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

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

Author information

1
Department of Genetics, University of Cambridge, Cambridge CB2 3EH, UK.
2
Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
3
Department of Genetics, University of Cambridge, Cambridge CB2 3EH, UK. Electronic address: afsmith@gen.cam.ac.uk.

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-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.

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