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

Elmer, Jessica L.; Ferguson‐Smith, Anne C.

doi:10.3390/v12080810

Cited by 14 publications

(6 citation statements)

References 138 publications

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“…Our work is consistent with previous research on strain-specific modifiers ( 35 ). A growing number of ERV-derived mouse mutations whose phenotypic penetrance is dependent on genetic background have been associated with modifier genes located in an interval on Chr13-cl.…”

Section: Discussionsupporting

confidence: 93%

KRAB zinc finger protein diversification drives mammalian interindividual methylation variability

Bertozzi

Elmer

Macfarlan

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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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.

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Section: Discussionsupporting

confidence: 93%

KRAB zinc finger protein diversification drives mammalian interindividual methylation variability

Bertozzi

Elmer

Macfarlan

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…In addition, while the other studies outlined above largely have not pinpointed causal factors, the overlapping molecular and physiological QTL harbor clusters of newly emergent murine KZFPs (Kauzlaric et al , 2017; Bruno et al , 2019). This provides exciting future work into assigning causality to a rapidly evolving gene family whose divergence in different strain backgrounds may account for evolution of regulatory function that shapes development and disease (Elmer & Ferguson‐Smith, 2020).…”

Section: Discussionmentioning

confidence: 99%

Genetic control of the pluripotency epigenome determines differentiation bias in mouse embryonic stem cells

et al. 2021

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Genetically diverse pluripotent stem cells display varied, heritable responses to differentiation cues. Here, we harnessed these disparities through derivation of mouse embryonic stem cells from the BXD genetic reference panel, along with C57BL/6J (B6) and DBA/2J (D2) parental strains, to identify loci regulating cell state transitions. Upon transition to formative pluripotency, B6 stem cells quickly dissolved na€ ıve networks adopting gene expression modules indicative of neuroectoderm lineages, whereas D2 retained aspects of na€ ıve pluripotency. Spontaneous formation of embryoid bodies identified divergent differentiation where B6 showed a propensity toward neuroectoderm and D2 toward definitive endoderm. Genetic mapping identified major trans-acting loci co-regulating chromatin accessibility and gene expression in both na€ ıve and formative pluripotency. These loci distally modulated occupancy of pluripotency factors at hundreds of regulatory elements. One trans-acting locus on Chr 12 primarily impacted chromatin accessibility in embryonic stem cells, while in epiblast-like cells, the same locus subsequently influenced expression of genes enriched for neurogenesis, suggesting early chromatin priming. These results demonstrate genetically determined biases in lineage commitment and identify major regulators of the pluripotency epigenome.

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“…Previous studies have shown that in some cases IAP methylation is modulated by genetic background ( Bertozzi et al, 2020 ; Elmer and Ferguson-Smith, 2020 ; Rakyan et al, 2003 ; Wolff, 1971 ). To assess whether this is the case for Iap5-1 methylation, we carried out reciprocal crosses between B6 and wild-derived CAST/EiJ (CAST) mice (BC, B6 female × CAST male; CB, CAST female × B6 male).…”

Section: Resultsmentioning

confidence: 99%

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

Bertozzi

Takahashi

Hanin

et al. 2021

eLife

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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.

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

Cited by 14 publications

References 138 publications

KRAB zinc finger protein diversification drives mammalian interindividual methylation variability

KRAB zinc finger protein diversification drives mammalian interindividual methylation variability

Genetic control of the pluripotency epigenome determines differentiation bias in mouse embryonic stem cells

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

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