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A molecular mechanism underlying ovarian dysfunction of polycystic ovary syndrome: hyperandrogenism induces epigenetic alterations in the granulosa cells

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Abstract

The objective of this study was to explore whether hyperandrogenism induces epigenetic alterations of peroxisome proliferator-activated receptor gamma 1 (PPARG1), nuclear corepressor 1 (NCOR1), and histone deacetylase 3 (HDAC3) genes in granulosa cells (GCs) of polycystic ovary syndrome (PCOS) women and whether these alterations are involved in the ovarian dysfunction induced by hyperandrogenism. Thirty-two infertile PCOS women and 147 infertile women with tubal blockage were recruited. PCOS women were divided into the hyperandrogenism (HA) PCOS group (n = 13) and nonhyperandrogenism (N-HA) PCOS group (n = 19). Sixty female Sprague-Dawley rats were used for PCOS model establishment. In GCs of HA PCOS women, PPARG1 mRNA expression was lower, whereas NCOR1 and HDAC3 mRNA expression were higher than N-HA PCOS women and controls (P < 0.05). When all women were divided into successful and failed pregnancy subgroups according to the following clinical pregnancy outcome, we found lower PPARG1 mRNA levels and higher NCOR1 and HDAC3 mRNA levels in the failed subgroup of HA PCOS (P < 0.05). Two hypermethylated CpG sites in the PPARG1 promoter and five hypomethylated CpG sites in the NCOR1 promoter were observed only in HA PCOS women (P < 0.01 to P < 0.0005). The acetylation levels of histone H3 at lysine 9 and p21 mRNA expression were decreased in human GCs treated with dihydrotestosterone in vitro (P < 0.05). PCOS rat models also showed alterations of PPARG1, NCOR1, and HDAC3 mRNA expression and methylation changes of PPARG1 and NCOR1, consistent with the results from humans. Hyperandrogenism induces the epigenetic alterations of PPARG1, NCOR1, and HDAC3 in GCs, which are involved in the ovarian dysfunction of HA PCOS.

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Acknowledgements

We thank Dr. Run-Ju Zhang, Dr. Yan-Ting Wu, Dr. Xin-Mei Liu, Dr. Ting-Ting Wang, Dr. Xi-Jing Chen (Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou, China), Ping-Ping Lv (School of Medicine, Zhejiang University, Hangzhou, China), and Dr. Jue Zhou (College of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, China) for their kind help with the present research.

Grants

This work was supported by the National Basic Research Program of China (2012CB944900), Key Projects in the National Science Technology Pillar Program in the Twelfth Five-Year Plan Period, China (no. 2012BAI32B00), China–Canada Joint Health Research Initiative—Grants Program (no. 30711120577), National Key Research Program of China (no. 2006CB944006), Zhejiang Provincial Natural Science Foundation of China (no. Z2110063), and Natural Science Foundation of Zhejiang Province, China (no. 2090387).

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No commercial or other associations that might pose a conflict of interest in connection with the submitted material are to be disclosed.

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Authors and Affiliations

  1. Department of Reproductive Endocrinology, Women’s Hospital, School of Medicine, Zhejiang University, 1 Xueshi Road, Hangzhou, Zhejiang, 310006, China

    Fan Qu, Fang-Fang Wang, Rong Yin, Guo-Lian Ding, Mohamed El-prince, Bi-Wei Shi, Hui-Hui Pan, Yi-Ting Huang, Min Jin, Peter C. K. Leung & He-Feng Huang

  2. Key Laboratory of Reproductive Genetics, Ministry of Education of China, Hangzhou, China, 310006

    Fan Qu, Bi-Wei Shi, Hui-Hui Pan, Min Jin, Jian-Zhong Sheng & He-Feng Huang

  3. Department of Pathophysiology, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China, 310058

    Qian Gao & Jian-Zhong Sheng

  4. Department of Obstetrics and Gynecology, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada, V6H 3N1

    Peter C. K. Leung

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  1. Fan Qu
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  2. Fang-Fang Wang
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  3. Rong Yin
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  9. Yi-Ting Huang
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  10. Min Jin
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  12. Jian-Zhong Sheng
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  13. He-Feng Huang
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Corresponding author

Correspondence to He-Feng Huang.

Additional information

Fan Qu and Fang-Fang Wang contributed equally to the study.

Precis

Hyperandrogenism induces methylation and acetylation alterations in ovaries, which are involved in the mechanism underlying ovarian dysfunction of polycystic ovary syndrome.

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Qu, F., Wang, FF., Yin, R. et al. A molecular mechanism underlying ovarian dysfunction of polycystic ovary syndrome: hyperandrogenism induces epigenetic alterations in the granulosa cells. J Mol Med 90, 911–923 (2012). https://doi.org/10.1007/s00109-012-0881-4

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  • DOI: https://doi.org/10.1007/s00109-012-0881-4

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