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

Abstract

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 (alphaGSU) and LHbeta] 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 alphaGSU and LHbeta reflects dynamic integration of a positive signal provided by GnRH from hypothalamic neurons and negative signals emanating from gonadal steroids. Although alphaGSU and LHbeta 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 alphaGSU and LHbeta 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 alphaGSU and LHbeta. This parallelism permits the dynamic and coordinate regulation of two genes that encode a single hormone.

Molecular characterisation and functional interrogation of a local natriuretic peptide system in rodent pituitaries, αT3-1 and LβT2 gonadotroph cells

“…The role of the CRE in mediating aGSU transcription is well characterised (Heckert et al 1996, Burrin et al 1998), and we have previously shown an altered response to cAMPmediated transcription of the human aGSU promoter between aT3-1 and LbT2 cells (Fowkes et al 2003). In our current study, CNP was able to significantly stimulate the proximal K244 bp construct of the human aGSU promoter in LbT2 cells, which is known to contain a tandem CRE, the gonadotroph-specific element that binds SF-1, and a consensus GATA site , Jorgensen et al 2004. Of these sites, the CREs are potential targets for CNP action, given that cGMP is able to enhance CREB phosphorylation (Lu & Hawkins 2002).…”

Negative Regulation of the Thyrotropin β Gene by Thyroid Hormone

“…Of note, it is known that estrogen (E2) inhibits expression of the TSH gene (Cohen and Wondisford, 2005) at the transcriptional level, although its magnitude is smaller than that by T3. E2 is also known to reduce expression of the GSU gene (Chaidarun et al, 1994;Shupnik et al, 1988), the promoter of which has a functional GATA-RE (Jorgensen et al, 2004;Steger et al, 1994). In agreement, the serum level of TSH in women has a tendency to elevate after the menopause (Nagayama et al, 2008).…”

“…6). This notion is supported by the observation that T3/TR 2 inhibits GATA2-induced activation of the GSU promoter and the endothelin-1 (ET-1) promoter, both of which are known to bear a functional GATA-RE (Jorgensen et al, 2004;Steger et al, 1994;Dorfman et al, 1992). In addition, T3/TR inhibited the CD34 gene-derived GATA-RE fused to a heterologous thymidine kinase promoter (Matsushita et al, 2007).…”

In vivo oestrogenic modulation of Egr1 and Pitx1 gene expression in female rat pituitary gland

“…Substantial progress has been made in the identification of the transcription factors that are required for basal, tissue-specific and GnRH-activated expression of the Lhb subunit gene. In the highly conserved proximal 140 bp Lhb promoter region, several specific cis-acting regulatory elements were found to interact with trans-acting early growth response protein 1, the orphan nuclear receptorsteroidogenic factor 1 (SF1) -and a paired-like homeodomain protein PITX1, whereas regulatory elements for SP1 protein and CArG box were identified in the distal domain of the rat sequence (Jorgenssen et al 2004). PITX1 exerts an essential role not only throughout pituitary development (Szeto et al 1996, Kurowani et al 1999, but also in postnatal life, when it regulates several pituitary-specific genes through direct interaction with other specific transcription factors (Tremblay et al 1998(Tremblay et al , 2000.…”