The main epigenetic marks include chemical modifications of the cytosine base within DNA (Figure 14.1) and post-translational modifications of histones. The main epigenetic mark on DNA in animals is the addition of a methyl group to the 5′position on cytosine residues when that cytosine is followed by a guanine – that is, a so-called CpG dinucleotide – to produce 5′methylcytosine (5mC). In addition, it has been discovered very recently that methylated cytosines in CpG dinucleotides can be further modified by oxidation to form hydroxymethylcytosine (5hmC; Figure 14.1). Relatively high concentrations of 5hmC are seen in the brain and in embryonic stem cells. The role of 5hmC is not well understood, but it appears that it may be an intermediate in the demethylation of 5mC; that is, an important part of the dynamic process through which methyl marks can be added to, and removed from, DNA.

Histones are the chief protein components of chromatin. Two of each of the core histones (H2A, H2B, H3 and H4) forms a globular protein complex around which 147 base pairs of DNA are wrapped in the nucleus, with a linker histone (H1) at each end locking the DNA in place. Protruding from the globular core are N-terminal protein ‘tails’ in which specific amino acid residues can be covalently modified by the addition of small chemical groups – that is, phosphate, methyl and acetyl groups – and by the addition of small regulatory proteins – that is, ubiquitin and SUMO (small ubiquitin-like modifier). These constitute the epigenetic ‘marks’ on histones. Epigenetic molecules fall into two groups. The first are the enzymes and other proteins that add or remove epigenetic marks and those that ‘read’ those marks to switch on, or switch off, expression of the corresponding gene. For example, this group of molecules includes DNA methyltransferase (DNMT) enzymes, which catalyse the addition of methyl groups to cytosines in DNA, and histone acetyl transferases (HATs) and histone deacetylases (HDACs), which catalyse the addition and removal, respectively, of acetyl groups on specific amino acids, for instance lysine, in histone tails. The second group of epigenetic molecules is composed of small RNAs (described as microRNA), which are typically 22 nucleotides long. These microRNA do not code for proteins, but regulate the expression of genes through base pairing with complementary sequences within the target mRNA species. In most cases, this binding to the 3′end of mRNA results in degradation of the target mRNA and, because this means that no protein is synthesised, the corresponding gene is effectively silenced (Figure 14.2). In mammals, there is only partial complementarity between the miRNA sequence and that of the corresponding mRNA. As a consequence, a given microRNA may have multiple mRNA targets and translation of a given mRNA may be regulated by a combination of microRNAs.

Epigenomics is the study of the totality of epigenetic marks and molecules within a cell or tissue, which is described as the epigenome. This is analogous to the terms genomics, transcriptomics, proteomics and metabolomics, which describe all the genes, mRNA species, proteins and metabolites, respectively, in a cell or other biological sample and are discussed in more detail in Chapter 13. Following the successful projects to map the human genome and to identify the genetic variants, such as single nucleotide polymorphisms (SNP) and copy number variants (CNV), in the human genome, there are now consortia attempting to map specific epigenomes. For example, the Human Epigenome Project (HEP) aims to identify, catalogue and interpret genome-wide DNA methylation patterns of all human genes in all major tissues (for details, see http://www.epigenome.org/).

14.4 Epigenetic regulation of gene expression

The genome of the fertilised human egg contains all the genetic information to direct development of the human adult, who contains over 200 different cell types, all of which contain exactly the same DNA but carry out distinctively different functions. Asymmetrical cell division leading to different cell types (cellular differentiation) occurs during embryogenesis and is very carefully orchestrated to ensure that each cell type expresses its characteristic complement of genes. This is achieved via chromatin, the DNA–nucleosome polymer, which is a dynamic molecule capable of existing in many configurations. The combination of epigenetic marks and molecules (epigenome) determines the higher-order organisation of chromatin. Those chromatin domains that are highly compacted (known as heterochromatin) contain genes that are silenced, whereas the more open chromatin regions (known as euchromatin) allow access by the transcriptional machinery and gene expression.

In the same way that optimum health requires each of the body’s organs and tissues to do its particular job efficiently in response to whatever challenge the body faces, so, at the cellular level, the proper function of each individual cell requires expression of the consortium of genes that is appropriate for that cell type, for instance an endothelial cell or an enterocyte, in its given environment. In addition, cells need to be able to respond correctly to changing conditions. For example, if we consume potentially hazardous chemicals (xenobiotics), hepatocytes may need to upregulate the expression of defence genes, such as those of the cytochrome P450 superfamily, to enable the body to detoxify those chemicals. Similarly, cells can save energy and other resources by shutting down the expression of genes that are not needed at that particular time. In summary, our genotype is fixed, but our phenotype is plastic and responds to life’s experiences and exposures.

14.5 Nutrition and epigenetics

It is now established that several dietary factors, and other environmental exposures, result in changes in epigenetic marks and molecules, some of which lead to alterations in gene expression (see Table 14.1).

In many cases, the strongest evidence for the impact of nutrition on epigenetic regulation of gene expression comes from studies using model systems (mammalian cells and animal models), but there is growing evidence for similar effects from studies carried out in humans. This has led to the hypothesis that epigenetic processes are potentially important mechanisms through which dietary exposures and nutritional status may influence health. In particular, this is an attractive hypothesis for explaining how nutrition can have very long-term effects on health. Because at least some epigenetic marks such as patterns of DNA methylation are copied from one cell generation to the next, altered DNA methylation caused by early-life nutrition could result in lifelong changes in gene expression, altered risk of disease and effects on life span. This is best illustrated by studies of the Agouti mouse. The coat colour of the offspring in this model is influenced by the supply of folate and other methyl donors provided to the dam during pregnancy (see Figure 14.3). Supplemented dams produce a higher proportion of offspring with darker (brown) coats rather than the predominantly yellow-coloured offspring of unsupplemented dams. This change in coat colour is due to altered expression of the Agouti gene caused by methylation of a regulatory region upstream of the gene. These effects of the maternal diet on DNA methylation are seen in every tissue of the body and the effects on coat colour endure throughout the animal’s life. In this mouse model, maternal methyl donor supply affects not only coat colour but also other important phenotypical characteristics. For example, the ‘yellow’ mice tend to be fatter and more susceptible to obesity-related diseases such as type 2 diabetes than their brown litter mates. Interestingly, maternal exposure to genistein (an isoflavone from soybeans) and to bisphenol A (an industrial chemical used in production of polycarbonate plastics) results in similar changes in DNA methylation and in coat colour in Agouti mice, although neither genistein nor bisphenol A is a methyl donor.

These ideas are conceptualised in the 4Rs of nutritional epigenomics model (Mathers 2008), illustrated in Figure 14.4. In this model, exposure to specific dietary factors produces marks on the genome such as an altered pattern of DNA methylation; that is, the ‘signal’ is Received and Recorded. To have long-term effects, there needs to be a mechanism through which evidence of that exposure is Remembered when the cell divides. In the case of DNA methylation, this memory mechanism is the copying of patterns of DNA methylation from the parental strand of DNA to the daughter strand by the enzyme DNMT1, which occurs immediately after synthesis of the new (daughter) DNA strand during mitosis. Since at least some changes in DNA methylation (and other epigenetic marks) result in changes in gene expression, this is the mechanism through which the functional consequences of the original nutritional exposure are Revealed (Figure 14.4

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