Maternal and zygotic ZFP57 regulate coronary vascular formation and myocardium maturation in mouse embryo.

BACKGROUND: Genomic and epigenomic dynamics both play critical roles during embryogenesis. Zfp57 maintains genomic imprinting with both maternal and zygotic functions. In our previous study, we found that maternal and zygotic Zfp57 modulate NOTCH signaling during cardiac development. In this study, we investigated Zfp57 mutants from E11.5 to E13.5 to delineate its function during cardiac development. RESULTS: Here, we describe novel roles of maternal and zygotic Zfp57 during cardiovascular system development. We found that maternal and zygotic Zfp57 was required for coronary vascular development. Maternal and zygotic loss of Zfp57 perturbed the sprouting of the sinus venosus-derived endothelial cells and led to underdeveloped coronary vasculature, meanwhile, there was an ectopic overproduction of blood islands over the ventricles. Furthermore, loss of Zfp57 and failed vasculature disturbed myocardium maturation. Loss of maternal and zygotic Zfp57 resulted in hyper trabeculation and failed myocardium compaction. Zfp57 zygotic mutant (M+ Z- ) hearts displayed noncompaction cardiomyopathy at E18.5. CONCLUSIONS: Our results suggest that maternal and zygotic ZFP57 are essential for coronary vascular formation and myocardium maturation in mice. Our research provides evidence for the role of genomic imprinting during embryogenesis.

Zfp57 Exerts Maternal and Sexually Dimorphic Effects on Genomic Imprinting.

Zfp57 has both maternal and zygotic functions in mouse. It maintains genomic imprinting at most known imprinted regions and controls allelic expression of the target imprinted genes in mouse embryos. The DNA methylation imprint at many imprinting control regions (ICRs) is lost when both maternal and zygotic Zfp57 are absent in Zfp57 maternal-zygotic mutant mouse embryos. Interestingly, we found that DNA methylation at a few ICRs was partially lost without maternal Zfp57 in Zfp57 heterozygous mouse embryos derived from Zfp57 homozygous female mice. This suggests that maternal Zfp57 is essential for the maintenance of DNA methylation at a small subset of imprinted regions in mouse embryos. This maternal effect of Zfp57 was applied to allelic expression switch as well as expression levels of the corresponding imprinted genes. It is rather surprising that DNA methylation imprint was affected differently at Rasgrf1 and AK008011 imprinted regions in the female or male Zfp57 maternal-zygotic mutant embryos, with more significant loss of DNA methylation observed in the male mutant embryos. Loss of ZFP57 resulted in gender-specific differences in allelic expression switch and expression level changes of some imprinted genes in female or male mutant embryos. These results indicate maternal and sexually dimorphic effects of ZFP57 on genomic imprinting in mouse.

ZFP57 dictates allelic expression switch of target imprinted genes.

ZFP57 is a master regulator of genomic imprinting. It has both maternal and zygotic functions that are partially redundant in maintaining DNA methylation at some imprinting control regions (ICRs). In this study, we found that DNA methylation was lost at most known ICRs in Zfp57 mutant embryos. Furthermore, loss of ZFP57 caused loss of parent-of-origin-dependent monoallelic expression of the target imprinted genes. The allelic expression switch occurred in the ZFP57 target imprinted genes upon loss of differential DNA methylation at the ICRs in Zfp57 mutant embryos. Specifically, upon loss of ZFP57, the alleles of the imprinted genes located on the same chromosome with the originally methylated ICR switched their expression to mimic their counterparts on the other chromosome with unmethylated ICR. Consistent with our previous study, ZFP57 could regulate the NOTCH signaling pathway in mouse embryos by impacting allelic expression of a few regulators in the NOTCH pathway. In addition, the imprinted Dlk1 gene that has been implicated in the NOTCH pathway was significantly down-regulated in Zfp57 mutant embryos. Our allelic expression switch models apply to the examined target imprinted genes controlled by either maternally or paternally methylated ICRs. Our results support the view that ZFP57 controls imprinted expression of its target imprinted genes primarily through maintaining differential DNA methylation at the ICRs.