A spontaneous genetically induced epiallele at a retrotransposon shapes host genome function

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.

ZFP92, a KRAB domain zinc finger protein enriched in pancreatic islets, binds to B1/Alu SINE transposable elements and regulates retroelements and genes

“…While KRAB-ZFPs are generally considered to be transcriptional repressors, some KRAB-ZFPs activate gene transcription through interaction with activating complexes [ 64 , 65 ]. In any case, our studies of Zfp92 add to the growing evidence that IAPs and other LTR transposons act as cis -modifiers of gene expression and that KRAB-ZFPs regulate them in locus-, tissue-, species-, and strain-specific manners [ 25 , 66 – 69 ].…”

A role for worm cutl-24 in background- and parent-of-origin-dependent ER stress resistance

“…It is thus tempting to speculate that a heritable epigenetic polymorphism, dependent on parent sex and background, could drive the differences in phenotypic impact we have seen between the strains' alleles at cutl-24 and contribute to the overall parent-of-origin effects we have noted in ED3077 x N2 crosses. Such a mechanism at cutl-24 would dovetail with the classic literature describing paramutation in maize (Pilu 2015) and the more modern mapping of epialleles to phenotype in a number of systems (Quadrana et al 2014;Bertozzi et al 2021;Pignatta et al 2018).…”

Regulation of endogenous retroviruses in murine embryonic stem cells and early embryos

“…Epigenetic control is at the battlefront to defend against ERVs. Epigenetic modifications stabilize the repression of ERVs resulting from transcriptional silencing ( Rowe et al., 2013 ) and safeguard cells from the retrotransposition and replication of ERVs ( Ribet et al., 2008 ; Maksakova et al., 2009 ; Macfarlan et al., 2012 ; Bertozzi et al., 2021 ). Upon recognition of ERVs, transcription factors recruit various epigenetic repressors to stably silence ERVs by inducing heterochromatin formation.…”