Telomeres play vital roles in ensuring chromosome stability and are thus closely linked with the onset of aging and human disease. Telomeres undergo extensive lengthening during early embryogenesis. However, the detailed molecular mechanism of telomere resetting in early embryos remains unknown. Here, we show that Dcaf11 (Ddb1- and Cul4-associated factor 11) participates in telomere elongation in early embryos and 2-cell-like embryonic stem cells (ESCs). The deletion of Dcaf11 in embryos and ESCs leads to reduced telomere sister-chromatid exchange (T-SCE) and impairs telomere lengthening. Importantly, Dcaf11-deficient mice exhibit gradual telomere erosion with successive generations, and hematopoietic stem cell (HSC) activity is also greatly compromised. Mechanistically, Dcaf11 targets Kap1 (KRAB-associated protein 1) for ubiquitination-mediated degradation, leading to the activation of Zscan4 downstream enhancer and the removal of heterochromatic H3K9me3 at telomere/subtelomere regions. Our study therefore demonstrates that Dcaf11 plays important roles in telomere elongation in early embryos and ESCs through activating Zscan4.

端粒在确保染色体稳定中起着至关重要的作用，因此与衰老和人类疾病的发作密切相关。端粒在早期胚胎发生过程中经历了广泛的延长。然而，早期胚胎中端粒重置的详细分子机制仍然是未知的。在这里，我们显示Dcaf11（Ddb1和Cul4相关因子11）参与早期胚胎和2细胞样胚胎干细胞（ESC）的端粒延长。Dcaf11在胚胎和胚胎干细胞中的删除导致端粒姐妹染色单体交换（T-SCE）减少，并损害端粒的延长。重要的是，Dcaf11缺陷小鼠连续几代表现出逐渐的端粒侵蚀，并且造血干细胞（HSC）活性也大大受损。从机理上讲，Dcaf11靶向Kap1（与KRAB相关的蛋白1）进行泛素化介导的降解，从而导致Zscan4下游增强子的活化和端粒/亚端粒区域H3K9me3杂色的去除。因此，我们的研究表明，Dcaf11通过激活Zscan4在早期胚胎和ESC的端粒延长中起重要作用。