2. Academic Validation
  3. Ubiquitin-Specific-Processing Protease 7 Regulates Female Germline Stem Cell Self-Renewal Through DNA Methylation

Ubiquitin-Specific-Processing Protease 7 Regulates Female Germline Stem Cell Self-Renewal Through DNA Methylation

  • Stem Cell Rev Rep. 2021 Jun;17(3):938-951. doi: 10.1007/s12015-020-10076-9.
Yongqiang Zhao 1,  Xiaoyong Li 1,  Geng Tian 1,  Xinyan Zhao 2,  Jiemin Wong 3,  Yue Shen 2,  Ji Wu 4 5
Affiliations

Affiliations

  • 1 Renji Hospital, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Bio-X Institutes, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200240, China.
  • 2 Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, Ningxia Medical University, Yinchuan, 750004, China.
  • 3 Shanghai Key Laboratory of Regulatory Biology, Fengxian District Central Hospital-ECNU Joint Center of Translational Medicine, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China.
  • 4 Renji Hospital, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Bio-X Institutes, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200240, China. jiwu@sjtu.edu.cn.
  • 5 Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, Ningxia Medical University, Yinchuan, 750004, China. jiwu@sjtu.edu.cn.
PMID: 33151468 DOI: 10.1007/s12015-020-10076-9
Abstract

Ubiquitin-specific-processing protease 7 (USP7) is a key Deubiquitinase controlling epigenetic modification and regulating the self-renewal, proliferation, and differentiation of stem cells. However, the functions and mechanisms of action of USP7 on female germline stem cells (FGSCs) are unknown. Here, we demonstrated that USP7 regulated FGSC self-renewal via DNA methylation. The results of Cell Counting Kit-8 and 5-ethynyl-20-deoxyuridine assays showed that the viability and proliferation of FGSCs were negatively regulated by USP7. Moreover, USP7 downregulated the expression of self-renewal genes, such as Oct4, Etv5, Foxo1, and Akt, but upregulated the expression of differentiation-related genes including Stra8 and Sycp3. Mechanistically, RNA-seq results showed that USP7 negatively regulated FGSC self-renewal but positively modulated differentiation in FGSCs. Meanwhile, both overexpression and knockdown of USP7 resulted in significant changes in DNA methylation and histone modification in FGSCs. Additionally, RNA-seq and MeDIP-seq analyses showed that USP7 regulates the self-renewal and differentiation of FGSCs mainly through DNA methylation rather than histone modification, which was also confirmed by a rescue assay. Our study not only offers a novel method to research FGSC self-renewal and differentiation in view of epigenetic modifications, but also provides a deep understanding of FGSC development. Graphical Abstract.

Keywords

DNA methylation; Differentiation; FGSCs; Histone modification; Self-renewal; Usp7.

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