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

2020 ◽  
Author(s):  
Tessa M. Bertozzi ◽  
Geula Hanin ◽  
Nozomi Takahashi ◽  
Anastasiya Kazachenka ◽  
Anne C. Ferguson-Smith
Keyword(s):  
Dna Methylation ◽  
Zinc Finger Protein ◽  
Epigenetic Modification ◽  
Full Length ◽  
Endogenous Retroviruses ◽  
Adjacent Gene ◽  
Long Terminal Repeats ◽  
Finger Protein ◽  
H3k9 Trimethylation ◽  
Functional Consequences

AbstractIntracisternal 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 (C57iap1solo) recently formed in the inbred C57BL/6J mouse strain. In contrast to the C57BL/6J full-length IAP at this locus (C57iap1full), C57iap1solo 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 C57iap1solo variant. C57iap1solo 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 C57iap1 as a genetically-induced epiallele with functional consequences establishes a new model to study transposable element repression and host-element co-evolution.

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

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Tessa M Bertozzi ◽  
Nozomi Takahashi ◽  
Geula Hanin ◽  
Anastasiya Kazachenka ◽  
Anne C Ferguson-Smith
Keyword(s):  
Dna Methylation ◽  
Zinc Finger Protein ◽  
Epigenetic Modification ◽  
Full Length ◽  
Endogenous Retroviruses ◽  
Adjacent Gene ◽  
Long Terminal Repeats ◽  
Finger Protein ◽  
H3k9 Trimethylation ◽  
Functional Consequences

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.

scholarly journals Zbtb24 binding protects promoter activity by antagonizing DNA methylation in mESCs

2019 ◽  
Author(s):  
Haoyu Wu ◽  
David San Leon Granado ◽  
Maja Vukic ◽  
Kelly K.D. Vonk ◽  
Cor Breukel ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Transcriptional Activation ◽  
Zinc Finger Protein ◽  
Epigenetic Modification ◽  
Embryonic Stem ◽  
Dna Hypomethylation ◽  
Finger Protein ◽  
Genome Bisulfite Sequencing ◽  
Methylation Patterns ◽  
Unmethylated State

ABSTRACTDNA methylation is a key epigenetic modification essential for normal development. How particular factors control DNA methylation patterns and activity of a given locus is incompletely understood. The zinc finger protein Zbtb24 has been implicated in transcriptional activation/repression and the DNA methylation maintenance pathway. Here, using whole genome bisulfite sequencing in mouse embryonic stem cells, we report that besides a general trend towards DNA hypomethylation, many genomic sites gain methylation in the absence of Zbtb24 and they include promoters of actively transcribed genes. DNA hypomethylation is not generally associated with gene expression changes, suggesting that additional epigenetic safeguards are in place that ensure silencing of the affected loci. Remarkably, we identify a set of genes that is particularly susceptible to Zbtb24 occupancy. At these sites, Zbtb24 binding is not only required for gene activity but also required for maintaining the unmethylated state of the promoter.

scholarly journals Ectopic targeting of CG DNA methylation in Arabidopsis with the bacterial SssI methyltransferase

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Wanlu Liu ◽  
Javier Gallego-Bartolomé ◽  
Yuxing Zhou ◽  
Zhenhui Zhong ◽  
Ming Wang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Zinc Finger ◽  
Zinc Finger Protein ◽  
Basic Research ◽  
Crop Plant ◽  
Open Chromatin ◽  
Histone Marks ◽  
It Impacts ◽  
Finger Protein

AbstractThe ability to target epigenetic marks like DNA methylation to specific loci is important in both basic research and in crop plant engineering. However, heritability of targeted DNA methylation, how it impacts gene expression, and which epigenetic features are required for proper establishment are mostly unknown. Here, we show that targeting the CG-specific methyltransferase M.SssI with an artificial zinc finger protein can establish heritable CG methylation and silencing of a targeted locus in Arabidopsis. In addition, we observe highly heritable widespread ectopic CG methylation mainly over euchromatic regions. This hypermethylation shows little effect on transcription while it triggers a mild but significant reduction in the accumulation of H2A.Z and H3K27me3. Moreover, ectopic methylation occurs preferentially at less open chromatin that lacks positive histone marks. These results outline general principles of the heritability and interaction of CG methylation with other epigenomic features that should help guide future efforts to engineer epigenomes.

scholarly journals Molecular basis for recognition of methylated and specific DNA sequences by the zinc finger protein Kaiso

2012 ◽  
Vol 109 (38) ◽  
pp. 15229-15234 ◽  
Author(s):  
Bethany A. Buck-Koehntop ◽  
Robyn L. Stanfield ◽  
Damian C. Ekiert ◽  
Maria A. Martinez-Yamout ◽  
H. Jane Dyson ◽  
...  
Keyword(s):  
Dna Sequence ◽  
Zinc Finger ◽  
Dna Sequences ◽  
Genome Stability ◽  
Target Genes ◽  
Zinc Finger Protein ◽  
Epigenetic Modification ◽  
Cpg Dinucleotides ◽  
Finger Protein ◽  
Dna Motif

