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Review
. 2020 Jul 27;12(8):810.
doi: 10.3390/v12080810.

Strain-Specific Epigenetic Regulation of Endogenous Retroviruses: The Role of Trans-Acting Modifiers

Jessica L Elmer  1 , Anne C Ferguson-Smith  1
Affiliations
Review

Strain-Specific Epigenetic Regulation of Endogenous Retroviruses: The Role of Trans-Acting Modifiers

Jessica L Elmer et al. Viruses. .

Abstract

Approximately 10 percent of the mouse genome consists of endogenous retroviruses (ERVs), relics of ancient retroviral infections that are classified based on their relatedness to exogenous retroviral genera. Because of the ability of ERVs to retrotranspose, as well as their cis-acting regulatory potential due to functional elements located within the elements, mammalian ERVs are generally subject to epigenetic silencing by DNA methylation and repressive histone modifications. The mobilisation and expansion of ERV elements is strain-specific, leading to ERVs being highly polymorphic between inbred mouse strains, hinting at the possibility of the strain-specific regulation of ERVs. In this review, we describe the existing evidence of mouse strain-specific epigenetic control of ERVs and discuss the implications of differential ERV regulation on epigenetic inheritance models. We consider Krüppel-associated box domain (KRAB) zinc finger proteins as likely candidates for strain-specific ERV modifiers, drawing on insights gained from the study of the strain-specific behaviour of transgenes. We conclude by considering the coevolution of KRAB zinc finger proteins and actively transposing ERV elements, and highlight the importance of cross-strain studies in elucidating the mechanisms and consequences of strain-specific ERV regulation.

Keywords: ERVs; KRAB zinc finger proteins; epigenetic regulation; metastable epialleles; modifiers; strain-specific; transgenes.

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Conflict of interest statement

The authors declare no conflicts of interest associated with this manuscript.

Figures

Figure 1
Figure 1
Schematics for the insertion sites of endogenous retroviruses (ERVs) subject to strain-specific regulation (upper panel) and the effects of strain-specific modifier activity (lower panel) for (A) Dac1j and Dac2j, (B) clf1, and (C) Stab2-IAP. Sticks with closed circles represent methylated CpGs in the long terminal repeat (LTR) of the ERV; sticks with open circles represent unmethylated CpGs. Black dotted lines depict introns; thick black lines depict intergenic regions. The information is based on the latest patch release of the 2011 mouse assembly on the UCSC Genome Browser (GRCm38.p6); the coordinates given are mm10.
Figure 2
Figure 2
The mapped intervals of four strain-specific ERV modifiers—Mdac, Clf2, Snerv1 and Snerv2 and Stab2-modifier—on Chromosome 13. The underlying genes are separated into Krüppel-associated box domain zinc-finger protein (KRAB-ZFP) genes and non-KRAB-ZFP genes; the KRAB-ZFP clusters are highlighted and named as in [59]. Multiple isoforms are not shown.
Figure 3
Figure 3
Schematics depicting the insertion sites of the metastable epialleles (A) Avy and (B) AxinFu. Upper panel shows the intracisternal A-type particle (IAP) insertion relative to the affected gene; lower panel shows the functional consequence of the variably methylated IAP element. Coordinates are mm10. Sticks with closed circles represent methylated CpGs in the LTR of the ERV; sticks with open circles represent unmethylated CpGs. Black dotted lines depict introns; thick black lines depict intergenic regions.
Figure 4
Figure 4
The effect of genetic background on the phenotypic spectrum and inheritance of Avy upon maternal or paternal transmission. (A—upper) Maternal and paternal transmission of the Avy allele on VY/Wf (VY), YS/ChWf (YS), or AT/Wf (AT) genetic backgrounds. The percentage of pseudoagouti (PA) offspring depends upon the maternal coat colour phenotype, but not the paternal coat colour phenotype. Paternal transmission of Avy results in a higher percentage of PA offspring than the maternal transmission of Avy. Both maternally and paternally transmitted alleles are sensitive to genetic background effects, albeit in different ways. (A—lower) Paternal transmission of Avy is largely influenced by the genetic background of the dam. Paternal coat colour information is not included, as it is not available for all of the inter-strain crosses. B6J = C57BL/6J; AKR = AKR/LwNIcr. The data shown in the upper and lower panel are combined (based on the genotype and parent-of-origin) and adapted from [87,89,90]. (B—upper) On a C57BL/6J background, the maternal coat colour phenotype influences the coat colour of the Avy/a offspring, but the paternal coat colour phenotype has no effect on the phenotypic distribution of the offspring. When the Avy allele is paternally inherited through a 129P4/RrRk-fertilised oocyte, the paternal coat colour phenotype influences the coat colour of the Avy/a offspring; the percentage of PA and mottled is increased after passage through a 129P4/RrRk-fertilised oocyte compared to a C57BL/6J-fertilised oocyte. (B—lower) On a 129P4/RrRk background, the maternal and paternal tail kink phenotype influences the tail kink phenotype in the AxinFu/+ offspring. The phenotypic distributions are different upon the maternal versus paternal transmission of the allele. When the AxinFu allele is paternally inherited through a C57BL/6J-fertilised oocyte, the tail kink phenotype of the sire has no bearing on the phenotypic distribution in the AxinFu/+ offspring. The data shown in the upper and lower panel are adapted from [80,83]. Pedigrees: circle—female; square—male; diamond—unspecified.
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