Aberrant histone modifications at the thyrotropin-releasing hormone gene in resistance to thyroid hormone: analysis of F455S mutant thyroid hormone receptor.
Aberrant histone modifications at the thyrotropin-releasing hormone gene in resistance to thyroid hormone: analysis of F455S mutant thyroid hormone receptor.
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DOI：
10.1210/en.2008-1738
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发表时间：
2009-07
期刊：
影响因子：
4.8
通讯作者：
Ryohei Umezawa;M. Yamada;Kazuhiko Horiguchi;S. Ishii;K. Hashimoto;S. Okada;T. Satoh;M. Mori
中科院分区：
文献类型：
--
作者：
Ryohei Umezawa;M. Yamada;Kazuhiko Horiguchi;S. Ishii;K. Hashimoto;S. Okada;T. Satoh;M. Mori
我们报道了一名垂体对甲状腺激素（RTH）抵抗的患者体内甲状腺激素受体（TR）-β的新突变，F455S，该患者表现出核受体辅阻遏物的释放受损和组蛋白脱乙酰化异常。在本研究中，我们进一步分析了TRH基因上的组蛋白修饰以及TR和RNA聚合酶II的动态。组蛋白 H3 的赖氨酸残基 9 (H3K9) 和 14 (K14) 在没有甲状腺激素 (TH) 的情况下被乙酰化，添加 TH 会导致两个残基暂时脱乙酰化。尽管 H3K4 在没有 T(3) 的情况下被二甲基化和三甲基化，但没有检测到 H3K9 或 K27 的甲基化。与 T(3) 长期孵育会降低三甲基化 H3K4 的水平、TR 的量以及磷酸化 RNA 聚合酶 II 的水平，但不会降低二甲基化 H3K4 的水平。用 H3K4 甲基转移酶抑制剂 5'-脱氧-5'-甲硫腺苷处理可降低基础启动子活性，但不影响 TH 的抑制。相反，MLL（一种 H3K4 特异性甲基转移酶）的过度表达会导致基础活性增加。在 F455S 存在的情况下，H3K4 的甲基化和 TR 的动力学完整，但 H3K9 和 H3K14 均高度乙酰化，并且 T(3) 诱导的脱乙酰化受损，导致高转录水平。这些发现表明：1) TH 对 TRH 基因的负调控涉及组蛋白尾部特定残基的乙酰化和甲基化以及 TR 数量的改变，2) F455S 中组蛋白修饰的主要损害是特定组蛋白尾部的过度乙酰化。
We reported a novel mutation of thyroid hormone receptor (TR)-beta, 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 T(3), no methylation of H3K9 or K27 was detected. Long-term incubation with T(3) 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 T(3)-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.