Ubiquitin-Specific-Processing Protease 7 Regulates Female Germline Stem Cell Self-Renewal Through DNA Methylation
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Ubiquitin-Specific-Processing Protease 7 Regulates Female Germline Stem Cell Self-Renewal Through DNA Methylation Yongqiang Zhao 1 & Xiaoyong Li 1 & Geng Tian 1 & Xinyan Zhao 2 & Jiemin Wong 3 & Yue Shen 2 & Ji Wu 1,2 Accepted: 27 October 2020 # The Author(s) 2020
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. Keywords Usp7 . FGSCs . DNA methylation . Histone modification . Self-renewal . Differentiation
Introduction It has been reported that about 48.5 million couples suffer from infertility worldwide [28]. Disorders in oogenesis are These authors “Yongqiang Zhao, Xiaoyong Li, Geng Tian, Xinyan Zhao” contribute equally to this work Supplementary Information The online version contains supplementary material available at https://doi.org/10.1007/s12015-02010076-9. * Ji Wu [email protected] 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
the main cause of female infertility. Oogenesis is a highly complex process that is intricately regulated by the interactions of multiple genes and various signaling molecules, which makes the investigation of oogenesis disorders extremely challenging. Many risk factors, such as
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