Identification, Characterization, and Heritability of Murine Metastable Epialleles: Implications for Non-genetic Inheritance.

Abstract

Generally repressed by epigenetic mechanisms, retrotransposons represent around 40% of the murine genome. At the Agouti viable yellow (Avy) locus, an endogenous retrovirus (ERV) of the intracisternal A-particle (IAP) class retrotransposed upstream of the agouti coat-colour locus, providing an alternative promoter which is variably DNA methylated in genetically identical individuals. This results in variable expressivity of coat colour that is inherited transgenerationally. Here, a systematic genome-wide screen identifies multiple C57BL/6J murine IAPs with Avy epigenetic properties. Each exhibits a stable methylation state within an individual but varies between individuals. Only in rare instances do they act as promoters 10 controlling adjacent gene expression. Their methylation state is locus-specific within an individual and their flanking regions are enriched for CTCF. Variably methylated IAPs are reprogrammed after fertilisation and reestablished as variable loci in the next generation, indicating reconstruction of metastable epigenetic states and challenging the generalizability of non-genetic inheritance at these regions.