2. Academic Validation
  3. USP17L promotes the 2-cell-like program through deubiquitination of H2AK119ub1 and ZSCAN4

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

  • Nat Commun. 2025 Aug 1;16(1):7071. doi: 10.1038/s41467-025-62303-x.
Panpan Shi # 1 2,  Xukun Lu # 3 4 5 6 7,  Kairang Jin 1 2,  Linlin Liu 1 2,  Guoxing Yin 1 2,  Wenying Wang 6 7,  Jiao Yang 1 2,  Lijuan Wang 6 7,  Lijun Dong 6 7,  Wei Xie 8 9,  Lin Liu 10 11 12 13
Affiliations

Affiliations

  • 1 State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China.
  • 2 Frontiers Science Center for Cell Responses, College of Life Sciences, Nankai University, Tianjin, China.
  • 3 State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, Shandong University, Jinan, Shandong, China.
  • 4 National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong, China.
  • 5 Key Laboratory of Reproductive Endocrinology (Shandong University), Ministry of Education, Jinan, Shandong, China.
  • 6 Tsinghua-Peking Center for Life Sciences, Beijing, China.
  • 7 Center for Stem Cell Biology and Regenerative Medicine, MOE Key Laboratory of Bioinformatics, New Cornerstone Science Laboratory, School of Life Sciences, Tsinghua University, Beijing, China.
  • 8 Tsinghua-Peking Center for Life Sciences, Beijing, China. xiewei121@tsinghua.edu.cn.
  • 9 Center for Stem Cell Biology and Regenerative Medicine, MOE Key Laboratory of Bioinformatics, New Cornerstone Science Laboratory, School of Life Sciences, Tsinghua University, Beijing, China. xiewei121@tsinghua.edu.cn.
  • 10 State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China. liulin@nankai.edu.cn.
  • 11 Frontiers Science Center for Cell Responses, College of Life Sciences, Nankai University, Tianjin, China. liulin@nankai.edu.cn.
  • 12 Tianjin Union Medical Center, Nankai University, Tianjin, China. liulin@nankai.edu.cn.
  • 13 Haihe Laboratory of Cell Ecosystem, Tianjin, China. liulin@nankai.edu.cn.
  • # Contributed equally.
PMID: 40750602 DOI: 10.1038/s41467-025-62303-x
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.

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