UK Agency for International Cancer Research. He is affiliated to the European network EpiGeneSys.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Related links
Glossary
- Epigenetic modifications
-
Chemical additions to the DNA and histones that are stably maintained and do not change the primary DNA sequence.
- Epigenomes
-
The overall epigenetic modifications of cells. An organism has multiple, cell type-specific, epigenomes.
- Intrinsic factors
-
Factors that are inherent to the individual animal or plant. Genetically determined, intrinsic factors induce considerable stochastic variation, such as different behaviour between cells.
- CpG dinucleotides
-
Indicates a cytosine followed (5′–3′) by a guanine. Cytosines at CpG dinucleotides constitute the principal target of DNA methylation in mammals. In plants, cytosine methylation occurs also in other sequence contexts.
- Heterochromatin
-
A densely packaged, transcriptionally silenced type of chromatin. Constitutive heterochromatin is found close to centromeres in all tissues. Facultative heterochromatin, such as that commonly found at gene promoters, can be developmentally reprogrammed.
- Phenotypic plasticity
-
The ability of a genotype to yield different phenotypes; for example, in response to environmental stimuli.
- Metastable epiallele
-
An allele for which the expression depends on environmentally influenced, stochastic establishment of epigenetic states during early development.
- Imprinted genes
-
Genes that express one of their two alleles only, in a parent-of-origin-specific manner.
- Folate
-
(Vitamin B9). A water-soluble B vitamin that is abundant in green vegetables and fruits. Folate derivatives are important substrates in many one-carbon-transfer reactions.
- Methionine
-
An essential amino acid that is abundant in fish, eggs and some seeds and vegetables.
- CpG islands
-
GC-rich DNA sequences (of 200–2,000 bp in length) that have a high density of CpG dinucleotides. Approximately half of the mammalian genes have a CpG island near the transcription start site, often with promoter activity.
- Vitamin B12
-
(Cobalamin). A vitamin that is abundant in meat, seafood, eggs and dairy foods. It is a fundamental cofactor in the regeneration of methionine from homocysteine, and in other biochemical reactions.
- Endocrine disruptors
-
Chemical compounds that affect endocrine regulation and cause developmental alterations, cancer and other pathologies.
- Polycomb group proteins
-
A family of chromatin-modifying proteins that are involved in chromatin silencing. They are organized into Polycomb repressive complexes (PRCs) that catalyse histone H3 lysine-27 trimethylation and histone H2A lysine-119 ubiquitination.
- Vitamin B6
-
(Pyridoxal phosphate). A vitamin that is abundant in meat, fish and some tubers and fruits. It is a crucial cofactor in the trans-sulphuration of homocysteine and in other biological reactions.
- Betaine
-
A molecule that is abundant in whole-wheat foods and some green vegetables. Some organisms can synthesize betaine from choline.
- Choline
-
A soluble molecule that is abundant in meat, fish, seafood, eggs, dairy foods and some vegetables, seeds and nuts.
- Methyl donor
-
A chemical compound that can donate a methyl group. The universal methyl donor for DNA methylation and histone methylation is S-adenosylmethionine (SAM).
- Butyrate
-
A short-chain carboxylic acid that is produced by bacteria in the gut as an end product of the fermentation of dietary carbohydrates.
- Sirtuins
-
A family of proteins that couple lysine deacetylation to NAD+.
- Bivalent chromatin
-
Regions of chromatin that have co-occurrence of histone H3 trimethylated on lysine-27 (H3K27me3) and H3K4me2/3 during embryonic development.
Rights and permissions
About this article
Cite this article
Feil, R., Fraga, M. Epigenetics and the environment: emerging patterns and implications. Nat Rev Genet 13, 97–109 (2012). https://doi.org/10.1038/nrg3142
Published:
Issue Date:
DOI: https://doi.org/10.1038/nrg3142
This article is cited by
-
Computational dissection of genetic variation modulating the response of multiple photosynthetic phenotypes to the light environment
BMC Genomics (2024)
-
Transgenerational Epigenetic Inheritance of Cardiovascular Diseases: A Network Medicine Perspective
Maternal and Child Health Journal (2024)
-
Smart carbon-based sensors for the detection of non-coding RNAs associated with exposure to micro(nano)plastics: an artificial intelligence perspective
Environmental Science and Pollution Research (2024)
-
Parity is associated with long-term differences in DNA methylation at genes related to neural plasticity in multiple sclerosis
Clinical Epigenetics (2023)
-
Caloric restriction remodels the hepatic chromatin landscape and bile acid metabolism by modulating the gut microbiota
Genome Biology (2023)
