title: Class-C SOX transcription factors control GnRH gene expression via the intronic transcriptional enhancer.
abstract: GnRH is a pivotal hypothalamic neurohormone governing reproduction and sexual development. Because transcriptional regulation is crucial for the spatial and temporal expression of the GnRH gene, a region approximately 3.0 kb upstream of the mammalian GnRH promoter has been extensive studied. In the present study, we demonstrate a transcription-enhancer located in the first intron (intron A) region of the GnRH gene. This transcriptional enhancer harbors putative sex-determining region Y-related high-mobility-group box (SOX) family transcription factor-binding sites, which are well conserved across many mammalian species. The class-C SOX member proteins (SOX-C) (SOX4 and SOX11) specifically augment this transcriptional activation by binding to these SOX-binding sites. In accordance, SOX11 is highly enriched in immortalized GnRH-producing GT1-1 cells, and suppression of its expression significantly decreases GnRH gene expression as well as GnRH secretion. Chromatin immunoprecipitation shows that endogenous SOX-C factors recognize and bind to the intronic enhancer in GT1-1 cells and the hypothalamus. Accompanying immunohistochemical analysis demonstrates that SOX4 or SOX11 are highly expressed in the majority of hypothalamic GnRH neurons in adult mice. Taken together, these findings demonstrate that SOX-C transcription factors function as important transcriptional regulators of cell type-specific GnRH gene expression by acting on the intronic transcriptional enhancer.
authors.affiliation: Department of Biological Sciences, Seoul National University, Brain Research Center for the 21st Century Frontier Program in Neuroscience, Seoul, Korea.
authors.forename: Hee-Dae
authors.initials: HD
authors.lastname: Kim
authors.forename: Han Kyoung
authors.initials: HK
authors.lastname: Choe
authors.forename: Sooyoung
authors.initials: S
authors.lastname: Chung
authors.forename: Myungjin
authors.initials: M
authors.lastname: Kim
authors.forename: Jae Young
authors.initials: JY
authors.lastname: Seong
authors.forename: Gi Hoon
authors.initials: GH
authors.lastname: Son
authors.forename: Kyungjin
authors.initials: K
authors.lastname: Kim
mesh_terms: D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D003001:Cloning, Molecular; D017124:Conserved Sequence; D004742:Enhancer Elements, Genetic; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D007987:Gonadotropin-Releasing Hormone / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007031:Hypothalamus / Q000166:cytology / Q000378:metabolism; D007438:Introns; D049410:Luciferases, Renilla / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008969:Molecular Sequence Data; D009474:Neurons / Q000378:metabolism; D051381:Rats; D055751:SOXC Transcription Factors / Q000378:metabolism*; D016415:Sequence Alignment; D014158:Transcription, Genetic
chemical_list: D055751:SOXC Transcription Factors; D007987:Gonadotropin-Releasing Hormone; D049410:Luciferases, Renilla