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KRAB Zinc Finger Protein Diversification Drives Mammalian Interindividual Methylation Variability

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KRAB zinc finger protein diversification drives mammalian interindividual methylation variability Tessa M. Bertozzia, Jessica L. Elmera, Todd S. Macfarlanb, and Anne C. Ferguson-Smitha,1 aDepartment of Genetics, University of Cambridge, CB2 3EH Cambridge, United Kingdom; and bThe Eunice Kennedy Shriver National Institute of Child Health and Human Development, The National Institutes of Health, Bethesda, MD 20892 Edited by Peter A. Jones, Van Andel Institute, Grand Rapids, MI, and approved October 28, 2020 (received for review August 19, 2020) Most transposable elements (TEs) in the mouse genome are DNA methylation of the Avy IAP is established early in devel- heavily modified by DNA methylation and repressive histone opment across genetically identical mice and is correlated with a modifications. However, a subset of TEs exhibit variable methyl- spectrum of coat color phenotypes, which in turn display trans- ation levels in genetically identical individuals, and this is associated generational inheritance and environmental sensitivity (11–13). with epigenetically conferred phenotypic differences, environ- Both the distribution and heritability of Avy phenotypes are mental adaptability, and transgenerational epigenetic inheritance. influenced by genetic background (14–16). Therefore, the iden- The evolutionary origins and molecular mechanisms underlying tification and characterization of the responsible modifier genes interindividual epigenetic variability remain unknown. Using a can provide insight into the mechanisms governing the early repertoire of murine variably methylated intracisternal A-particle establishment of stochastic methylation states at mammalian (VM-IAP) epialleles as a model, we demonstrate that variable DNA transposable elements. methylation states at TEs are highly susceptible to genetic back- We recently conducted a genome-wide screen for individual ground effects. Taking a classical genetics approach coupled with variably methylated IAPs (VM-IAPs) in the C57BL/6J (B6) in- genome-wide analysis, we harness these effects and identify a bred mouse strain (17, 18). The screen yielded a robust set of cluster of KRAB zinc finger protein (KZFP) genes that modifies experimentally validated regions to use as a model to investigate trans VM-IAPs in in a sequence-specific manner. Deletion of the interindividual epigenetic variability. Most VM-IAPs belong to cluster results in decreased DNA methylation levels and altered the IAPLTR1_Mm and IAPLTR2_Mm subclasses. Approxi- histone modifications at the targeted VM-IAPs. In some cases, mately half of them are full-length IAPs with an internal coding these effects are accompanied by dysregulation of neighboring region flanked by near-identical long terminal repeats (LTRs); genes. We find that VM-IAPs cluster together phylogenetically the other half are solo LTRs. While solo LTRs lack autonomous and that this is linked to differential KZFP binding, suggestive of retrotransposition potential, they are rich in regulatory se- an ongoing evolutionary arms race between TEs and this large quences and thus have the ability to affect host gene expression. family of epigenetic regulators. These findings indicate that KZFP vy divergence and concomitant evolution of DNA binding capabilities As observed for A , methylation variability is reestablished at are mechanistically linked to methylation variability in mammals, VM-IAPs from one generation to the next regardless of parental with implications for phenotypic variation and putative paradigms methylation states. Importantly, VM-IAP methylation levels are of mammalian epigenetic inheritance. consistent across all tissues of a single mouse, suggesting that individual-specific methylation states are acquired in early DNA methylation | endogenous retrovirus | KRAB zinc finger proteins | metastable epiallele | VM-IAP Significance omplex genetic interactions contribute to evolutionary fit- Transposable elements (TEs) are repetitive sequences with Cness, phenotypic variation, and disease risk. This is high- potential to mobilize, causing genetic diversity. To restrict this, lighted by comparative research across inbred mouse strains most TEs in the mouse are heavily epigenetically modified by showing that genetic background not only influences basic fitness DNA methylation. However, a few TEs exhibit variable meth- traits such as litter size and sperm count but also modulates the ylation levels that differ between individuals and confer an penetrance and expressivity of numerous gene mutations (1, 2). epigenetic, rather than genetic, influence on phenotype. The Despite the extensive documentation of strain-specific epistatic mechanism underlying