Prospects for epigenetic epidemiology

Abstract

Epigenetic modification can mediate environmental influences on gene expression and can modulate the disease risk associated with genetic variation. Epigenetic analysis therefore holds substantial promise for identifying mechanisms through which genetic and environmental factors jointly contribute to disease risk. The spatial and temporal variance in epigenetic profile is of particular relevance for developmental epidemiology and the study of aging, including the variable age at onset for many common diseases. This review serves as a general introduction to the topic by describing epigenetic mechanisms, with a focus on DNA methylation; genetic and environmental factors that influence DNA methylation; epigenetic influences on development, aging, and disease; and current methodology for measuring epigenetic profile. Methodological considerations for epidemiologic studies that seek to include epigenetic analysis are also discussed.

Figures

Figure 1.

Diagrammatic representation of CpG methylation (where cytosine (C) and guanine (G) are linked by a phosphate molecule). Approximately 60% of genes have CpG islands in a region called the promoter. This segment of DNA acts to control the activity, or expression, of that gene. An important property of CpG sites is that the cytosine can be methylated, by adding a methyl (CH3) molecule, to form methyl-CpG. Note that, because DNA is double stranded, with strands running in opposite directions, and cytosine bases on one strand pair with guanine on the other, CpG sites are methylated on both strands.

Figure 2.

One-carbon metabolism, which involves the transfer of a methyl group from one “donor” to the next, ending with the DNA methyltransferase (DNMT)–catalyzed transfer of a methyl group to DNA. Methyl donors are shown in boxes and cofactors in ellipses; dietary factors are shaded yellow. Note that, for simplicity, only part of the pathway is shown. CpG, cytosine (C) and guanine (G) linked by a phosphate molecule. Methyl donors: SAH, S-adenosylhomocysteine; SAM, S-adenosylmethionine; THF, tetrahydrofolate; 5meTHF, 5-methyl-THF. Enzymes: BHMT, betaine-homocysteine S-methyltransferase; B2, vitamin B2; B6, vitamin B6; B12, vitamin B12; MAT, methionine adenosyltransferase; MS, methionine synthase; MTHFR, 5,10-methylenetetrahydrofolate reductase; MTRR, 5-methyltetrahydrofolate-homocysteine methyltransferase reductase; SAHH, S-adenosylhomocysteine hydrolase; Zn, zinc.

Figure 3.

Epigenetics, environment, and development. A. Dynamic epigenetic profile throughout the life course, with both genome-wide remodeling and tissue-specific programming events. Stochastic and environmentally induced epigenetic changes accumulated throughout the life course and may be passed through the germline to subsequent generations. Both paternal and maternal genomes are demethylated following fertilization. The exception is imprinted loci that are selectively marked during gametogenesis in either a paternal- or maternal-specific pattern. B. The process of cell differentiation in early development that produces different cell types involves distinct and specific epigenetic modifications. This process is largely completed prior to birth. C. Predicted periods of development likely to be sensitive to specific environmental exposures, including maternal diet and lifestyle, assisted reproductive technologies (ART), environmental toxins, or postnatal diet. D. Biospecimens available for epigenetic analysis included prenatal cerebrovascular system (CVS) and amniocentesis cells; full-term placenta, umbilical cord, and cord blood at birth; and several peripheral tissues thereafter, which can be resampled at multiple time points to track temporal epigenetic change.