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

Cell. 2018 Nov 15;175(5):1259-1271.e13. doi: 10.1016/j.cell.2018.09.043. Epub 2018 Oct 25.


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-color locus, providing an alternative promoter that is variably DNA methylated in genetically identical individuals. This results in variable expressivity of coat color 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 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 fertilization and re-established as variable loci in the next generation, indicating reconstruction of metastable epigenetic states and challenging the generalizability of non-genetic inheritance at these regions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Agouti Signaling Protein / genetics
  • Animals
  • Binding Sites
  • CCCTC-Binding Factor / chemistry
  • CCCTC-Binding Factor / metabolism
  • DNA Methylation*
  • Epigenesis, Genetic*
  • Genes, Intracisternal A-Particle*
  • Genetic Loci
  • Genome
  • Genomic Instability*
  • Heredity
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Protein Binding
  • Retroelements
  • Transcription, Genetic


  • Agouti Signaling Protein
  • CCCTC-Binding Factor
  • Ctcf protein, mouse
  • Retroelements