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| The EMBO Journal
(1999) 18, 5389–5398, doi:10.1093/emboj/18.19.5389 |
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Ligand-induced recruitment of a histone deacetylase in the negative-feedback regulation of the thyrotropin  gene |
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| Shigekazu Sasaki1, 2, Leslie A. Lesoon-Wood3, Anup Dey1, Takeshi Kuwata1, Bruce D. Weintraub4, Glen Humphrey1, Wen-Ming Yang5, Edward Seto5, Paul M. Yen6, Bruce H. Howard1 and Keiko Ozato1 |
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1 Laboratory of Molecular Growth Regulation, National Institute of Child Health and Human Development, Bethesda, MD 20892-2753, USA 2 Present address: Second Department of Internal Medicine, Hamamatsu University, School of Medicine, 3600 Handa-cho, Hamamatsu 431-3192, Japan 3 Molecular Carcinogenesis, Cancer Research Center of Hawaii, University of Hawaii, HI 96813, USA 4 Division of Endocrinology, University of Maryland, School of Medicine and Laboratory of Molecular Endocrinology, Institute of Human Virology, Baltimore, MD 21201, USA 5 H.Lee Moffitt Cancer Center and Research Institute, Department of Medical Microbiology and Immunology, University of South Florida, Tampa, FL 33612, USA 6 Clinical Endocrinology Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-2753, USA To whom correspondence should be addressed Keiko Ozato, Ozatok@nih.gov Received 11 December 1998; Revised 6 May 1999; Accepted 6 August 1999. |
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| Abstract |
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| We have investigated ligand-dependent negative regulation of the thyroid-stimulating hormone (TSH) gene. Thyroid hormone (T3) markedly repressed activity of the TSH promoter that had been stably integrated into GH3 pituitary cells, through the conserved negative regulatory element (NRE) in the promoter. By DNA affinity binding assay, we show that the NRE constitutively binds to the histone deacetylase 1 (HDAC1) present in GH3 cells. Significantly, upon addition of T3, the NRE further recruited the thyroid hormone receptor (TR) and another deacetylase, HDAC2. This recruitment coincided with an alteration of in vivo chromatin structure, as revealed by changes in restriction site accessibility. Supporting the direct interaction between TR and HDAC, in vitro assays showed that TR, through its DNA binding domain, strongly bound to HDAC2. Consistent with the role for HDACs in negative regulation, an inhibitor of the enzymes, trichostatin A, attenuated T3-dependent promoter repression. We suggest that ligand-dependent histone deacetylase recruitment is a mechanism of the negative-feedback regulation, a critical function of the pituitary–thyroid axis. |
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| Keywords: histone deacetylases, negative feedback, thyroid hormone, thyrotropin |
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