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Allele-specific binding of ZFP57 in the epigenetic regulation of imprinted and non-imprinted monoallelic expression.


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Authors

Strogantsev, Ruslan 
Krueger, Felix 
Yamazawa, Kazuki 
Shi, Hui 
Gould, Poppy 

Abstract

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.

Description

Keywords

Alleles, Animals, Binding Sites, Cell Line, DNA Methylation, DNA-Binding Proteins, Genetic Variation, Genomic Imprinting, Histone Code, Kruppel-Like Transcription Factors, Mice, Mice, Inbred C57BL, Repressor Proteins

Journal Title

Genome Biol

Conference Name

Journal ISSN

1474-7596
1474-760X

Volume Title

16

Publisher

Springer Science and Business Media LLC
Sponsorship
Wellcome Trust (095606/Z/11/Z)
Biotechnology and Biological Sciences Research Council (BB/G020930/1)
European Commission (290123)
European Commission (317146)
The authors acknowledge support from the Wellcome Trust, BBSRC, and EU FP7 Initial Training Networks INGENIUM (Marie-Curie Action 290123) and EpiHealthNet (Marie Curie Action 317146).