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.

ZFP57是基因印迹的主要调节剂。它既具有母本功能又具有合子功能，在维持某些印迹控制区（ICR）的DNA甲基化方面部分冗余。在这项研究中，我们发现在Zfp57突变体胚胎中，大多数已知的ICR中DNA甲基化丢失。此外，ZFP57的缺失导致靶印迹基因的原产地依赖性单等位基因表达缺失。等位基因表达开关在ZFP57靶印迹基因在差动DNA甲基化的丧失在所述的ICR S发生Zfp57突变体胚胎。具体而言，在ZFP57缺失后，位于与原始甲基化ICR相同的染色体上的印迹基因的等位基因会切换其表达，以模拟未甲基化ICR的另一条染色体上的对应基因。与我们之前的研究一致，ZFP57可以通过影响NOTCH途径中一些调节子的等位基因表达来调节小鼠胚胎中的NOTCH信号通路。此外，已牵涉到NOTCH途径的印迹Dlk1基因在Zfp57中显着下调突变体胚胎。我们的等位基因表达转换模型适用于由母亲或父亲甲基化的ICR控制的受检目标印迹基因。我们的结果支持以下观点：ZFP57主要通过维持ICR处的差异DNA甲基化来控制其目标印迹基因的印迹表达。