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

Abstract

SummaryGenerally 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.

Environmentally sensitive hotspots in the methylome of the early human embryo

“…This was also observed at MEs on the Illumina array, confirming our previous observations 18,22 . Enrichment of ERVs at SoC-CpGs is notable since most environment-sensitive mouse MEs are associated with IAPs (which are rodent-specific ERVs) 27 , and Krab zinc-finger protein (KZFP)-mediated repression of transposable elements (TEs) including ERVs has been proposed as a driver of the rapid evolution of gene regulation 38 . The KZFP ZFP57 is particularly interesting in this respect since its binding to DNA is linked both to repression of TEs and to the maintenance of genomic imprints in the pre-implantation embryo 20,39 .…”

“…Variable methylation states at MEs are associated with neighbouring transposable elements (TEs) in murine models 26,27 , and we have previously observed enrichment for specific proximal endogenous retroviruses (ERV1 and ERVK) in screens for human MEs 18,22 . Here we found evidence for enrichment of human ERV1 and ERVK at SoC-CpGs, and for 4 ERV classes at MEs mapping to array background: ERV1, ERVK, ERVL and ERV-MaLR (Supplementary Table 7).…”

What viruses tell us about evolution and immunity: beyond Darwin?

“…The total number of IAP elements in the mouse genome is about 1000. About 100 of them have been identified recently as being variably methylated in C57BL/6 mice, they might, therefore, be involved in epigenetic regulation of gene expression, similar to agouti and axin fused . In germline cells, epigenetic marks are normally erased and remodeled in a process termed epigenetic reprogramming .…”

“…However, in some cases, modifications may escape eradication and they can be passed on to the offspring, whereby the altered epigenetic modifications typically return to the normal state within a few generations by dilution . For example, the epigenetic marks regulating agouti, axin fused , and a third locus have been shown to be transgenerationally inheritable . Epigenetic inheritance not directly mediated by DNA modifications but by small RNAs, termed paramutations, is presumably more stable over time .…”

Potential Impact of Space Environments on Developmental and Maturational Programs Which Evolved to Meet the Boundary Conditions of Earth: Will Maturing Humans Be Able to Establish a Functional Biologic System Set Point under Non-Earth Conditions?

“…Thus, while acknowledging that rats are not humans and rodent data does not translate well to humans, data from parallel mouse or rat experiments performed on Earth and on the ISS regarding pregnancy, birth, and maturation with two or more genetically different mouse strains could yield some interesting results regarding species-specific epigenetic changes, strain-specific changes, sex-specific alterations, and whether some systems are affected more than others. However, some reports indicate that epigenetic mechanisms may not be operative regarding inheritance in inbred mice [44], but that might be related to their ability to be inbred and not reflective of humans. In spite of this potential limitation, mice may be a good starting point.…”