Histone Deacetylases Regulate Gonadotropin-Releasing Hormone I Gene Expression via Modulating Otx2-Driven Transcriptional Activity

Autor: Yun-Fei Xiao, Lin Deng, Sisi Wu, Hongbo Xin, Ying Liu, Wei Zhang, Lu Gan, Chang-Yan Sun, Pei-Yan Ni, Yan Ge, Wei Jiang
Jazyk: angličtina
Rok vydání: 2012
Předmět:
Transcription
Genetic
Regulator
lcsh:Medicine
Electrophoretic Mobility Shift Assay
Gonadotropin-releasing hormone
Hydroxamic Acids
Biochemistry
Gonadotropin-Releasing Hormone
Mice
Molecular cell biology
Endocrinology
Transcription (biology)
Gene expression
Transcriptional regulation
Signaling in Cellular Processes
lcsh:Science
Promoter Regions
Genetic
Nuclear receptor co-repressor 2
Genetics
Multidisciplinary
Hormone Synthesis
Otx Transcription Factors
biology
Neurochemistry
Cell biology
Histone
Medicine
hormones
hormone substitutes
and hormone antagonists
Research Article
Signal Transduction
endocrine system
Chromatin Immunoprecipitation
DNA transcription
Blotting
Western
Enzyme-Linked Immunosorbent Assay
Histone Deacetylases
Cell Line
Reproductive Endocrinology
Animals
Biology
Endocrine Physiology
Valproic Acid
lcsh:R
Neuroendocrinology
RNA stability
Hormones
Gene Expression Regulation
biology.protein
lcsh:Q
Transcriptional Signaling
Endocrine Cells
Chromatin immunoprecipitation
Zdroj: PLoS ONE
PLoS ONE, Vol 7, Iss 6, p e39770 (2012)
ISSN: 1932-6203
Popis: 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. METHODOLOGY/PRINCIPAL FINDINGS: 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/SIGNIFICANCE: 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.
Databáze: OpenAIRE
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