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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