Figure 1. Developmental origins of metastable epialleles and how this is reflected in DNA methylation.

(A) For some parts of the genome, the decision to establish a euchromatic (left, bottom panel) or heterochromatic state (right, lower panel) is stochastic, occurs prior to germ layer specification and can vary from cell to cell. There is evidence that environmental factors can shift the balance of this decision towards one state or the other. Once the epigenetic state is established for a given cell, it is stably inherited to the mitotic progeny of that cell (middle panel). Therefore, the adult organism is an epigenetic mosaic representative of the proportion of cells that established one state or the other in early development. In the case of metastatic epialleles at the Agouti locus in mice, this is reflected by coat colour (top panel). Only 0.1% of the genome seems to behave in this manner. (B) The epigenetic state of metastable epialleles is established prior to differentiation of the three germ layers. This is reflected by covariation in the bulk methylation level of tissues derived from each germ layer (endoderm, mesoderm, ectoderm).