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

Panpan Shi, Xukun Lu, Kairang Jin, Linlin Liu, Guoxing Yin, Wenying Wang, Jiao Yang, Lijuan Wang, Lijun Dong, Wei Xie () and Lin Liu ()
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Panpan Shi: Nankai University
Xukun Lu: Shandong University
Kairang Jin: Nankai University
Linlin Liu: Nankai University
Guoxing Yin: Nankai University
Wenying Wang: Tsinghua-Peking Center for Life Sciences
Jiao Yang: Nankai University
Lijuan Wang: Tsinghua-Peking Center for Life Sciences
Lijun Dong: Tsinghua-Peking Center for Life Sciences
Wei Xie: Tsinghua-Peking Center for Life Sciences
Lin Liu: Nankai University

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-62303-x

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