Abstract
Most transposable elements (TEs) in the mouse genome are heavily modified by DNA methylation and repressive histone modifications. However, a subset of TEs exhibit variable methylation levels in genetically identical individuals, and this is associated with epigenetically conferred phenotypic differences, environmental adaptability, and transgenerational epigenetic inheritance. The evolutionary origins and molecular mechanisms underlying interindividual epigenetic variability remain unknown. Using a repertoire of murine variably methylated intracisternal A-particle (VM-IAP) epialleles as a model, we demonstrate that variable DNA methylation states at TEs are highly susceptible to genetic background effects. Taking a classical genetics approach coupled with genome-wide analysis, we harness these effects and identify a cluster of KRAB zinc finger protein (KZFP) genes that modifies VM-IAPs in trans in a sequence-specific manner. Deletion of the cluster results in decreased DNA methylation levels and altered histone modifications at the targeted VM-IAPs. In some cases, these effects are accompanied by dysregulation of neighboring genes. We find that VM-IAPs cluster together phylogenetically and that this is linked to differential KZFP binding, suggestive of an ongoing evolutionary arms race between TEs and this large family of epigenetic regulators. These findings indicate that KZFP divergence and concomitant evolution of DNA binding capabilities are mechanistically linked to methylation variability in mammals, with implications for phenotypic variation and putative paradigms of mammalian epigenetic inheritance.
Highlights
Most transposable elements (TEs) in the mouse genome are heavily modified by DNA methylation and repressive histone modifications
Similar effects have been reported on the methylation state of endogenous retroviruses (ERVs), as exemplified by the MusD ERV insertion Dac1J, which is methylated in mouse strains that carry the unlinked Mdac modifier gene (7, 8)
Through backcrossing and genetic mapping experiments, we identify a cluster of KRAB zinc finger proteins (KZFPs) on chromosome 4 responsible for the strain-specific trans-acting hypermethylation of multiple B6 variably methylated intracisternal A-particle (VM-intracisternal A-particle (IAP))
Summary
Most transposable elements (TEs) in the mouse genome are heavily modified by DNA methylation and repressive histone modifications. We find that VM-IAPs cluster together phylogenetically and that this is linked to differential KZFP binding, suggestive of an ongoing evolutionary arms race between TEs and this large family of epigenetic regulators These findings indicate that KZFP divergence and concomitant evolution of DNA binding capabilities are mechanistically linked to methylation variability in mammals, with implications for phenotypic variation and putative paradigms of mammalian epigenetic inheritance. DNA methylation of the Avy IAP is established early in development across genetically identical mice and is correlated with a spectrum of coat color phenotypes, which in turn display transgenerational inheritance and environmental sensitivity (11–13). Both the distribution and heritability of Avy phenotypes are influenced by genetic background (14–16). In strains lacking the Mdac allele, Dac1J is unmethylated and the mice exhibit limb malformation
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