Class-C SOX Transcription Factors Control GnRH Gene Expression via the Intronic Transcriptional Enhancer
Class-C SOX Transcription Factors Control GnRH Gene Expression via the Intronic Transcriptional Enhancer
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DOI：
10.1210/me.2010-0332
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发表时间：
2011-07-01
影响因子：
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通讯作者：
Kim, Kyungjin
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文献类型：
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作者：
Kim, Hee-Dae;Choe, Han Kyoung;Kim, Kyungjin
促性腺激素释放激素（GnRH）是一种控制生殖和性发育的关键性下丘脑神经激素。由于转录调控对GnRH基因的时空表达至关重要，哺乳动物GnRH启动子上游约3.0 kb的区域已被广泛研究。在本研究中，我们证明了一个转录增强子位于第一内含子（内含子A）区域的GnRH基因。这种转录增强子含有假定的性别决定区Y相关的高迁移率族盒（SOX）家族转录因子结合位点，这些位点在许多哺乳动物物种中非常保守。C类SOX成员蛋白（SOX-C）（SOX 4和SOX 11）通过与这些SOX结合位点结合而特异性地增强这种转录激活。因此，SOX 1 - 1在产生GnRH的永生化GT 1 -1细胞中高度富集，抑制其表达可显著降低GnRH基因表达和GnRH分泌。染色质免疫沉淀显示内源性SOX-C因子识别并结合GT 1 -1细胞和下丘脑中的内含子增强子。伴随的免疫组织化学分析表明，SOX 4或SOX 11在成年小鼠下丘脑GnRH神经元中的大多数中高度表达。总之，这些发现表明，SOX-C转录因子的功能作为重要的转录调节细胞类型特异性GnRH基因表达的内含子转录增强子上的作用。（分子内分泌学25：1184-1196，2011）
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. (Molecular Endocrinology 25: 1184-1196, 2011)