Allele-specific binding of ZFP57 in the epigenetic regulation of imprinted and non-imprinted monoallelic expression
Open accessAbstract
Background: Selective maintenance of genomic epigenetic imprints during pre-implantation development is required for parental origin-specific expression of imprinted genes. The Kruppel-like zinc finger protein ZFP57 acts as a factor necessary for maintaining the DNA methylation memory at multiple imprinting control regions in early mouse embryos and embryonic stem (ES) cells. Maternal-zygotic deletion of ZFP57 in mice presents a highly penetrant phenotype with no animals surviving to birth. Additionally, several cases of human transient neonatal diabetes are associated with somatic mutations in the ZFP57 coding sequence. Results: Here, we comprehensively map sequence-specific ZFP57 binding sites in an allele-specific manner using hybrid ES cell lines from reciprocal crosses between C57BL/6J and Cast/EiJ mice, assigning allele specificity to approximately two-thirds of all binding sites. While half of these are biallelic and include endogenous retrovirus (ERV) targets, the rest show monoallelic binding based either on parental origin or on genetic background of the allele. Parental-origin allele-specific binding is methylation-dependent and maps only to imprinting control differentially methylated regions (DMRs) established in the germline. We identify a novel imprinted gene, Fkbp6, which has a critical function in mouse male germ cell development. Genetic background-specific sequence differences also influence ZFP57 binding, as genetic variation that disrupts the consensus binding motif and its methylation is often associated with monoallelic expression of neighboring genes. Conclusions: The work described here uncovers further roles for ZFP57-mediated regulation of genomic imprinting and identifies a novel mechanism for genetically determined monoallelic gene expression.
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In a ChIP-Seq use case for ZFP57, alignments to an N-masked reference genome for reciprocal crosses between Black 6 and Cast/EiJ mice using Bowtie 2 followed by SNPsplit sorting identified allele-specific binding of ZFP57 to several imprinting control regions in a parental origin-specific manner.
“Alignments to an N-masked reference genome were performed for reciprocal crosses between Black 6 and Cast/EiJ mice using Bowtie 2, followed by SNPsplit sorting. This process was able to identify allele-specific binding of ZFP57 to several different imprinting control regions in a parental origin-specific manner, exemplified for the SNRPN locus in Figure 2.”
From SNPsplit: Allele-specific splitting of alignments between genomes with known SNP genotypes (2016) · cites this paper as [17]
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Experimental — accuracy not yet measuredZFP57 binding is methylation dependent and can be found exclusively on the maternal allele at the SNRPN locus.
“The binding of ZFB57 is methylation dependent and can be found exclusively on the maternal allele (genetic background of mother in forward cross: Black 6; mother in reverse cross: Cast).”
From SNPsplit: Allele-specific splitting of alignments between genomes with known SNP genotypes (2016) · cites this paper as [17]
ZFP57 interacts with the methylated parental-origin allele in hybrid embryonic stem cells.
“ZFP57 binding sites were mapped in hybrid ES cells, and ZFP57 was found to interact with the methylated parental-origin allele60.”
From Transcription factors as readers and effectors of DNA methylation (2016) · cites this paper as [60]
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DNA methylation dynamics of genomic imprinting in mouse development†
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- Authors
- Strogantsev, R., Krueger, F., Yamazawa, K., Shi, H., Gould, P., Goldman-Roberts, M., McEwen, K., Sun, B., Pedersen, R., & Ferguson-Smith, A. C.
- Affiliations
- Babraham Institute (GB)
- University of Cambridge (GB)
- Venue
- Genome Biology
- Published
- 2015-05-30
- Volume
- 16
- Issue
- 1
- Pages
- 112-112
- ISSN
- 1465-6906 (ISSN-L)
- PMC
- PMC4491874
- OpenAlex
- W2098398752
- Cited by
- 152
- References
- 69
- Citations by year
- 2026: 11 · 2025: 8 · 2024: 4 · 2023: 11 · 2022: 24 · 2021: 8 · 2020: 15 · 2019: 22 · 2018: 12 · 2017: 15 · 2016: 15 · 2015: 7
- FWCI
- 11.05
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Genome biology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Funders
- Wellcome Trust (095606, 095606/Z/11/Z)
- European Commission (317146, 290123)
- Biotechnology and Biological Sciences Research Council (BB/G020930/1)
- Japan Society for the Promotion of Science (15K15478, 25713040)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Syndromes and Imprinting
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- ZFP57, genomic imprinting, monoallelic expression, allele-specific binding, DNA methylation, imprinting control regions, differentially methylated regions, FKBP6, endogenous retroviruses, embryonic stem cells, genetic background effects, male germ cell development, transient neonatal diabetes, Krüppel-like zinc finger protein
- MeSH terms
- Alleles, Animals, Binding Sites, Cell Line, DNA-Binding Proteins, Mice, Inbred C57BL, Repressor Proteins, Genetic Variation, Genomic Imprinting, DNA Methylation, Histone Code, Mice, Kruppel-Like Transcription Factors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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