Background: Epigenetic mechanisms provide one potential explanation for how environmental influences in early life cause long-term changes in chronic disease susceptibility. Whereas epigenetic dysregulation is increasingly implicated in various rare developmental syndromes and cancer, the role of epigenetics in complex chronic diseases, such as cardiovascular disease, type 2 diabetes and obesity, remains largely uncharacterized. Extensive work in animal models is required to develop specific hypotheses that can be practicably tested in humans. Animal Models: We have developed a mouse model showing that methyl donor supplementation prevents transgenerational amplification of obesity, suggesting a role for DNA methylation in the developmental establishment of body weight regulation. Conclusions: Coupling such models with recently developed epigenomic technologies should ultimately enable us to determine if epigenetics is an important link between early life events and adult disease.

1.
Lucas A: Programming by early nutrition in man. Ciba Found Symp 1991;156:38–50.
2.
Barker DJ: The developmental origins of adult disease. J Am Coll Nutr 2004;23:588S–595S.
3.
Waterland RA, Michels KB: Epigenetic epidemiology of the developmental origins hypothesis. Annu Rev Nutr 2007;27:363–388.
4.
Waterland RA, Garza C: Potential mechanisms of metabolic imprinting that lead to chronic disease. Am J Clin Nutr 1999;69:179–197.
5.
Jaenisch R, Bird A: Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet 2003;33(suppl):245–254.
6.
Constancia M, Kelsey G, Reik W: Resourceful imprinting. Nature 2004;432:53–57.
7.
Heard E: Delving into the diversity of facultative heterochromatin: the epigenetics of the inactive X chromosome. Curr Opin Genet Dev 2005;15:482–489.
8.
Lande-Diner L, Cedar H: Silence of the genes – mechanisms of long-term repression. Nat Rev Genet 2005;6:648–654.
9.
Waterland RA, Jirtle RL: Early nutrition, epigenetic changes at transposons and imprinted genes, and enhanced susceptibility to adult chronic diseases. Nutrition 2004;20:63–68.
10.
Wolff GL, Kodell RL, Moore SR, Cooney CA: Maternal epigenetics and methyl supplements affect agouti gene expression in Avy/a mice. FASEB J 1998;12:949–957.
11.
Waterland RA, Jirtle RL: Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Mol Cell Biol 2003;23:5293–5300.
12.
Rakyan VK, Blewitt ME, Druker R, Preis JI, Whitelaw E: Metastable epialleles in mammals. Trends Genet 2002;18:348–351.
13.
Waterland RA, Dolinoy DC, Lin JR, Smith CA, Shi X, Tahiliani KG: Maternal methyl supplements increase offspring DNA methylation at Axin Fused. Genesis 2006;44:401–406.
14.
Dolinoy DC, Huang D, Jirtle RL: Maternal nutrient supplementation counteracts bisphenol A-induced DNA hypomethylation in early development. Proc Natl Acad Sci USA 2007;104:13056–13061.
15.
Feinberg AP: Epigenetics at the epicenter of modern medicine. JAMA 2008;299:1345–1350.
16.
Weksberg R, Shuman C, Caluseriu O, Smith AC, Fei YL, Nishikawa J, Stockley TL, Best L, Chitayat D, Olney A, Ives E, Schneider A, Bestor TH, Li M, Sadowski P, Squire J: Discordant KCNQ1OT1 imprinting in sets of monozygotic twins discordant for Beckwith-Wiedemann syndrome. Hum Mol Genet 2002;11:1317–1325.
17.
Cui H, Cruz-Correa M, Giardiello FM, Hutcheon D, Kafonek D, Brandenburg S, Wu Y, He X, Powe NR, Feinberg AP: Loss of IGF2 imprinting: a potential marker of colorectal cancer risk. Science 2003;299:1753–1755.
18.
Rankinen T, Zuberi A, Chagnon YC, Weisnagel SJ, Argyropolous G, Walts B, Perusse L, Bouchard C: The human obesity gene map: the 2005 update. Obesity (Silver Spring) 2006;14:529–644.
19.
Flier JS: Obesity wars: molecular progress confronts an expanding epidemic. Cell 2004;116:337–350.
20.
Cropley JE, Suter CM, Beckman KB, Martin DI: Germ-line epigenetic modification of the murine Avy allele by nutritional supplementation. Proc Natl Acad Sci USA 2006;103:17308–17312.
21.
Waterland RA, Travisano M, Tahiliani KG: Diet-induced hypermethylation at agouti viable yellow is not inherited transgenerationally through the female. FASEB J 2007;21:3380–3385.
22.
Waterland RA, Travisano M, Tahiliani KG, Rached MT, Mirza S: Methyl donor supplementation prevents transgenerational amplification of obesity. Int J Obes 2008. In press.
23.
Shen L, Kondo Y, Guo Y, Zhang J, Zhang L, Ahmed S, Shu J, Chen X, Waterland RA, Issa JP: Genome-wide profiling of DNA methylation reveals a class of normally methylated CpG island promoters. PLoS Genet 2007;3:2023–2036.
24.
Shen L, Guo Y, Chen X, Ahmed S, Issa JP: Optimizing annealing temperature overcomes bias in bisulfite PCR methylation analysis. Biotechniques 2007;42:48, 50, 52 passim.
25.
Holliday R: The inheritance of epigenetic defects. Science 1987;238:163–170.
26.
Jones PA, Baylin SB: The fundamental role of epigenetic events in cancer. Nat Rev Genet 2002;3:415–428.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.