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Aberrant Histone Modifications at the Thyrotropin-Releasing Hormone Gene in Resistance to Thyroid Hormone: Analysis of F455S Mutant Thyroid Hormone Receptor

Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Gunma 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.

We reported a novel mutation of thyroid hormone receptor (TR)-β, F455S, in a patient with pituitary resistance to thyroid hormone (RTH), who showed impaired release of nuclear receptor corepressor and abnormal histone deacetylation. In the present study, we further analyzed the histone modifications and the dynamics of TR and RNA polymerase II on the TRH gene. The lysine residues 9 (H3K9) and 14 (K14) of the histone H3 were acetylated in the absence of thyroid hormone (TH), and addition of TH caused a temporary deacetylation of both residues. Although H3K4 was di- and trimethylated in the absence of T₃, no methylation of H3K9 or K27 was detected. Long-term incubation with T₃ decreased the level of trimethylated H3K4, the amount of TR, and the level of phosphorylated RNA polymerase II but not dimethylated H3K4. Treatment with an inhibitor for H3K4 methyltransferase, 5'-deoxy-5'-methylthioadenosine, decreased basal promoter activity but did not affect the repression by TH. Conversely, overexpression of MLL, an H3K4-specific methyltransferase, caused an increase in basal activity. In the presence of F455S, methylation of H3K4 and the dynamics of TR were intact, but both H3K9 and H3K14 were hyperacetylated, and T₃-induced deacetylation was impaired, resulting in a high transcriptional level. These findings demonstrated that 1) negative regulation of the TRH gene by TH involves both the acetylation and methylation of specific residues of histone tails and changing the amount of TR, and 2) the major impairment to histone modifications in F455S was hyperacetylation of the specific histone tails.