Multiple and Overlapping Combinatorial Codes Orchestrate Hormonal Responsiveness and Dictate Cell-Specific Expression of the Genes Encoding Luteinizing Hormone

Normal reproductive function in mammals requires precise control of LH synthesis and secretion by gonadotropes of the anterior pituitary. Synthesis of LH requires expression of two genes [-glycoprotein subunit (GSU) and LH] located on different chromosomes. Hormones from the hypothalamus and gonads modulate transcription of both genes as well as secretion of the biologically active LH heterodimer. In males and females, the transcriptional tone of the genes encoding GSU and LH reflects dynamic integration of a positive signal provided by GnRH from hypothalamic neurons and negative signals emanating from gonadal steroids. Although GSU and LH genes respond transcriptionally in the same manner to changes in hormonal input, different combinations of regulatory elements orchestrate their response. These hormone-responsive regulatory elements are also integral members of much larger combinatorial codes responsible for targeting expression of GSU and LH genes to gonadotropes. In this review, we will profile the genomic landscape of the promoter-regulatory region of both genes, depicting elements and factors that contribute to gonadotrope-specific expression and hormonal regulation. Within this context, we will highlight the different combinatorial codes that control transcriptional responses, particularly those that mediate the opposing effects of GnRH and one of the sex steroids, androgens. We will use this framework to suggest that GnRH and androgens attain the same transcriptional endpoint through combinatorial codes unique to GSU and LH. This parallelism permits the dynamic and coordinate regulation of two genes that encode a single hormone. (Endocrine Reviews 25: 521-542, 2004) I. Introduction A. LH, one hormone encoded by two genes B. Hypothalamic and gonadal hormones regulate synthesis and secretion of LH C. Transcriptional regulation of LH: a critical foundation that underlies regulated LH secretion II. Cell-Specific and Hormonal Regulation: The GSU Genomic Landscape A. Regulatory elements that confer cell-specific expression B. Regulatory elements that confer hormone responsiveness C. Convergence of basal and hormonal regulation of GSU expression III. Cell-Specific and Hormonal Regulation: The LH Genomic Landscape A. Regulatory elements that confer cell-specific expression B. Regulatory elements that confer hormone responsiveness C. Convergence of basal and hormonal regulation of LH expression IV. Conclusions and Future Directions A. Conclusions B.