Epigenetics and Epigenomics: Implications for Diabetes and Obesity

Abstract

The American Diabetes Association convened a research symposium, "Epigenetics and Epigenomics: Implications for Diabetes and Obesity" on 17-19 November 2017. International experts in genetics, epigenetics, computational biology, and physiology discussed the current state of understanding of the relationships between genetics, epigenetics, and environment in diabetes and examined existing evidence for the role of epigenetic factors in regulating metabolism and the risk of diabetes and its complications. The authors summarize the presentations, which highlight how the complex interactions between genes and environment may in part be mediated through epigenetic changes and how information about nutritional and other environmental stimuli can be transmitted to the next generation. In addition, the authors present expert consensus on knowledge gaps and research recommendations for the field.

Figure 1

From GWAS to functional candidates. Most complex trait variants are localized to the noncoding regions of the genome. Causal variants are enriched on cell-type–specific regulatory elements and alter transcription factor binding and influence the expression of causal genes. Given the small effect of each variant on gene regulation and disease phenotype, it is likely that networks of genes influence disease.

Figure 2

Effects of nutrients, circadian rhythm, and other environmental cues on the epigenome and pathogenesis of type 2 diabetes. Systemic environmental factors affect cellular metabolism and concentrations of intermediate metabolites that are used as substrates and cofactors for enzymes that coordinate epigenetic status (i.e., histone- and DNA-modifying enzymes). Alterations to the epigenome can have lasting effects on cellular responses that persist independent of the environmental stimulus (“metabolic memory”). The epigenetic reprogramming of insulin target tissues, islet cells, and immune cells contributes to the development of type 2 diabetes, while reprogramming of gametes has transgenerational effects. Hyperglycemia leads to persisting epigenetic changes in tissues involved in diabetes complications.

Figure 3

Effects of adverse intrauterine exposures and postnatal environmental factors on pathogenesis of adult metabolic disease and transgenerational disease risk. A: Epigenetic marks within parental germ cells, such as DNA methylation, histone modification, or noncoding RNA (ncRNA) (e.g., in semen) may influence early postfertilization transcriptional responses, altering development and ultimate health of offspring. Adverse intrauterine exposures (B) and postnatal environmental factors (C) may also contribute to disease risk via epigenetic modifications. D: Transcriptional and epigenetic dysregulation associated with adult metabolic disease can also impact germ cells, promoting transgenerational disease risk. Note that these effects occur in the context of the individual’s genetic background, which can modulate responses to environmental exposures.