USP17L promotes the 2-cell program through deubiquitination of H2AK119ub1 and ZSCAN4 [ChIP-Seq]

Zygotic genome activation (ZGA) is the first transcription event after fertilization. A minor wave of ZGA (minor ZGA) precedes and is essential for the major wave of ZGA (major ZGA) in two-cell (2C) mouse embryos. A subset of minor ZGA genes (known as “2C” genes) are also activated in a rare population of embryonic stem cells (ESCs) (2C-like cells), which possess expanded developmental plasticity to both embryonic and extra-embryonic tissues, like 2-cell embryos. However, the functions of these 2C genes remain to be fully understood. Here, through knockdown, overexpression, and biochemical analyses, we find that one family of such 2C genes, Usp17l, plays essential roles in both transcriptional and post-translational regulation of the 2C program. Specifically, USP17LE, a member of the USP17L family, deubiquitinates H2AK119ub1 and promotes the expression of Dux and the downstream 2C genes, including Zscan4, Tcstv1, and retrotransposons such as MERVL, in ESCs. Moreover, USP17LE deubiquitinates and stabilizes ZSCAN4. In mouse pre-implantation embryos, Dux is marked by strong H2AK119ub1 at most stages except for the 1-cell and early 2-cell stages, and overexpression of Usp17le reduces H2AK119ub and further promotes the activation of Dux and 2C genes. Thus, our findings identify USP17L as a key regulator of the 2C program.