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Aberrant Dynamics of Histone Deacetylation at the Thyrotropin-Releasing Hormone Gene in Resistance to Thyroid Hormone

Department of Medicine and Molecular Science (S.I., M.Y., T.S., T.M., K.H., N.S., M.M.) and Department of Pediatrics and Developmental Medicine (K.O., A.M.), Gunma University Graduate School of Medicine, Maebashi 371-8511, Japan

Address all correspondence and requests for reprints to: Masanobu Yamada, M.D., Ph.D., Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine 3-39-15 Showa-machi, Maebashi, Gunma 371-8511, Japan. E-mail: myamada{at}med.gunma-u.ac.jp.

Histone acetylation status influences transcriptional activity, and the mechanism of negative gene regulation by thyroid hormone remains unclear, although its impairment by a mutant thyroid hormone receptor (TR) is critical for resistance to thyroid hormone (RTH). We found a novel RTH mutant, F455S, that exhibited impaired repression of the TRH gene and had a strong dominant-negative effect on the gene. F455S strongly interacted with nuclear receptor corepressor (NCoR) and was hard to dissociate from it. To analyze the dynamics of histone acetylation status in vivo, we established cell lines stably expressing the TRH promoter and wild-type or F455S TR. Treatment with a histone deacetylase (HDAC) inhibitor completely abolished the repression of the gene by T₃. The histones H3 and H4 at the TRH promoter were acetylated, and addition of T₃ caused recruitment of HDACs 2 and 3 within 15 min, resulting in a transient deacetylation of the histone tails. TR and NCoR were located on the promoter, and T₃ caused NCoR dissociation and steroid receptor coactivator-1 recruitment. In the presence of F455S, the histones were hyperacetylated, and HDAC recruitment and histone deacetylation were significantly impaired. This is the first report demonstrating the direct involvement of aberrant dynamics of chromatin modification in RTH.

NURSA Molecule Pages Link:

Nuclear Receptors:   TRα  |  TRβ  |  RXRα

Coregulators:   HDAC2  |  HDAC3  |  SRC-1  |  NCOR

Ligands:   Thyroid hormone

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