this remains unknown. We report the effects in the mouse and their important implications for identification of a polymorphic cluster of KRAB zinc finger mechanistic insight and experimental reproducibility, the un- proteins (KZFPs) responsible for the epigenetic properties of derlying modifier genes remain uncharacterized in most cases. these variably methylated TEs, with deletion of the cluster Studies on foreign DNA insertions in the mouse genome profoundly influencing their DNA methylation and expression demonstrate that modifier genes can act via epigenetic pathways of adjacent genes. We propose that rapid KZFP divergence to drive genetic background–dependent phenotypes. A number underlies variable epigenetic states in mammals, with impli- of transgenes show predictable strain-specific DNA methylation cations for epigenetically conferred phenotypic differences patterns that are associated with transgene expression levels between individuals within and across generations. (3–6). Similar effects have been reported on the methylation Author contributions: T.M.B. and A.C.F.-S. designed research; T.M.B. and J.L.E. performed state of endogenous retroviruses (ERVs), as exemplified by the research; T.S.M. contributed new reagents/analytic tools; T.M.B. and J.L.E. analyzed data; 1J MusD ERV insertion Dac , which is methylated in mouse and T.M.B. and A.C.F.-S. wrote the paper. strains that carry the unlinked Mdac modifier gene (7, 8). In The authors declare no competing interest. 1J strains lacking the Mdac allele, Dac is unmethylated and the This article is a PNAS Direct Submission. mice exhibit limb malformation. This open access article is distributed under Creative Commons Attribution License 4.0 vy Another example is provided by the Agouti viable yellow (A ) (CC BY). metastable epiallele, in which a spontaneously inserted intra- 1To whom correspondence may be addressed. Email: [email protected]. cisternal A-particle (IAP) element influences the expression of This article contains supporting information online at https://www.pnas.org/lookup/suppl/ the downstream coat-color gene Agouti (9). IAPs are an evolu- doi:10.1073/pnas.2017053117/-/DCSupplemental. tionarily young and highly active class of ERV (10). Variable First published November 25, 2020. 31290–31300 | PNAS | December 8, 2020 | vol. 117 | no. 49 www.pnas.org/cgi/doi/10.1073/pnas.2017053117 Downloaded by guest on September 27, 2021 development prior to tissue differentiation. The interindividual of methylation variability in a pure B6 context. Based on our variability suggests that the establishment of VM-IAP methyl- findings, we propose that KZFP diversification is at the center of ation levels involves an early stochastic phase. the mechanism leading to variable epigenetic states within and Here, we introduce genetic variation to the study of VM-IAPs. across mouse strains. We report that half of the IAPs found to be variably methylated in B6 are present in 129 substrains, while the vast majority are Results absent from the CAST/EiJ (CAST) genome. We find that a VM-IAPs Exhibit Strain-Specific Methylation States. To determine subset of the shared loci between B6 and 129 display variable whether B6 VM-IAPs are variably methylated in other inbred methylation in both stains; the remainder are hypermethylated in mouse strains, we first cataloged their presence or absence in the × 129. Further methylation quantification in reciprocal B6 CAST 129S1/SvlmJ (129) and CAST strains based on a previous anal- F1 hybrids reveals pervasive maternal and zygotic genetic back- ysis of polymorphic ERVs (19). The classification was verified, ground effects. Through backcrossing and genetic mapping ex- and at times corrected, by visually assessing each locus in the 129 periments, we identify a cluster of KRAB zinc finger proteins and CAST reference genomes (20). Out of 51 experimentally (KZFPs) on chromosome 4 responsible for the strain-specific trans-acting hypermethylation of multiple B6 VM-IAPs. We validated B6 VM-IAPs (18), 25 of the IAPs are present in 129 and show that deletion of the KZFP cluster leads to a decrease in 3 are present in CAST (Fig. 1A). These numbers are consistent DNA and H3K9 methylation, an increase in H3K4 trimethyla- with our previous work showing that VM-IAPs are evolutionarily tion, and alterations in nearby gene expression at the targeted young IAPs (17) and were expected given the evolutionary rela- VM-IAPs. A phylogenetic sequence analysis demonstrates that tionship between these three strains: B6 and 129 are classical in- genetic sequence plays a crucial role not only in the targeting of bred laboratory strains derived from several subspecies, while VM-IAPs by strain-specific KZFPs but also in the establishment CAST is wild derived and evolutionarily more distant. A IAPLTR4 Present Absent RLTR46B RLTR46A2 LTR int.
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