Distinct mechanisms involving diverse histone deacetylases repress expression of the two gonadotropin beta-subunit genes in immature gonadotropes, and their actions are overcome by gonadotropin-releasing hormone.
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 beta-subunit (FSHbeta) 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 beta-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 FSHbeta gene involving phosphorylation of several class IIa HDACs associated with both the FSHbeta and Nur77 genes, and we propose a model for the mechanisms involved. In contrast, derepression of the LH beta-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.
Lim
Stefan
S
Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, Singapore 117542, Republic of Singapore.
Luo
Min
M
Koh
Mingshi
M
Yang
Meng
M
bin Abdul Kadir
Mohammed Nizam
MN
Tan
Jing Hui
JH
Ye
Zhiyong
Z
Wang
Wen
W
Melamed
Philippa
P
D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation; D037201:Follicle Stimulating Hormone, beta Subunit / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D052681:Gonadotrophs / Q000166:cytology / Q000502:physiology*; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism*; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D037101:Luteinizing Hormone, beta Subunit / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D011987:Receptors, Steroid / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
D004268:DNA-Binding Proteins; D037201:Follicle Stimulating Hormone, beta Subunit; D007527:Isoenzymes; D037101:Luteinizing Hormone, beta Subunit; C539818:Nr4a1 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D021122:Protein Subunits; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D012097:Repressor Proteins; D014157:Transcription Factors; D007987:Gonadotropin-Releasing Hormone; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C517598:Camk1 protein, mouse; C517681:Pnck protein, mouse; D019703:Calcineurin; D006655:Histone Deacetylases