{"title":"Testosterone-Induced H3K27 Deacetylation Participates in Granulosa Cell Proliferation Suppression and Pathogenesis of Polycystic Ovary Syndrome.","authors":"Xiaomei Tong, Zhanhong Hu, Hanjing Zhou, Yingyi Zhang, Yin-Li Zhang, Songying Zhang, Jiamin Jin","doi":"10.1016/j.ajpath.2024.08.012","DOIUrl":null,"url":null,"abstract":"<p><p>Polycystic ovary syndrome (PCOS) is the leading cause of infertility in reproductive-age women. Hyperandrogenism, polycystic ovaries, and chronic anovulation are its typical clinical features. However, the correlation between hyperandrogenism and ovarian follicle growth aberrations remains undisclosed. To advance our understanding of the molecular alterations in ovarian granulosa cells (GCs) with excessive androgen, epigenetic changes and affected gene expression in human granulosa-lutein cells and immortalized human GCs were evaluated. A PCOS mouse model induced by dihydrotestosterone was also established. This study found excessive testosterone significantly decreased the acetylation of lysine 27 on histone H3 (H3K27ac). H3K27ac chromatin immunoprecipitation- sequencing data showed down-regulated expression of cell cycle-related genes (CCND1/CCND3/PCNA), which was confirmed by real-time quantitative PCR and Western blot analysis. Testosterone application impeding cell proliferation was also proved by Ki-67 immunofluorescence and flow-cytometric analysis. Moreover, testosterone influenced CK2α nuclear translocation, which increased the phosphorylation level of histone deacetylase 2 (HDAC2). Inhibition of CK2α nuclear translocation or silenced HDAC2 expression efficiently retarded H3K27 acetylation. Meanwhile, PCOS mouse model experiments also demonstrated decreased H3K27ac and enhanced HDAC2 phosphorylation in GCs. Cell proliferation-related genes were also down-regulated in PCOS mouse GCs. In conclusion, hyperandrogenism in human and mouse GCs caused H3K27Ac aberrations, which are associated with CK2α nuclear translocation and HDAC2 phosphorylation, participating in abnormal follicle development in patients with PCOS.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":null,"pages":null},"PeriodicalIF":4.7000,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"American Journal of Pathology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.ajpath.2024.08.012","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PATHOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Polycystic ovary syndrome (PCOS) is the leading cause of infertility in reproductive-age women. Hyperandrogenism, polycystic ovaries, and chronic anovulation are its typical clinical features. However, the correlation between hyperandrogenism and ovarian follicle growth aberrations remains undisclosed. To advance our understanding of the molecular alterations in ovarian granulosa cells (GCs) with excessive androgen, epigenetic changes and affected gene expression in human granulosa-lutein cells and immortalized human GCs were evaluated. A PCOS mouse model induced by dihydrotestosterone was also established. This study found excessive testosterone significantly decreased the acetylation of lysine 27 on histone H3 (H3K27ac). H3K27ac chromatin immunoprecipitation- sequencing data showed down-regulated expression of cell cycle-related genes (CCND1/CCND3/PCNA), which was confirmed by real-time quantitative PCR and Western blot analysis. Testosterone application impeding cell proliferation was also proved by Ki-67 immunofluorescence and flow-cytometric analysis. Moreover, testosterone influenced CK2α nuclear translocation, which increased the phosphorylation level of histone deacetylase 2 (HDAC2). Inhibition of CK2α nuclear translocation or silenced HDAC2 expression efficiently retarded H3K27 acetylation. Meanwhile, PCOS mouse model experiments also demonstrated decreased H3K27ac and enhanced HDAC2 phosphorylation in GCs. Cell proliferation-related genes were also down-regulated in PCOS mouse GCs. In conclusion, hyperandrogenism in human and mouse GCs caused H3K27Ac aberrations, which are associated with CK2α nuclear translocation and HDAC2 phosphorylation, participating in abnormal follicle development in patients with PCOS.
期刊介绍:
The American Journal of Pathology, official journal of the American Society for Investigative Pathology, published by Elsevier, Inc., seeks high-quality original research reports, reviews, and commentaries related to the molecular and cellular basis of disease. The editors will consider basic, translational, and clinical investigations that directly address mechanisms of pathogenesis or provide a foundation for future mechanistic inquiries. Examples of such foundational investigations include data mining, identification of biomarkers, molecular pathology, and discovery research. Foundational studies that incorporate deep learning and artificial intelligence are also welcome. High priority is given to studies of human disease and relevant experimental models using molecular, cellular, and organismal approaches.