title: A molecular mechanism underlying ovarian dysfunction of polycystic ovary syndrome: hyperandrogenism induces epigenetic alterations in the granulosa cells.
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.
authors.affiliation: Department of Reproductive Endocrinology, Women's Hospital, School of Medicine, Zhejiang University, 1 Xueshi Road, Hangzhou, Zhejiang 310006, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Qu
authors.forename: Fang-Fang
authors.initials: FF
authors.lastname: Wang
authors.forename: Rong
authors.initials: R
authors.lastname: Yin
authors.forename: Guo-Lian
authors.initials: GL
authors.lastname: Ding
authors.forename: Mohamed
authors.initials: M
authors.lastname: El-Prince
authors.forename: Qian
authors.initials: Q
authors.lastname: Gao
authors.forename: Bi-Wei
authors.initials: BW
authors.lastname: Shi
authors.forename: Hui-Hui
authors.initials: HH
authors.lastname: Pan
authors.forename: Yi-Ting
authors.initials: YT
authors.lastname: Huang
authors.forename: Min
authors.initials: M
authors.lastname: Jin
authors.forename: Peter C K
authors.initials: PC
authors.lastname: Leung
authors.forename: Jian-Zhong
authors.initials: JZ
authors.lastname: Sheng
authors.forename: He-Feng
authors.initials: HF
authors.lastname: Huang
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D054304:Anti-Mullerian Hormone / Q000235:genetics; D002478:Cells, Cultured; D019175:DNA Methylation / Q000187:drug effects / Q000235:genetics; D013196:Dihydrotestosterone / Q000494:pharmacology; D005260:Female; D006107:Granulosa Cells / Q000187:drug effects / Q000378:metabolism; D006655:Histone Deacetylases / Q000235:genetics; D006801:Humans; D017588:Hyperandrogenism / Q000235:genetics*; D056971:Nuclear Receptor Co-Repressor 1 / Q000235:genetics; D011085:Polycystic Ovary Syndrome / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D000099186:Histone Deacetylase 3
chemical_list: D054304:Anti-Mullerian Hormone; D013196:Dihydrotestosterone; D006655:Histone Deacetylases; D056971:Nuclear Receptor Co-Repressor 1; D000099186:Histone Deacetylase 3; C539127:NCOR1 protein, human; C539129:Ncor1 protein, rat