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Endocrine Reviews 25 (4): 521-542
Copyright © 2004 by The Endocrine Society

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

Joan S. Jorgensen, Christine C. Quirk and John H. Nilson

Department of Veterinary Biosciences (J.S.J.), University of Illinois, Urbana, Illinois 61802; Medical Sciences Program (C.C.Q.), Indiana University, Bloomington, Indiana 47405; and School of Molecular Biosciences (J.H.N.), Washington State University, Pullman, Washington 99164-4660

Correspondence: Address all correspondence and requests for reprints to: John H. Nilson, Ph.D., School of Molecular Biosciences, 639 Fulmer Hall, Washington State University, Pullman, Washington 99164-4660. E-mail: jhn{at}wsu.edu

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 [{alpha}-glycoprotein subunit ({alpha}GSU) and LHß] 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 {alpha}GSU and LHß reflects dynamic integration of a positive signal provided by GnRH from hypothalamic neurons and negative signals emanating from gonadal steroids. Although {alpha}GSU and LHß 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 {alpha}GSU and LHß 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 {alpha}GSU and LHß. This parallelism permits the dynamic and coordinate regulation of two genes that encode a single hormone.




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