Ligand-induced recruitment of a histone deacetylase in the negative-feedback regulation of the thyrotropin β gene

We have investigated ligand‐dependent negative regulation of the thyroid‐stimulating hormone β (TSHβ) gene. Thyroid hormone (T3) markedly repressed activity of the TSHβ promoter that had been stably integrated into GH 3 pituitary cells, through the conserved negative regulatory element (NRE) in the...

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Bibliographic Details
Published in:The EMBO journal 1999-10, Vol.18 (19), p.5389-5398
Main Authors: Sasaki, Shigekazu, Lesoon-Wood, Leslie A., Dey, Anup, Kuwata, Takeshi, Weintraub, Bruce D., Humphrey, Glen, Yang, Wen-Ming, Seto, Edward, Yen, Paul M., Howard, Bruce H., Ozato, Keiko
Format: Article
Language:English
Subjects:
Base Sequence
Chromatin - chemistry
Cyclic AMP - pharmacology
DNA
Feedback
Gene Expression Regulation - drug effects
Genes, Reporter
histone deacetylases
Histone Deacetylases - metabolism
Ligands
negative feedback
Protein Binding
Regulatory Sequences, Nucleic Acid
Sequence Deletion
Sequence Homology, Nucleic Acid
thyroid hormone
thyrotropin
Thyrotropin - genetics
Thyrotropin - metabolism
Triiodothyronine - pharmacology
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Summary:We have investigated ligand‐dependent negative regulation of the thyroid‐stimulating hormone β (TSHβ) gene. Thyroid hormone (T3) markedly repressed activity of the TSHβ promoter that had been stably integrated into GH 3 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 GH 3 cells. Significantly, upon addition of T3, the NRE further recruited the thyroid hormone receptor (TRβ) 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.
ISSN:0261-4189
1460-2075
1460-2075
DOI:10.1093/emboj/18.19.5389