Epigenomics in translational research.

This issue of Translational Research features articles reviewing the progress and promise of epigenomics in the context of human health and disease. These articles provide examples of epigenomics, the study of genomic modifications causing and maintaining heritable changes in gene expression that cannot be attributed to changes in the primary DNA sequence, in a wide range of disorders from cancer (Nickel et al., Figueroa et al., Costa et al. Stadler et al., Langevin et al., Kishi et al.) to neurodegenerative (Bennett et al.) and metabolic (Evans-Molina et al.) diseases. This diversity in diseases highlights the breadth of the potential for clinical applications of epigenomics. At their most basic level, epigenomic studies help to elucidate disease etiology and pathogenesis. Building on this foundation, epigenomic insights can guide the development of diagnostic and prognostic tools. As epigenetic marks can be responsive to the environment, there is a lot of interest in their potential role mediators of the effect of non-genetic risk factors for disease; these mechanistic insights into the consequences of environmental and other risk factors may provide targets for drug development. Further, (Arnett et al.) the cell-type specificity of epigenomic marks suggests that drugs that specifically target diseased epigenomic states, such as histone deacetylase (HDAC) and DNA methyltransferase (DNMT) inhibitors, may be useful in the context of cancers and inflammatory diseases (Lopez et al.). Finally, tools arising from engineered epigenomic states, such as induced pluripotent stem cells, hold potential to fundamentally alter drug testing, disease modeling, tissue repair, and transplantation (Kobayashi et al.). Translational epigenomics ultimately seeks to leverage associations between epigenomic marks and clinical outcomes. This field is still in its infancy and will require parallel efforts to (1) improve and reduce the cost of epigenotyping technologies, (2) develop new analytic methods, and (3) establish the fundamental lexicon that relates epigenomic marks to one another and establishes functional units for each mark. All three efforts have recently accelerated thanks to large projects such as the Encyclopedia of DNA Elements (ENCODE) (https://www.encodeproject.org) and the National Institutes of Health’s Roadmap Epigenomics Project (http://www.roadmapepigenomics.org); however, much remains to be done before a large-scale epigenome-wide association study (EWAS) become an approach that is not limited to a small number of specialized laboratories. Also, while these large public projects have generated tremendous resources, they have sampled only a relatively modest number of individuals, cell types and particularly cell states: the extent of interindividual variation in the landscape of healthy profiles (particularly at the extremes of age) remains poorly understood and diseased epigenomic states are only beginning to be sampled. In this commentary, we discuss the methodological insights gained from previous epigenetic and genetic studies, particularly EWAS, genome-wide association studies (GWAS), and expression quantitative trait locus (eQTL) studies, in the hope that future studies will translate into novel disease insights and therapeutics.