Bimonthly update: Edited by Alan Rees
Epigenetics studies mechanisms of gene regulation that are not a consequence of changes in DNA sequence, but rather rely on specific chromatin architectures. Perhaps the best understood modifications of the genetic material that are involved in epigenetic regulation are DNA methylation and histone posttranslational processing . Because of the intrinsic flexibility of chromatin structure both in response to diet and environment, and as a result of foreseeable therapeutic interventions, epigenetics has emerged as a promising conceptual frame to investigate chronic degenerative disorders . This applies particularly to diet-driven and environment-driven metabolic disorders, such as obesity and its complications including atherosclerosis. Consequently, a number of groups have investigated the occurrence of abnormal DNA methylation patterns during the natural history of atherosclerosis and whether lipoproteins and other relevant molecules can elicit any epigenetic responses. These efforts have demonstrated that native lipoproteins, selected fatty acids and homocysteine among other factors, can modulate DNA methylation [3,4]. One particularly important and fascinating issue in the epigenetic theory of metabolic diseases is transgenerational transmission of risk. Pioneer work has demonstrated generation-to-generation effects of dietary regime on diabetes and other conditions predisposing to atherosclerosis in a Swedish cohort. These studies suggested that stable aberrant DNA methylation patterns may be imposed in the germ line by lipids and other dietary factors at critical phases of foetal and postnatal development, thus determining adult disease risk [5,6]. More recently, evidence for transgenerational transmission of atherosclerosis risk has steadily accumulated and has been extensively reviewed by DeRuiter et al.[7•]. Here, we will report two very recent advances in the field. The first is based on the Avy mouse model, in which variable methylation at the Avy (agouti) locus causes a range of phenotypes from yellow fur and obesity in hypomethylated Avy-bearing mice to agouti colour and normal weight in mice with a hypermethylated Avy locus. Methyl donor supplementation to maternal diet produces mostly agouti, lean offspring bearing a hypermethylated Avy locus . Although the Avy mouse model clearly demonstrated that simple dietary intervention can transgenerationally affect DNA methylation and the occurrence of an important cardiovascular risk factor, its relevance for human metabolic diseases remained untested. Dissipating these doubts would provide a valuable animal model and, more importantly, would further support epigenetic gene regulation as an important player in these diseases. A recent study by Waterland et al.[9•] represents one important step in this direction. The authors analysed the trend of body weight across three successive generations each inheriting obesity from obese Avy mothers. The results confirmed the initial hypothesis that, as apparently occurring in the human population, persistent maternal obesity causes a generation-to-generation amplification of body weight. Methyl donor supplementation of maternal diet abolished obesity accumulation, thus suggesting a central role for DNA methylation in these phenomena. Perhaps the most noticeable result of the study is the lack of association between coat colour and adult body weight. Such an association would be expected if the methylation state of the Avy locus were the only or most important determinant of obesity in this model. Rather, as the authors point out, cumulative obesity must be the result of epigenetic alterations at loci controlling body weight other than Avy. Whether or not the same loci are affected in human obesity, these results represent a firm stepping stone towards a detailed analysis of the epigenome of obese patients. One likely outcome of these studies will be the identification of loci targeted for epigenetic modifications by dietary lipoprotein components and other relevant factors determining CVD risk. This information, furthermore, is likely to provide novel testable mechanisms for gene regulation and cell biology in atherogenesis.
The second work reviewed here follows a similar path and has to do with the idea that one group of loci expected to undergo epigenetic alterations during transgenerational transmission of CVD risk is the one involved in inflammation [10•]. The study shows that maternal methyl donor supplementation exacerbates airway inflammation in an asthma mouse model. These results open the possibility that dietary factor-elicited epigenetic activation of proinflammatory genes in utero or in infancy may be an important risk-enhancing factor.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
1 Berger SL. The complex language of chromatin regulation during transcription. Nature 2007; 447:407–412.
2 Zaina S, Lund G. Epigenetics and cardiovascular disease. In: Esteller M, editor. Epigenetics in biology and medicine. Boca Raton: Taylor & Francis Group LLC; 2008. pp. 207–223.
3 Lund G, Andersson L, Lauria M, et al
. DNA methylation polymorphisms precede any histological sign of atherosclerosis in mice lacking apolipoprotein E. J Biol Chem 2004; 279:29147–29154.
4 Castro R, Rivera I, Struys EA, et al
. Increased homocysteine and S-adenosylhomocysteine concentrations and DNA hypomethylation in vascular disease. Clin Chem 2003; 49:1292–1296.
5 Pembrey ME, Bygren LO, Kaati G, et al
. Sex-specific, male-line transgenerational responses in humans. Eur J Hum Genet 2006; 14:159–166.
6 Pembrey ME. Time to take epigenetic inheritance seriously. Eur J Hum Genet 2002; 10:669–670.
7• DeRuiter MC, Alkemade FE, Gittenberger-de Groot AC, et al
. Maternal transmission of risk for atherosclerosis. Curr Opin Lipidol 2008; 19:333–337. A recent, complete review explaining the potential importance of epigenetic mechanisms in the aetiology of atherosclerosis.
8 Waterland RA, Jirtle RL. Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Mol Cell Biol 2003; 23:5293–5300.
9• Waterland RA, Travisano M, Tahiliani KG, et al
. Methyl donor supplementation prevents transgenerational amplification of obesity. Int J Obesity 2008; 32:1373–1379. An important study showing transgenerational inheritance and amplification of maternal obesity in a mouse model. The results are likely to provide a molecular basis to corresponding trends of obesity and CVD risk and in human populations.
10• Hollingsworth JW, Maruoka S, Boon K, et al
. In utero supplementation with methyl donors enhances allergic airway disease in mice. J Clin Invest 2008; 118:3462–3469. This work shows transgenerational effects of methyl donor supplementation on airway inflammation in a mouse model. A wide range of issues are touched by these results, ranging from mechanisms of inheritance of inflammation predisposition, to consequences of preventive vitamin supplementation.