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.

Dr. Xinyi Lu is a Principal Investigator of State Key Lab of Medicinal Chemical Biology, Nankai University. He obtained his PhD from National University of Singapore on 2013 and carried out his PostDoc training in Genome Institute of Singapore. He obtained supports from National Thousand Young Talents Program in 2015 and joined Nankai University in the same year. His current research directions are 1. Epigenetic regulation of endogenous retroviruses in stem cells; 2. Function of transposable elements (TE) and TE-derived lncRNAs; 3. Function of RNA binding proteins in diseases. Dr. Xinyi Lu has published on Nature Cell Biology, Nature Structural & Molecular Biology, Nucleic Acids Research and other journals as corresponding author or first author.