State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300350, People's Republic of China.
College of Pharmacy, Nankai University, Tianjin 300350, People's Republic of China.
Nucleic Acids Res. 2019 Sep 19;47(16):8485-8501. doi: 10.1093/nar/gkz594.
Endogenous retroviruses (ERVs) contribute to ∼10 percent of the mouse genome. They are often silenced in differentiated somatic cells but differentially expressed at various embryonic developmental stages. A minority of mouse embryonic stem cells (ESCs), like 2-cell cleavage embryos, highly express ERV MERVL. However, the role of ERVs and mechanism of their activation in these cells are still poorly understood. In this study, we investigated the regulation and function of the stage-specific expressed ERVs, with a particular focus on the totipotency marker MT2/MERVL. We show that the transcription factor Zscan4c functions as an activator of MT2/MERVL and 2-cell/4-cell embryo genes. Zinc finger domains of Zscan4c play an important role in this process. In addition, Zscan4c interacts with MT2 and regulates MT2-nearby 2-cell/4-cell genes through promoting enhancer activity of MT2. Furthermore, MT2 activation is accompanied by enhanced H3K4me1, H3K27ac, and H3K14ac deposition on MT2. Zscan4c also interacts with GBAF chromatin remodelling complex through SCAN domain to further activate MT2 enhancer activity. Taken together, we delineate a previously unrecognized regulatory axis that Zscan4c interacts with and activates MT2/MERVL loci and their nearby genes through epigenetic regulation.
内源性逆转录病毒 (ERVs) 约占小鼠基因组的 10%。它们通常在分化的体细胞中沉默，但在不同的胚胎发育阶段表达不同。少数小鼠胚胎干细胞 (ESCs)，如 2 细胞期胚胎，高度表达 ERV MERVL。然而，ERVs 在这些细胞中的作用及其激活机制仍知之甚少。在这项研究中，我们研究了阶段特异性表达的 ERVs 的调控和功能，特别关注全能性标记 MT2/MERVL。我们表明，转录因子 Zscan4c 作为 MT2/MERVL 和 2 细胞/4 细胞胚胎基因的激活因子发挥作用。Zscan4c 的锌指结构域在这个过程中起着重要作用。此外，Zscan4c 与 MT2 相互作用，并通过促进 MT2 的增强子活性来调节 MT2 附近的 2 细胞/4 细胞基因。此外，MT2 的激活伴随着 MT2 上 H3K4me1、H3K27ac 和 H3K14ac 沉积的增强。Zscan4c 还通过 SCAN 结构域与 GBAF 染色质重塑复合物相互作用，进一步激活 MT2 增强子活性。总之，我们描绘了一个以前未被识别的调节轴，即 Zscan4c 通过表观遗传调控与 MT2/MERVL 基因座及其附近基因相互作用并激活它们。
