Distinct Mechanisms Involving Diverse Histone Deacetylases Repress Expression of the Two Gonadotropin β-Subunit Genes in Immature Gonadotropes, and Their Actions Are Overcome by Gonadotropin-Releasing Hormone

Abstract

The gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH) are produced in the embryonic pituitary in response to delivery of the hypothalamic gonadotropin releasing hormone (GnRH). GnRH has a pivotal role in reestablishing gonadotropin levels at puberty in primates, and for many species with extended reproductive cycles, these are reinitiated in response to central nervous system-induced GnRH release. Thus, a clear role is evident for GnRH in overcoming repression of these genes. Although the mechanisms through which GnRH actively stimulates LH and FSH ␤-subunit (FSH␤) gene transcription have been described in some detail, there is currently no information on how GnRH overcomes repression in order to terminate reproductively inactive stages. We show here that GnRH overcomes histone deacetylase (HDAC)-mediated repression of the gonadotropin ␤-subunit genes in immature gonadotropes. The repressive factors associated with each of these genes comprise distinct sets of HDACs and corepressors which allow for differentially regulated derepression of these two genes, produced in the same cell by the same regulatory hormone. We find that GnRH activation of calcium/calmodulin-dependent protein kinase I (CaMKI) plays a crucial role in the derepression of the FSH␤ gene involving phosphorylation of several class IIa HDACs associated with both the FSH␤ and Nur77 genes, and we propose a model for the mechanisms involved. In contrast, derepression of the LH ␤-subunit gene is not CaMK dependent. This demonstration of HDACmediated repression of these genes could explain the temporal shut-down of reproductive function at certain periods of the life cycle, which can easily be reversed by the actions of the hypothalamic regulatory hormone.In the mouse embryo, the pituitary gonadotropes become fully differentiated between embryonic day (E)11.5 when the common ␣-subunit is first expressed, and E16.5 when the luteinizing hormone ␤-subunit (LH␤) gene is first detected, while expression of the follicle-stimulating hormone ␤-subunit (FSH␤) gene appears on the following day. The expression of these genes is facilitated by unique cell-specific groups of transcription factors which are expressed in response to local signals, and most are present by E9 to 13.5 (6, 23, 50). Expression of these transcription factors (e.g., SF-1, Egr-1, and Pitx-1 for LH and SF-1, AP-1, Lhx3, Ptx1, and Ptx2 for FSH) has been shown to be sufficient to induce activity of the transiently transfected LH␤ and FSH␤ promoters in reporter gene assays in heterologous cells (9,20,27,41,55,56,61,67). However, LH␤ and FSH␤ gene expression in the developing gonadotrope appears only following the migration of the gonadotropin releasing hormone (GnRH) neurons in the hypothalamus and GnRH delivery to the pituitary, which starts around E16. This indicates a role for GnRH in initiating gonadotropin gene expression, which might be distinct from its stimulating increases in gonadotropin gene expression in mature gonadotropes, in which the gonadotropin genes ...

Dioxin Silences Gonadotropin Expression in Perinatal Pups by Inducing Histone Deacetylases

“…The reason why FSH␤ is insensitive to HDAC induction is thought to be due to the isoform specificity in the induction of HDAC by TCDD. It has been reported that while HDAC1, 5, and 7 are preferentially associated with the repression of LH␤ gene, HDAC2 and 3 mainly contribute to the suppression of FSH␤ transcription (33). In the present study, although HDAC1, 5, and 7 were induced in the fetal and neonatal pituitary by maternal exposure to TCDD, HDAC2 was not sensitive to TCDD treatment.…”

“…It has been suggested that HDAC plays an important role as a transcriptional repressor for gonadotropin ␤-subunits (19,32,33). In agreement with this, TCDD markedly deacetylated histones H3 and H4 twined around the promoter of the fetal LH␤ gene, but not the promoters of other pituitary hormone genes (FSH␤, ␣GSU, TSH␤, and GH).…”

Calcineurin Mediates the Gonadotropin-Releasing Hormone Effect on Expression of Both Subunits of the Follicle-Stimulating Hormone through Distinct Mechanisms

“…It also induces an increase in intracellular calcium levels by stimulating calcium release from intracellular stores as well as the influx of extracellular calcium through voltage-sensitive channels (7, 42). One of the effects of this increase in calcium levels is the activation of calmodulin and calmodulin-dependent kinases (CaMKs), which mediate various aspects of GnRH-induced signaling, including inhibition of histone deacetylases and regulation of extracellular signal-regulated kinase (ERK) activity (6,10,23,24,34,44,61). Calmodulin also activates the serine/threonine protein phosphatase calcineurin to regulate the expression of various genes (26).…”

Trichostatin A specifically stimulates gonadotropin FSHβ gene expression in gonadotroph LβT2 cells

“…Lim et al previously reported that the gonadotropin β-subunit gene was repressed by histone deacetylase in immature gonadotrophs such as αT3-1 cells and LβT2 cells. They further found that GnRH activation of calcium/calmodulin-dependent protein kinase I plays a crucial role in the derepression of the FSHβ gene by phosphorylation of histone deacetylase [27]. These finding suggest that GnRH could also modulate the activity of histone modifying enzymes in gonadotrophs.…”