DNA Methylation and Environmental Exposures

Complementing its role in cell type specification, DNA methylation is also emerging as a mechanism by which cells “remember” past exposures. Although DNA methylation is stable in that it is generally faithfully transmitted from mother to daughter cells, paradoxically it also appears to be malleable in response to exposures and experiences [41-43]. Researchers have examined environmentally-induced changes in DNA methylation in both gene-specific contexts as well as genome-wide changes, such as average methylation across repetitive elements [44,45]. These changes may be transient and revert back to their original state after the exposure ends, but in some cases they can remain associated long after the exposure has passed [46]. It is currently hypothesized that early life is a particularly sensitive time for the long-term embedding of epigenetic signatures of exposures, but in many cases it is not until later in life that health outcomes associated with these exposures are revealed. As such, the environmental exposures that accumulate as a person ages can leave behind a biological residue that might influence long-term health.

Some specific environmental exposures have been associated with long-lasting DNA methylation signatures that persist after the exposure itself. For example, a number of DNA methylation changes are strongly associated with previous and current cigarette smoke exposure[47, 48] . The cigarette smoke-related DNA methylation change in the promoter of a well-characterized tumor suppressor gene, aryl hydrocarbon receptor repressor (AHRR), is currently the best replicated environmentally induced epigenetic alteration. In the AHRR gene, changes in both DNA methylation and gene expression have been observed upon exposure to firsthand and secondhand cigarette smoke, as well as prenatal exposure to maternal smoking [47]. The AHRR protein regulates an enzyme responsible for binding nicotine, thus supporting a plausible mechanism for a DNA methylation response to cigarette smoke exposure.

Lifestyle and the environment can have important effects on DNA methylation, which in turn, may influence immune function, as described in two recent studies. One study examined DNA methylation in African populations with recent divergence in habitat and lifestyle. The study found that a population which had recently diverged into two different habitats, forest versus urban, showed distinct DNA methylation differences between the groups, which were enriched for genes involved in immune function [49]. Another study examined adolescents raised in the American Midwest and compared those who spent the first few years of their lives in Eastern European orphanages to those who were born and raised in their biological families in the US. A significant difference in the ratio of CD4+ T to CD8+ T cells was found in their blood. As well, a DNA methylation pattern unique to the adopted children was enriched for genes involved in development, gene regulation, and behaviour [50]. Together, these examples suggest that the immune system may use DNA methylation as a way to adapt to the environment.

An equally intriguing example of exposure related DNA methylation changes is the reported epigenetic connection between early life adversity and regulation of the inflammatory response in later life. One study examining the association between DNA methylation and early life socioeconomic status (SES) found that while DNA methylation was associated with early life SES, this association was only visible after correction for white blood cell type, reinforcing the evidence for an interaction between DNA methylation and blood cell lineages [11]. Other studies have shown alterations in gene expression and DNA methylation of immune-related genes in adulthood that are associated with low socioeconomic status in childhood [51, 52]. Further work will determine whether this biological signature from early life influences the trajectories of immune ageing.

It is possible that the establishment of these DNA methylation patterns in response to environmental exposures serve to predict future phenotype, including immune responses. For example, pre-stimulation DNA methylation differences in leukocytes can predict their cytokine responses when stimulated through the TLR pathway [11]. As the variability in these baseline patterns was representative of the differences in lifetime environmental exposures between the cells, DNA methylation may function both as a memory of past exposures as well as a predictor of future immune response.

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