Regulation of gonadotropin-releasing hormone gene transcription

Abstract

The GT1-7 cell line, derived from gonadotropin-releasing hormone (GnRH) neurons of the mouse hypothalamus, has provided a useful system for the analysis of GnRH gene regulation. We have used these cells to examine the mechanism of glucocorticoid repression of GnRH gene transcription. One GnRH negative glucocorticoid response element (nGRE) that contributes to glucocorticoid repression is not bound directly by the glucocorticoid receptor (GR). Rather, GR is tethered to this nGRE by virtue of its interaction with a DNA-bound POU domain transcription factor (i.e. Oct-1). DNA-dependent conformational changes in Oct-1 play a major role in recruiting GR to the distal nGRE and impacts transcriptional repression brought about by either glucocorticoids or tumor-promoting phorbol esters. GT1-7 cell-specific transcription of the mouse GnRH gene is controlled by an enhancer element that shares a high degree of sequence homology with the rat GnRH gene enhancer. As in the rat gene, Oct-1 is important for mGnRH enhancer activity. Furthermore, enhancer activity appears to be influenced by the DNA-dependent conformation adopted by bound Oct-1. Thus, the precise sequence recognized by Oct-1 appears to play a important role in both cell-specific and hormonal regulation of GnRH gene transcription.