Premium
Ligand‐induced recruitment of a histone deacetylase in the negative‐feedback regulation of the thyrotropin β gene
Author(s) -
Sasaki Shigekazu,
LesoonWood Leslie A.,
Dey Anup,
Kuwata Takeshi,
Weintraub Bruce D.,
Humphrey Glen,
Yang WenMing,
Seto Edward,
Yen Paul M.,
Howard Bruce H.,
Ozato Keiko
Publication year - 1999
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/18.19.5389
Subject(s) - trichostatin a , biology , histone deacetylase 2 , histone deacetylase , hdac1 , microbiology and biotechnology , thyroid hormone receptor , histone deacetylase inhibitor , histone deacetylase 5 , chromatin , repressor , histone , transcription factor , biochemistry , receptor , 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 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.