Potential Role of DNA Methylation as a Driver of Plastic Responses to the Environment Across Cells, Organisms, and Populations.

There is great interest in exploring epigenetic modifications as drivers of adaptive organismal responses to environmental change. Extending this hypothesis to populations, epigenetically driven plasticity could influence phenotypic changes across environments. The canonical model posits that epigenetic modifications alter gene regulation and subsequently impact phenotypes. We first discuss origins of epigenetic variation in nature, which may arise from genetic variation, spontaneous epimutations, epigenetic drift, or variation in epigenetic capacitors. We then review and synthesize literature addressing three facets of the aforementioned model: (i) causal effects of epigenetic modifications on phenotypic plasticity at the organismal level, (ii) divergence of epigenetic patterns in natural populations distributed across environmental gradients, and (iii) the relationship between environmentally induced epigenetic changes and gene expression at the molecular level. We focus on DNA methylation, the most extensively studied epigenetic modification. We find support for environmentally associated epigenetic structure in populations and selection on stable epigenetic variants, and that inhibition of epigenetic enzymes frequently bears causal effects on plasticity. However, there are pervasive confounding issues in the literature. Effects of chromatin-modifying enzymes on phenotype may be independent of epigenetic marks, alternatively resulting from functions and protein interactions extrinsic of epigenetics. Associations between environmentally induced changes in DNA methylation and expression are strong in plants and mammals but notably absent in invertebrates and nonmammalian vertebrates. Given these challenges, we describe emerging approaches to better investigate how epigenetic modifications affect gene regulation, phenotypic plasticity, and divergence among populations.