Connecting the epigenome, metabolome and proteome for a deeper understanding of disease

Epigenome-wide association studies (EWAS) identify genes that are dysregulated by the studied clinical endpoints, thereby indicating potential new diagnostic biomarkers, drug targets and therapy options. Combining EWAS with deep molecular phenotyping, such as approaches enabled by metabolomics and proteomics, allows further probing of the underlying disease-associated pathways. For instance, methylation of the TXNIP gene is associated robustly with prevalent type 2 diabetes and further with metabolites that are short-term markers of glycaemic control. These associations reflect TXNIP's function as a glucose uptake regulator by interaction with the major glucose transporter GLUT1 and suggest that TXNIP methylation can be used as a read-out for the organism's exposure to glucose stress. Another case is the association between DNA methylation of the AHRR and F2RL3 genes with smoking and a protein that is involved in the reprogramming of the bronchial epithelium. These examples show that associations between DNA methylation and intermediate molecular traits can open new windows into how the body copes with physiological challenges. This knowledge, if carefully interpreted, may indicate novel therapy options and, together with monitoring of the methylation state of specific methylation sites, may in the future allow the early diagnosis of impending disease. It is essential for medical practitioners to recognize the potential that this field holds in translating basic research findings to clinical practice. In this review, we present recent advances in the field of EWAS with metabolomics and proteomics and discuss both the potential and the challenges of translating epigenetic associations, with deep molecular phenotypes, to biomedical applications.