DNA Methylation and Disease

The etiologies of complex diseases are particularly challenging to decode as they often have both environmental and genetic contributors. As DNA methylation has a role in the interface between the genome and the environment, it has been investigated as a mediator between environmental exposure and disease manifestation. DNA methylation could be associated with current or future disease, either mechanistically or as a biomarker. In terms of mechanism, DNA methylation could influence the development of disease via moderation of a genetic risk or embedding of a past environmental exposure, for example. Concurrent disease-related changes in DNA methylation or patterns that predict future disease that do not have an identified mechanistic link to the disease may be biomarkers that could be used for patient stratification or assessment of intervention. Here, examples from the immune system illustrate some of the recent findings connecting DNA methylation and disease.

A number of immune diseases have recently been investigated for epigenetic mediation of genetic risk, in which DNA methylation of immune-related genes alters the penetrance of a risk allele. Investigations of rheumatoid arthritis and peanut allergy have both shown evidence that DNA methylation of the major histocompatibility complex (MHC) in combination with genetic factors alters risk of disease development [53, 54]. The source of the variation in DNA methylation is not known for either of these diseases, but possibilities include stochastic changes or embedded environmental signatures. Future work on the MHC region will be required to elucidate whether environmental exposures alter DNA methylation in that area, as well as whether these can be mitigated to alter disease trajectory.

One of the first autoimmune diseases predicted to have an epigenetic contribution was systemic lupus erythematosus. Potential environmental contributions have led researchers to examine DNA methylation patterns to determine whether genes involved in the production of anti-nuclear antibodies are differentially methylated in lupus patients [55]. In a study examining multiple white blood cell types, abnormally low DNA methylation was observed near interferon-related genes, in both active and quiescent lupus [56]. This implies that the DNA methylation changes are not associated with disease flare-ups, but rather reflect a basal difference in DNA methylation in patients with lupus regardless of their disease status, which may be indicative of molecular “poising” awaiting a specific trigger. The clinical implications of these findings include potential targets for interventions to reduce the active lupus symptoms, or as biomarkers of those who may be at risk for a flare-up.

Other immune diseases show specific patterns of DNA methylation dysregula- tion, but the mechanistic contribution of DNA methylation is currently not understood. Differences in DNA methylation and gene expression in l eukocytes have recently been found between twins discordant for two autoimmune diseases which show generally low concordance: psoriasis and Type 1 diabetes [57, 58]. DNA methylation dysregulation has also been observed in synovial cells of patients with rheumatoid arthritis [59].

DNA methylation has also been identified as a factor involved in microbial infection with two distinct relationships; in some cases it is associated with immune adaptation and in others it is associated with facilitating intracellular parasitic infection. For example, epigenetic remodeling was observed in monocyte-derived dendritic cells in response to Mycobacterium tuberculosis, the primary cause of tuberculosis in humans. Infected cells showed DNA methylation changes that altered the regulation of immune transcription factors in a way that contributed to a short-term memory of infection in innate immune cells [60]. Another study demonstrated numerous DNA methylation changes in a macrophage cell line were associated with Leishmania donovani infection. Many of these changes were associated with host immune defense pathways such as the AK/STAT signaling pathway and the MAPK signaling pathway [61]. On the other hand, Anaplasma phagocytophi- lum, a prokaryotic pathogen, has been shown to elicit epigenetic changes in human neutrophils that promote infection by enabling pathogen survival and replication [62]. These results highlight an interesting branch of immune epigenetics, showcasing the complex roles DNA methylation has in the process of microbial infection.

In all of these cases, it is not yet known whether the DNA methylation changes observed are a mechanism of disease development or a concurrent biomarker of disease. Regardless of the origin of these changes, they raise the tantalizing possibility that epigenetics in general and DNA methylation in particular may be a new frontier for research into the development of complex immune diseases and phenotypes.

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