The human genome contains information that is not fully described by the DNA sequence alone. This so-called epigenetic information (from the Greek , meaning “on” or “over”) is laid over the genetic information in the genome. It fundamentally affects the way in which the sequence information in DNA is used, and it is essential to the identity and the healthy functioning of cells. Epigenetic processes have been implicated in a wide range of health outcomes including cancer, cognition, cardiovascular disease, diabetes, and reproductive function; and our understanding of the effect of environmental factors, such as diet and lifestyle on epigenetic status, is growing rapidly.

Epigenetics encompasses a collection of mechanisms that define the phenotype of a cell without affecting the genotype (1). In molecular terms, it represents a range of mechanisms including DNA methylation, histone modification, remodeling of nucleosomes and higher order chromatin reorganization, and regulation by noncoding RNAs (1). A key characteristic of the epigenetic signal is that it is heritable and can be passed from somatic cell to daughter cell during mitosis and even across the generations during meiosis (1, 2, 3, 4, 5, 6). Understanding of the epigenetic regulation of individual genes has increased greatly, but coordinated epigenetic control of the genome on a much larger scale may be even more important. The human genome is made up of accessible regions of euchromatin and poorly accessible regions of heterochromatin, and these regions determine the ability of the transcriptional machinery of the cell to access genetic information (5, 6). These regions may span many genes, and epigenetic regulation is critical to the transition between these states (7).

DNA methylation is probably the most widely studied epigenetic mechanism in relation to nutrition. Methylation in mammalian cells takes place at a cytosine located 5′ to a guanosine (CpG site). A significant component of the global methylation signature (average level of methylation across the entire genome) is accounted for by the transposable elements that make up approximately 45% of the entire genome and are usually heavily methylated (˜90%). The transposons include the long interspersed nuclear elements (LINE1), the intracisternal A particle (IAP), short interspersed nuclear elements (SINE), and the Alu family of human SINE elements characterized by the action of the Alu restriction endonuclease (8, 9). Some classes of transposon are able to move around the genome and can cause abnormal function and disease if they are inserted into an important conserved sequence (5, 8, 9). Within the genes that code for proteins, the most striking epigenetic distinction is between the imprinted and the nonimprinted genes. Most autosomal genes are expressed equally from both parental alleles, but imprinted genes are an exception.

Genomic imprinting refers to the epigenetic marking of genes in a manner specific to the parent of origin within the germ cells such that the subsequent expression pattern depends on the parent from whom the allele was derived (1, 4, 5, 6). Imprinted genes are particularly important in prenatal growth, placental function, and brain function and behavior (10, 11, 12). Imprinted genes are unusually found downstream of regions of DNA that have a high density of CpG sites (5). Approximately 80% of imprinted genes are found in clusters with other imprinted genes, and this arrangement is thought to reflect coordinated regulation of the genes within a chromosomal domain (5). Regions rich in CpG sites, known as CpG islands, are found in gene bodies, endogenous repeats, and transposable elements and are thought to be important in transcriptional repression (3). The process of demethylation is in many ways as important to epigenetic regulation as is methylation. Demethylation occurs in the mismatch repair pathway, but it is not known whether this is the primary mechanism by which removal of methyl groups is achieved
in epigenetic remodeling (13). Epigenetic status varies among individuals (14, 15, 16) and even between genetically identical monozygotic twins (17). Much research has been carried out to determine whether this variation is important to health and whether it is influenced by nutrition.

Investigators are currently interested in the importance of epigenetic factors in the origin of human disease (4, 18). Epigenetic change has been implicated in all the major chronic diseases affecting humans. Historically, cancer is the disease in which epigenetics has been studied most extensively. A common observation in human tumors is epigenetic change, including altered methylation of DNA (19, 20, 21) and the histones associated with DNA (22). Hypomethylation in tumor cells is thought to be an early trigger that predisposes cells to genomic instability and hypermethylation of specific genes thought to be involved in carcinogenesis and disease progression (23). Certain imprinted genes are known tumor suppressors involved in cell proliferation (24). Loss of imprinting (gain or loss of DNA methylation or loss of allele-specific gene expression) is also a common characteristic of many cancer types, including breast, lung, colon, liver, and ovary (24). Imprinting syndromes, in which the imprint is disrupted or absent, are associated with diabetes (25) and cancer risk (26), in addition to impairment of normal function that leads to obesity and impaired cognitive development (2). Although only approximately 1% of all human genes are imprinted, our understanding that imprinting status may be important for several health outcomes is growing (4).

Patients with vascular disease have significantly altered DNA methylation compared with healthy controls (27). Altered global DNA methylation has also been observed in mouse and rabbit atherosclerotic lesions (28), and studies in an atherogenic mouse model have shown that altered DNA methylation precedes the development of atherosclerosis (29). Altered methylation of the estrogen receptor-α gene has also been demonstrated in coronary atherosclerotic plaques compared with normal proximal aorta; the methylation status changes with aging (30). Epigenetic mechanisms have been implicated in Alzheimer disease (31), mental impairment, and normal cognitive function (12, 32, 33, 34).