KRAB zinc finger proteins (KZFPs) represent one of the largest families of DNA-binding proteins in vertebrate genomes and appear to have evolved to silence transposable elements (TEs) including endogenous retroviruses through sequence-specific targeting of repressive chromatin states. ZFP57 is required to maintain the post-fertilization DNA methylation memory of parental origin at genomic imprints. Here we conduct RNA-seq and ChIP-seq analyses in normal and ZFP57 mutant mouse ES cells to understand the relative importance of ZFP57 at imprints, unique and repetitive regions of the genome. Over 80% of ZFP57 targets are TEs, however, ZFP57 is not essential for their repression. The remaining targets lie within unique imprinted and non-imprinted sequences. Though the loss of ZFP57 influences imprinted genes as expected, the majority of unique gene targets lose H3K9me3 with little effect on DNA methylation and very few exhibit alterations in expression. Comparison of ZFP57 mutants with DNA methyltransferase-deleted ES cells (TKO) identifies a remarkably similar pattern of H3K9me3 loss across the genome. These data define regions where H3K9me3 is secondary to DNA methylation and we propose that ZFP57 is the principal if not sole methylation-sensitive KZFP in mouse ES cells. Finally, we examine dynamics of DNA and H3K9 methylation during pre-implantation development and show that sites bound by ZFP57 in ES cells maintain DNA methylation and H3K9me3 at imprints and at non-imprinted regions on the maternally inherited chromosome throughout preimplantation development. Our analyses suggest the evolution of a rare DNA methylation-sensitive KZFP that is not essential for repeat silencing, but whose primary function is to maintain DNA methylation and repressive histone marks at germline-derived imprinting control regions.

中文翻译：

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ZFP57 对印迹域内外的转座因子和基因表达的调控。

KRAB 锌指蛋白 (KZFP) 代表了脊椎动物基因组中最大的 DNA 结合蛋白家族之一，并且似乎已经进化为通过抑制染色质状态的序列特异性靶向来沉默转座因子 (TE)，包括内源性逆转录病毒。ZFP57 需要在基因组印记处维持亲本来源的受精后 DNA 甲基化记忆。在这里，我们对正常和 ZFP57 突变小鼠 ES 细胞进行 RNA-seq 和 ChIP-seq 分析，以了解 ZFP57 在印记、基因组独特和重复区域的相对重要性。超过 80% 的 ZFP57 目标是 TE，但是，ZFP57 对于它们的镇压并不是必不可少的。其余目标位于独特的印记和非印记序列中。尽管 ZFP57 的丢失如预期的那样影响了印记基因，大多数独特的基因靶标丢失 H3K9me3，对 DNA 甲基化几乎没有影响，并且很少表现出表达改变。ZFP57 突变体与 DNA 甲基转移酶缺失的 ES 细胞 (TKO) 的比较确定了整个基因组中 H3K9me3 丢失的非常相似的模式。这些数据定义了 H3K9me3 继发于 DNA 甲基化的区域，我们认为 ZFP57 是小鼠 ES 细胞中的主要甲基化敏感 KZFP，如果不是唯一的话。最后，我们检查了植入前发育过程中 DNA 和 H3K9 甲基化的动态，并表明在整个植入前发育过程中，ES 细胞中 ZFP57 结合的位点在印记和母系遗传染色体上的非印记区域保持 DNA 甲基化和 H3K9me3。