Epigenetics at the Crossroads of Genes and the Environment.

Epigenetics refers to information transmitted during cell division other than the DNA sequence per se, and it is the language that distinguishes stem cells from somatic cells, one organ from another, and even identical twins from each other. Examples include (1) DNA methylation, a covalent modification of the nucleotide cytosine, that is copied during cell division at CpG dinucleotides by the maintenance enzyme DNA methyltransferase I; (2) posttranslational modifications of nucleosome proteins about which the DNA double helix is wrapped; and (3) the density of nucleosomes and higher-order packaging of chromatin within the nucleus, including its relationship to the nuclear lamina. In contrast to the DNA sequence, the epigenome is relatively susceptible to modification by the environment as well as stochastic perturbations over time, adding to phenotypic diversity in the population. A classic example is the environmentally modified phenotype of the Agouti gene, which regulates coat color and weight in mice and is manifest through epigenetic changes. A repetitive DNA variant within this gene can activate the gene in a nonregulated way, causing a yellow coat and obesity in the mice. This activation can be suppressed by DNA methylation, which can be modulated by supplying more or less dietary methionine, the essential amino acid that is the precursor of all DNA methylation in the cell.1 Similar epigenetically mediated changes can be evoked via chemical exposure and even maternal behavior.2 In humans, there has long been suspicion of the importance of nutrition in early life in modulating the epigenome. The classic epidemiological example of Överkalix, Norway, showed lower life expectancy for boys whose grandfathers had experienced famine prepubertally.3 During the Dutch Hunger Winter and Great Leap Forward, which involved starvation of huge numbers of people, children exposed in utero to the famine during their first trimester show DNA methylation changes in genes associated with birth weight and low-density lipoprotein cholesterol.4 A recent study of in utero nutritional deprivation in mice showed epigenetic changes continuing via the germline to the next generation but not beyond.5 For nearly all common diseases, both genetic predisposition and environmental influences shape risk, which typically increases with age. Even though both genetic and environmental exposures can be measured, there are currently limitations to how well they inform disease risk prediction or the underlying biological mechanisms leading to disease. Epigenetic marks on the genome may provide critical data to inform both prediction, in the age of precision medicine, and etiologic insight. This is because epigenetic marks are biologically related to both environmental exposure experience and to genes, and thus may be a measurable gauge of both genetic and environmental influence on disease risk. The interplay between genes, environment, epigenetics, and disease is complicated and still poorly understood. However, it is clear from both animal models and human studies that epigenetic marks such as DNA methylation can be modified by multiple types of environmental change, may be partially controlled by genetic variation, and certainly regulate gene expression, and thus how and when the genetic code is translated into biological action. In the era of precision medicine, genetic risk scores are emerging as a potentially useful metric of risk. However, a risk metric based on inherited genes alone is static, because it does not incorporate age and environmental experience. Thus, most sophisticated approaches to risk prediction can include age, other demographic features, and specific environmental risk factors if known. This is challenging because many disease-specific environmental risk factors are not yet known, or the cumulative individual exposure (over time or across exposures) is not easily measured. Epigenetic marks can be used as biological measures of age,6 and have shown promise as biomarkers of cumulative or specific exposure such as prenatal exposure to maternal cigarette smoking.7 DNA methylation is stable in stored blood samples, and thus could have clinically feasible function for adding a metric of age and exposure risk to estimated inherited genetic risk to inform individual risk prediction. The fields of genetic medicine and environmental health are not only concerned with risk prediction, but perhaps more importantly, with identifying and understanding causes of disease that can be acted upon for prevention and treatment. This is an important distinction because risk prediction does not necessarily need a specified mechanism. If a set of genetic markers can accurately predict which individuals will get (or already have) disease, and prediction is the goal, the mechanism of such genes, or whether they are simply proxy markers of some unmeasured mechanism, is irrelevant. However, if the goal is biological understanding of the disease, to inform prevention or treatment strategies, this information is critical. Epigenetic epidemiology is beginning to show utility in this regard. Some genetic associations with autoimmune disease have been shown to be mediated through epigenetic mechanisms. For example, a variVIEWPOINT