A Maternal-Zygotic Effect Gene, Zfp57, Maintains Both Maternal and Paternal Imprints

Abstract

Summary The mechanisms responsible for maintaining genomic methylation imprints in mouse embryos are not understood. We generated a knockout mouse in the Zfp57 locus encoding a KRAB zinc finger protein. Loss of just the zygotic function of Zfp57 causes partial neonatal lethality, while eliminating both maternal and zygotic functions of Zfp57 results in a highly penetrant embryonic lethality. In oocytes, absence of Zfp57 results in failure to establish maternal methylation imprints at the Snrpn imprinted region. Intriguingly, methylation imprints are re-acquired specifically at the maternally derived Snrpn imprinted region when the zygotic Zfp57 is present in embryos. This suggests that there may be DNA methylation-independent memory for genomic imprints. Zfp57 is also required for the post-fertilization maintenance of maternal and paternal methylation imprints at multiple imprinted domains. The effects on genomic imprinting are consistent with the maternal-zygotic lethality of Zfp57 mutants.

Genomic imprinting and its relevance to congenital disease, infertility, molar pregnancy and induced pluripotent stem cell

“…Zfp57 is an oocytederived maternal factor involved in preimplantation maintenance of both paternal and maternal imprints at multiple loci such as the paternally methylated intergenic ICR (IG-DMR) within the Dlk1-Meg3 locus (Meg3 is also known as Gtl2) and the maternally methylated Mest, Peg3 and Snrpn ICRs (Figure 1). 30 However, there are ICRs that are not affected in Zfp57 mutants (for example, H19 and Igf2r ICRs). 30 The mechanistic detail of this locus-specific protection is still lacking.…”

“…30 However, there are ICRs that are not affected in Zfp57 mutants (for example, H19 and Igf2r ICRs). 30 The mechanistic detail of this locus-specific protection is still lacking.…”

“…54 The phenotype can be explained by defects in either establishment or maintenance of methylation imprints but, as noted above, studies on Zfp57 knock-out mice showed that its predominant role is in maintenance after fertilization. 30 However, it is important to note that some individuals with hypomethylation at multiple ICRs carry no mutation in ZFP57, indicating the existence of other factors.…”

“…30 Among these, the first three seem common to all oocyte-methylated ICRs and could be prerequisites for imprint establishment. Transcription through ICRs may make the chromatin more accessible by the Dnmt3a-Dnmt3L complex; 26 unmethylated, but not methylated, H3K4 is the high-affinity binding target of Dnmt3L; 27 two CpG sites located 10-bp apart fit very well with the catalytic centers of the heterotetrameric Dnmt3a-Dnmt3L complex.…”

“…The involvement of Zfp57 appears to be more restricted, and so far the Snrpn ICR is its only known target in oocytes, although it is involved in imprint maintenance at multiple ICRs after fertilization (see later). 30 Therefore, the process of specificity determination seems complicated, and perhaps combinations of common and ICR-specific factors may eventually produce the specificity. An alternative view is that there is no specific targeting of methylation to DMRs; instead, they represent a subset of CpG islands that acquire methylation in oocytes in response to general mechanisms of methylation.…”