Androgen receptor repression of gonadotropin-releasing hormone gene transcription via enhancer 1

• Published in: Molecular and cellular endocrinology Vol. 363; no. 1-2; pp. 92 - 99
• Main Authors: Brayman, Melissa J., Pepa, Patricia A., Mellon, Pamela L.
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier Ireland Ltd 05.11.2012
• Subjects: agonists; Androgen receptor; androgen receptors; androgens; animal ovaries; Animals; Base Sequence; Binding Sites; Cell Line; Chromatin Immunoprecipitation; DNA; Down-Regulation; Enhancer; Enhancer Elements, Genetic; gel electrophoresis; Gene Expression Regulation; Genes, Reporter; GnRH; gonadotropin-releasing hormone; Gonadotropin-Releasing Hormone - genetics; Gonadotropin-Releasing Hormone - metabolism; Hypothalamus; Luciferases - biosynthesis; Luciferases - genetics; messenger RNA; Metribolone - pharmacology; Mice; Molecular Sequence Data; mutation; polycystic ovary syndrome; Protein Binding; Receptors, Androgen - physiology; Repression; secretion; Sequence Analysis, DNA; steroid hormones; Testosterone Congeners - pharmacology; Tetradecanoylphorbol Acetate - pharmacology; transcription (genetics); transcription factors; Transcription, Genetic; Oct-1; Enhancer; MMTV; DBD; Pbx; GnRH-E; Repression; Hypothalamus; LBD; Nkx2.1; cs; DHT; PMSF; RSVe; TK; Androgen receptor; GnRH-P; GnRH; RSVp; HPG
• ISSN: 0303-7207; 1872-8057
• DOI: 10.1016/j.mce.2012.07.012

► AR-mediated repression of GnRH gene expression involves enhancer 1. ► AR represses GnRH enhancer 1 via interaction with the -1796/-1791 region. ► Our study provides a new mechanism involved in the repression of GnRH by androgens. Gonadotropin-releasing hormone (GnRH) plays a major role in the hypothalamic-pituitary–gonadal (HPG) axis, and synthesis and secretion of GnRH are regulated by gonadal steroid hormones. Disruptions in androgen levels are involved in a number of reproductive defects, including hypogonadotropic hypogonadism and polycystic ovarian syndrome. Androgens down-regulate GnRH mRNA synthesis in vivo and in vitro via an androgen receptor (AR)-dependent mechanism. Methyltrienolone (R1881), a synthetic AR agonist, represses GnRH expression through multiple sites in the proximal promoter. In this study, we show AR also represses GnRH transcription via the major enhancer (GnRH-E1). A multimer of the −1800/−1766 region was repressed by R1881 treatment. Mutation of two bases, −1792 and −1791, resulted in decreased basal activity and a loss of AR-mediated repression. AR bound to the −1796/−1791 sequence in electrophoretic mobility shift assays, indicating a direct interaction with DNA or other transcription factors in this region. We conclude that AR repression of GnRH-E1 acts via multiple AR-responsive regions, including the site at −1792/−1791.