title: Histone deacetylases regulate gonadotropin-releasing hormone I gene expression via modulating Otx2-driven transcriptional activity.
abstract: BACKGROUND
  Precise coordination of the hypothalamic-pituitary-gonadal axis orchestrates the normal reproductive function. As a central regulator, the appropriate synthesis and secretion of gonadotropin-releasing hormone I (GnRH-I) from the hypothalamus is essential for the coordination. Recently, emerging evidence indicates that histone deacetylases (HDACs) play an important role in maintaining normal reproductive function. In this study, we identify the potential effects of HDACs on Gnrh1 gene transcription.
  
  
  RESULTS
  Inhibition of HDACs activities by trichostatin A (TSA) and valproic acid (VPA) promptly and dramatically repressed transcription of Gnrh1 gene in the mouse immortalized mature GnRH neuronal cells GT1-7. The suppression was connected with a specific region of Gnrh1 gene promoter, which contains two consensus Otx2 binding sites. Otx2 has been known to activate the basal and also enhancer-driven transcription of Gnrh1 gene. The transcriptional activity of Otx2 is negatively modulated by Grg4, a member of the Groucho-related-gene (Grg) family. In the present study, the expression of Otx2 was downregulated by TSA and VPA in GT1-7 cells, accompanied with the opposite changes of Grg4 expression. Chromatin immunoprecipitation and electrophoretic mobility shift assays demonstrated that the DNA-binding activity of Otx2 to Gnrh1 gene was suppressed by TSA and VPA. Overexpression of Otx2 partly abolished the TSA- and VPA-induced downregulation of Gnrh1 gene expression.
  
  
  CONCLUSIONS
  Our data indicate that HDAC inhibitors downregulate Gnrh1 gene expression via repressing Otx2-driven transcriptional activity. This study should provide an insight for our understanding on the effects of HDACs in the reproductive system and suggests that HDACs could be potential novel targets for the therapy of GnRH-related diseases.
authors: Laboratory of Cardiovascular Diseases and Laboratory of Cellular and Molecular Biology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, People's Republic of China.
authors: Lu
authors: L
authors: Gan
authors: Pei-Yan
authors: PY
authors: Ni
authors: Yan
authors: Y
authors: Ge
authors: Yun-Fei
authors: YF
authors: Xiao
authors: Chang-Yan
authors: CY
authors: Sun
authors: Lin
authors: L
authors: Deng
authors: Wei
authors: W
authors: Zhang
authors: Si-Si
authors: SS
authors: Wu
authors: Ying
authors: Y
authors: Liu
authors: Wei
authors: W
authors: Jiang
authors: Hong-Bo
authors: HB
authors: Xin
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D024202:Electrophoretic Mobility Shift Assay; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation / Q000502:physiology*; D007987:Gonadotropin-Releasing Hormone / Q000235:genetics*; D006655:Histone Deacetylases / Q000378:metabolism* / Q000502:physiology; D006877:Hydroxamic Acids / Q000494:pharmacology; D051379:Mice; D051857:Otx Transcription Factors / Q000502:physiology*; D011401:Promoter Regions, Genetic; D014158:Transcription, Genetic / Q000502:physiology; D014635:Valproic Acid / Q000494:pharmacology
chemical_list: D006877:Hydroxamic Acids; D051857:Otx Transcription Factors; D007987:Gonadotropin-Releasing Hormone; C012589:trichostatin A; D014635:Valproic Acid; D006655:Histone Deacetylases