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Molecular and Cellular Biology, June 2007, p. 4105-4120, Vol. 27, No. 11
0270-7306/07/$08.00+0     doi:10.1128/MCB.00248-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

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

Stefan Lim,^1, Min Luo,^2, Mingshi Koh,^2, Meng Yang,² Mohammed Nizam bin Abdul Kadir,² Jing Hui Tan,² Zhiyong Ye,² Wen Wang,² and Philippa Melamed^2*

National University of Singapore, Graduate School for Integrative Sciences and Engineering, Centre for Life Sciences, 05-01 28 Medical Drive, Singapore 117456, Republic of Singapore,¹ Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, Singapore 117542, Republic of Singapore²

Received 11 February 2007/ Accepted 9 March 2007

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 ß-subunit (FSHß) 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 ß-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 FSHß gene involving phosphorylation of several class IIa HDACs associated with both the FSHß and Nur77 genes, and we propose a model for the mechanisms involved. In contrast, derepression of the LH ß-subunit gene is not CaMK dependent. This demonstration of HDAC-mediated 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.

Published ahead of print on 19 March 2007.

S.L., M.L., and M.K. contributed equally to this work.

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