USP17L promotes the 2-cell-like program through deubiquitination of H2AK119ub1 and ZSCAN4

In mouse, minor zygotic genome activation (ZGA) precedes and is essential for major ZGA in two-cell (2C) embryos. A subset of ZGA genes (known as “2C” genes) are also activated in a rare population of embryonic stem cells (ESCs) (2C-like cells). However, the functions of the 2C genes are not fully understood. Here, we find that one family of the 2C genes, Usp17l , plays critical roles in transcriptional and post-translational regulation of the 2C-like state in mESCs. Specifically, USP17LE, a member of the USP17L family, deubiquitinates H2AK119ub1 and promotes the expression of Dux and the downstream 2C genes and retrotransposons. Moreover, USP17LE deubiquitinates and stabilizes ZSCAN4. In mouse pre-implantation embryos, Dux is marked by strong H2AK119ub1 except for the 1-cell and early 2-cell stages. Usp17le overexpression reduces H2AK119ub1 and promotes Dux and 2C gene activation. Thus, our findings identify USP17L as a potential regulator of the 2C program.