Nat. Genet. https://doi.org/10.1038/s41588-021-00898-9 (2021)
Non-genetic inheritance, and the potential effect of the environment on epigenetic states, is a topic of considerable societal interest. One model to study epigenetic inheritance is metastable epialleles, like the murine Agouti viable yellow (Avy) locus, which functions as a promoter for the coat color gene Agouti when unmethylated. Recently, an array of mouse metastable epialleles have been identified, in which endogenous retroviruses of the intracisternal A-particle (IAP) class present different degrees of DNA methylation in genetically identical individuals. Writing in Nature Genetics, Tessa Bertozzi and colleagues systematically investigate whether this repertoire of metastable epialleles is sensitive to different environmental alterations previously thought to impact epigenetic states. The authors show that neither ageing nor several other environmental perturbations—maternal exposure to the endocrine-disruptor bisphenol A (BPA), obesogenic diet, and dietary exposure to methyl-donors—have significant effects on the DNA methylation levels of these metastable epialleles. Furthermore, while the authors identify changes in DNA methylation and nearby transcription at these regions in a mouse model of abnormal folate metabolism, they provide evidence that most of these effects are probably genetically driven, mediated by differential targeting of strain-specific KRAB zinc-finger proteins. Overall, these findings question the extent to which environmental perturbations can actually affect epigenetic states in mammals. This has implications for human disease and for our understanding of the mechanisms underlying gene–environment interactions.
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