title: Androgen receptor repression of GnRH gene transcription.
abstract: Alterations in androgen levels lead to reproductive defects in both males and females, including hypogonadotropic hypogonadism, anovulation, and infertility. Androgens have been shown to down-regulate GnRH mRNA levels through an androgen receptor (AR)-dependent mechanism. Here, we investigate how androgen regulates expression from the GnRH regulatory region in the GT1-7 cell line, a model of GnRH neurons. A synthetic androgen, R1881, repressed transcription from the GnRH promoter (GnRH-P) in an AR-dependent manner, and liganded AR associated with the chromatin at the GnRH-P in live GT1-7 cells. The three known octamer-binding transcription factor-1 (Oct-1) binding sites in GnRH-P were required for AR-mediated repression, although other sequences were also involved. Although a multimer of the consensus Oct-1 binding site was not repressed, a multimer of the cluster of Oct-1, Pre-B cell leukemia transcription factor (Pbx)/Prep, and NK2 homeobox 1 (Nkx2.1) binding sites, found at -106/-91 in GnRH-P, was sufficient for repression. In fact, overexpression of any of these factors disrupted the androgen response, indicating that a balance of factors in this tripartite complex is required for AR repression. AR bound to this region in EMSA, indicating a direct interaction of AR with DNA or with other transcription factors bound to GnRH-P at this sequence. Collectively, our data demonstrate that GnRH transcription is repressed by AR via multiple sequences in GnRH-P, including three Oct-1 binding sites, and that this repression requires the complex interaction of several transcription factors.
authors.affiliation: Department of Reproductive Medicine and The Center for Reproductive Science and Medicine, University of California, San Diego, La Jolla, California 92093-0674, USA.
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Brayman
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Pepa
authors.forename: Sara E
authors.initials: SE
authors.lastname: Berdy
authors.forename: Pamela L
authors.initials: PL
authors.lastname: Mellon
mesh_terms: D000728:Androgens / Q000378:metabolism; D001665:Binding Sites; D002460:Cell Line; D002843:Chromatin; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000235:genetics*; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D008297:Male; D015741:Metribolone / Q000494:pharmacology; D009474:Neurons / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D050811:Octamer Transcription Factor-1 / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D000728:Androgens; D002843:Chromatin; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; D050811:Octamer Transcription Factor-1; C106682:PKNOX1 protein, human; D012333:RNA, Messenger; D011944:Receptors, Androgen; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors; D015741:Metribolone; D007987:Gonadotropin-Releasing Hormone
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