Methylation of CpG dinucleotides in DNA is a common epigenetic modification in eukaryotes that plays a central role in maintenance of genome stability, gene silencing, genomic imprinting, development, and disease. Kaiso, a bifunctional Cys2His2 zinc finger protein implicated in tumor-cell proliferation, binds to both methylated CpG (mCpG) sites and a specific nonmethylated DNA motif (TCCTGCNA) and represses transcription by recruiting chromatin remodeling corepression machinery to target genes. Here we report structures of the Kaiso zinc finger DNA-binding domain in complex with its nonmethylated, sequence-specific DNA target (KBS) and with a symmetrically methylated DNA sequence derived from the promoter region of E-cadherin. Recognition of specific bases in the major groove of the core KBS and mCpG sites is accomplished through both classical and methyl CH···O hydrogen-bonding interactions with residues in the first two zinc fingers, whereas residues in the C-terminal extension following the third zinc finger bind in the opposing minor groove and are required for high-affinity binding. The C-terminal region is disordered in the free protein and adopts an ordered structure upon binding to DNA. The structures of these Kaiso complexes provide insights into the mechanism by which a zinc finger protein can recognize mCpG sites as well as a specific, nonmethylated regulatory DNA sequence.

scholarly journals Methylomic Analysis Identifies Frequent DNA Methylation of Zinc Finger Protein 582 (ZNF582) in Cervical Neoplasms

PLoS ONE ◽  
2012 ◽  
Vol 7 (7) ◽  
pp. e41060 ◽  
Author(s):  
Rui-Lan Huang ◽  
Cheng-Chang Chang ◽  
Po-Hsuan Su ◽  
Yu-Chih Chen ◽  
Yu-Ping Liao ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Zinc Finger ◽  
Zinc Finger Protein ◽  
Cervical Neoplasms ◽  
Finger Protein

scholarly journals KRAB zinc finger protein diversification drives mammalian interindividual methylation variability

2020 ◽  
Vol 117 (49) ◽  
pp. 31290-31300 ◽  
Author(s):  
Tessa M. Bertozzi ◽  
Jessica L. Elmer ◽  
Todd S. Macfarlan ◽  
Anne C. Ferguson-Smith
Keyword(s):  
Dna Methylation ◽  
Zinc Finger ◽  
Histone Modifications ◽  
Molecular Mechanisms ◽  
Zinc Finger Protein ◽  
Large Family ◽  
Epigenetic Inheritance ◽  
Evolutionary Origins ◽  
Finger Protein ◽  
Genetic Background Effects

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 intransin 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.

scholarly journals Gv1, a zinc finger gene controlling endogenous MLV expression

2021 ◽  
Author(s):  
George R Young ◽  
Aaron K W Ferron ◽  
Veera Panova ◽  
Urszula Eksmond ◽  
Peter L Oliver ◽  
...  
Keyword(s):  
Zinc Finger ◽  
Zinc Finger Protein ◽  
Inbred Mice ◽  
Leukemia Virus ◽  
Endogenous Retroviruses ◽  
Finger Protein ◽  
Long Read ◽  
Necessary And Sufficient ◽  
Epigenetic Suppression

Abstract The genomes of inbred mice harbor around 50 endogenous murine leukemia virus (MLV) loci, although the specific complement varies greatly between strains. The Gv1 locus is known to control the transcription of endogenous MLVs and to be the dominant determinant of cell-surface presentation of MLV envelope, the GIX antigen. Here we identify a single Krüppel-associated box zinc finger protein (ZFP) gene, Zfp998, as Gv1 and show it to be necessary and sufficient to determine the GIX+ phenotype. By long-read sequencing of BAC clones from 129 mice, the prototypic GIX+ strain, we reveal the source of sufficiency and deficiency as splice-acceptor variations and highlight the varying origins of the chromosomal region encompassing Gv1. Zfp998 becomes the second identified ZFP gene responsible for epigenetic suppression of endogenous MLVs in mice and further highlights the prominent role of this gene family in control of endogenous retroviruses.

scholarly journals Rate of Recombinational Deletion among Human Endogenous Retroviruses

2007 ◽  
Vol 81 (17) ◽  
pp. 9437-9442 ◽  
Author(s):  
Robert Belshaw ◽  
Jason Watson ◽  
Aris Katzourakis ◽  
Alexis Howe ◽  
John Woolven-Allen ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
Full Length ◽  
Endogenous Retroviruses ◽  
Single Mutation ◽  
Long Terminal Repeats ◽  
Recombination Rates ◽  
Human Endogenous Retroviruses ◽  
Deletion Rate ◽  
Terminal Repeats ◽  
The Relationship

ABSTRACT The fate of most human endogenous retroviruses (HERVs) has been to undergo recombinational deletion. This process involves homologous recombination between the flanking long terminal repeats (LTRs) of a full-length element, leaving a relic structure in the genome termed a solo LTR. We examined loci in one family, HERV-K(HML2), and found that the deletion rate decreased markedly with age: the rate among recently integrated loci was almost 200-fold higher than that among loci whose insertion predated the divergence of humans and chimpanzees (8 × 10−5 and 4 × 10−7 recombinational deletion events per locus per generation, respectively). One hypothesis for this finding is that increasing mutational divergence between the flanking LTRs reduces the probability of homologous recombination and thus the rate of solo LTR formation. Consistent with this idea, we were able to replicate the observed rates by a simulation in which the probability of recombinational deletion was reduced 10-fold by a single mutation and 100-fold by any additional mutations. We also discuss the evidence for other factors that may influence the relationship between locus age and the rate of deletion, for example, host recombination rates and selection, and highlight the consequences of recombinational deletion for dating recent HERV integrations.

Sign in / Sign up

Export Citation Format

Share Document