Epigenetics: How Genes and Environment Interact

Abstract

Two epigenetically regulated targets involved in the developmental origins of disease susceptibility are genes that are imprinted and those with metastable epialleles. Genes with metastable epialleles have highly variable expressions that result from random allelic changes in the epigenome. The isogenic agouti viable yellow (Avy) mouse harbors a metastable Agouti gene. Maternal exposure of the Avy mouse during pregnancy with nutritional supplements (e.g., methyl donors and genistein), toxicological agents (e.g., bisphenol A), and physical agents (e.g., ionizing radiation) changes the coat color and adult disease incidence in the offspring by altering DNA methylation at the Avy locus. These studies clearly demonstrate that the developmental origins of disease risk can result from alterations in the epigenome. Genomic imprinting is an epigenetic form of gene silencing that results in monoallelic, parent-oforigin- dependent gene expression. It evolved in mammals with the advent of placentation and viviparity approximately 150 million years ago. Since only a single mutation or epigenetic event is required to alter imprinted gene function, these genes are implicated in a number of complex diseases and neurological conditions. Imprinting is controlled by parental-specific epigenetic marks that are established during gametogenesis and in early embryonic development. We refer to the complete set of these cis-acting epigenetic regulatory elements as the imprintome, a distinct and specially tasked subset of the epigenome. Significant species variation in the repertoire of imprinted genes and their epigenetic regulation mean that only humans can be used to define our imprintome.