Abstract
Intracisternal A-particles (IAPs) are endogenous retroviruses (ERVs) responsible for most insertional mutations in the mouse. Full-length IAPs harbour genes flanked by long terminal repeats (LTRs). Here, we identify a solo LTR IAP variant (Iap5-1solo) recently formed in the inbred C57BL/6J mouse strain. In contrast to the C57BL/6J full-length IAP at this locus (Iap5-1full), Iap5-1solo lacks DNA methylation and H3K9 trimethylation. The distinct DNA methylation levels between the two alleles are established during preimplantation development, likely due to loss of KRAB zinc finger protein binding at the Iap5-1solo variant. Iap5-1solo methylation increases and becomes more variable in a hybrid genetic background yet is unresponsive to maternal dietary methyl supplementation. Differential epigenetic modification of the two variants is associated with metabolic differences and tissue-specific changes in adjacent gene expression. Our characterisation of Iap5-1 as a genetically induced epiallele with functional consequences establishes a new model to study transposable element repression and host-element co-evolution.
Highlights
More than 10% of the mouse genome is made up of endogenous retroviruses (ERVs) (Smit et al, 2015)
This provides evidence for short-distance spreading of DNA methylation levels from Intracisternal A-particles (IAPs)-Pgm2 into bordering DNA and suggests that the methylation differences observed between individuals are intrinsic to the IAP-Pgm2 element rather than a reflection of differential methylation of the insertion site prior to integration
We demonstrated that the Iap5-1full and Iap5-1solo variants display distinct DNA and H3K9 methylation profiles which are associated with differential adjacent gene expression and altered metabolism, establishing the Iap5-1 locus as a valuable endogenous system to study the mechanisms, evolution, and functional implications of transposable elements (TEs) repression in both the germline and soma
Summary
More than 10% of the mouse genome is made up of endogenous retroviruses (ERVs) (Smit et al, 2015). Most ERVs have lost their mobilisation potential due to mutational decay, they retain the ability to modulate host genome function through the use of transcriptional regulation motifs contained in their sequences. Our bodies have evolved the ability to chemically strap down retroviral sequences by adding methyl groups to them and by modifying the proteins they are wrapped around Some of these endogenous retroviruses can dodge such so-called epigenetic modifications and disrupt genome function as a result. Our study establishes the Iap locus as a naturally occurring and biologically relevant model in the widely studied reference mouse strain to investigate the mechanisms underlying TE repression, inter-individual methylation variability, and TE-induced disruptions to host genome function
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