Search

The rapid rise in the incidence of obesity and associated metabolic disorders is a major public health challenge. Moreover, the frequency of disease risk has increased by an order of magnitude within a few decades. Despite our awareness that metabolic disease arises at the interface between genetic susceptibility and environmental factors (such as overnutrition and inactivity), we have not been able to curb the incidence of these disorders. With the advent of cost-effective whole-genome sequencing technologies has come the search for the genetic underpinnings of metabolic disorders; however, to date, only a small percentage of metabolic disease risk has been associated with genetic variants. This weak association with genetic variants has raised the intriguing possibility that metabolic disease risk could be transmitted from generation to generation via potentially modifiable non-genetic signals present in parental germ cells.

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.