Noteworthy experimental results, taken together, indicate that epigenetic processes could plausibly mediate effects of environmental exposures to influence disease susceptibility in mammals, since (1) specific exposures induced measurable changes in epigenetic state, (2) new epigenetic state was shown to persist after cessation of exposure, and (3) measureable phenotype was associated with exposure-related changes in epigenetic state. A fourth element, exposure-induced alteration of epigenetic marks of germ cell lineage DNA, seems necessary for transgenerational transmission of environmentally induced epigenetic changes. On this background, we interpret observational human data illustrating associations of exposures to epigenetic state and epigenetic state to disease to indicate that epigenetic mechanisms may plausibly mediate exposure effects on a wide range of human diseases.
Perhaps the greatest significance of this line of research is the potential for designing novel interventions articulated by Dolinoy and Jirtle (200
unlike genetic mutations, epigenetic profiles are potentially reversible. Therefore, epigenetic approaches for prevention and treatment, such as nutritional supplementation and/or pharmaceutical therapies may be developed to counteract negative epigenomic profiles.
As an example, Huang et al. (2012) have developed a therapy for reactivating the Ube3a allele that is epigenetically silenced in Angelman syndrome. However, before we begin to realize this translational potential, much research along parallel tracks needs to be conducted.
We need to better understand basic epigenetic mechanisms that operate during selected periods when the epigenome may be particularly vulnerable to environmental exposures (e.g., prenatal and early postnatal periods, childhood, puberty) as well as mechanisms that routinely maintain proper epigenetic states. We also need to understand mechanisms relevant to cumulative effects of exposure and associations with aging, since duration of exposure and aging are co-linear. A better understanding of basic mechanisms at different time points in life would guide genetic epidemiology studies in selecting environmental exposures that are more likely to affect epigenetic processes, identify the most relevant periods of exposure, identify biomarkers of exposure, and suggest biological intermediates to study.
It may be helpful to more deliberately deconstruct the steps whereby an environmental exposure may affect risk of disease via epigenetic mechanisms. For example, studies of the association of environmental exposures with selected epigenetic events as endpoints (rather than intermediates in a complex pathway) may be fruitful and will likely help us better conceive of studies to elucidate an entire pathway, from an exposure acting at least in part through epigenetic mechanisms to disease risk.
As we proceed, it will be important to consider seriously the environmental exposures to study, since we will want to select the most promising candidate exposures (those most likely to affect epigenetic processes), measuring these exposures at relevant time periods and with reasonable accuracy. Also, we cannot ignore genetic influences on epigenetic processes. We see above that studies of the epigenetic state of specific candidate genes are yielding interesting results and more such studies are warranted. Given limited knowledge of this genetic–epigenetic interface, to complement the candidate gene approach, integrative genomics approaches should be contemplated in order to combine GWAS data with epigenomic data. Clearly, statistical and bioinformatics approaches will be required to enable the efficient conduct of these analyses, especially as we expand to genome-wide scale. Similarly, research on feasible, efficient study designs, akin to current research on optimum designs for sequencing-based studies, will be needed. Finally, as with other emerging fields (e.g., the standardization of testing criteria for microsatellite instability or MSI), standardization of terminology and testing protocols will facilitate future communication of hypotheses, scientific approaches, and results.