Zscan4c activates endogenous retrovirus MERVL and cleavage embryo genes

作者：Weiyu Zhang, Fuquan Chen, Ruiqing Chen, Dan Xie, Jiao Yang, Xin Zhao, Renpeng Guo, Yongwang Zhang, Yang Shen, Jonathan Göke, Lin Liu, Xinyi Lu · 发表于：Nucleic Acids Research · 年份：2019 · DOI：10.1093/nar/gkz594 · 被引用次数：117 · 研究领域：Chromosomal and Genetic Variations、CRISPR and Genetic Engineering、Genomics and Chromatin Dynamics

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.