Zinc finger protein Zscan4 is selectively expressed in mouse two-cell (2C) embryos undergoing zygotic genome activation (ZGA) and in a rare subpopulation of embryonic stem cells with 2C-like features. Here, we show that Zscan4 specifically recognizes a subset of (CA)_n microsatellites, repeat sequences prone to genomic instability. Zscan4-associated microsatellite regions are characterized by low nuclease sensitivity and high histone occupancy. In vitro, Zscan4 binds nucleosomes and protects them from disassembly upon torsional strain. Furthermore, Zscan4 depletion leads to elevated DNA damage in 2C mouse embryos in a transcription-dependent manner. Together, our results identify Zscan4 as a DNA sequence–dependent microsatellite binding factor and suggest a developmentally regulated mechanism, which protects fragile genomic regions from DNA damage at a time of embryogenesis associated with high transcriptional burden and genomic stress.

锌指蛋白 Zscan4 在正在进行合子基因组激活 (ZGA) 的小鼠双细胞 (2C) 胚胎以及具有 2C 样特征的罕见胚胎干细胞亚群中选择性表达。在这里，我们表明 Zscan4 特异性识别 (CA) _{n 个}微卫星的子集，即容易导致基因组不稳定的重复序列。 Zscan4 相关微卫星区域的特点是低核酸酶敏感性和高组蛋白占据率。在体外，Zscan4 结合核小体并保护它们在扭转应变时不被分解。此外，Zscan4 缺失会以转录依赖性方式导致 2C 小鼠胚胎中 DNA 损伤增加。总之，我们的结果将 Zscan4 确定为 DNA 序列依赖性微卫星结合因子，并提出了一种发育调节机制，可在与高转录负担和基因组应激相关的胚胎发生时保护脆弱的基因组区域免受 DNA 损伤。