Abstract
BackgroundSelective 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.ResultsHere, 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.ConclusionsThe work described here uncovers further roles for ZFP57-mediated regulation of genomic imprinting and identifies a novel mechanism for genetically determined monoallelic gene expression.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-015-0672-7) contains supplementary material, which is available to authorized users.
Highlights
Selective maintenance of genomic epigenetic imprints during pre-implantation development is required for parental origin-specific expression of imprinted genes
chromatin immunoprecipitation (ChIP)-seq reads were aligned in a strain-specific manner using a purpose developed allelespecific alignment pipeline (ASAP) using ~20.5 million single nucleotide polymorphisms (SNPs) between BL6 and Cast genomes obtained from Biomart and Sanger mouse genome databases [24, 25] with an overall BL6/ Cast read ratio close to one (Table 1)
158 endogenous ZFP57 targets were identified in embryonic stem (ES) cells (Additional file 2)
Summary
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. Previous studies demonstrated a critical role for the KRAB zinc finger protein ZFP57 in the maintenance of DNA methylation at multiple imprinted germline DMRs in mice and human [19, 20]. Failure to maintain DNA methylation imprints upon maternal-zygotic deletion of the protein resulted in embryonic lethality by E16.5. Two recently published studies analyzing ZFP57 null embryonic stem (ES) cells have shown hypomethylation at multiple imprinted loci akin to those observed in the maternal-zygotic mutants [21, 22]. This is consistent with studies demonstrating that methylation of a CpG within the binding motif is necessary for ZFP57 binding in vitro [21]
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