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首页> 外文期刊>Endocrinology >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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Aberrant histone modifications at the thyrotropin-releasing hormone gene in resistance to thyroid hormone: analysis of F455S mutant thyroid hormone receptor.

机译：促甲状腺激素释放激素基因的异常组蛋白修饰对甲状腺激素的抵抗：F455S突变型甲状腺激素受体的分析。

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摘要

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.
机译：我们报道了一名垂体对甲状腺激素（RTH）有垂体抵抗力的患者中的甲状腺激素受体（TR）-β，F455S的一种新型突变，该患者表现出核受体降压药的释放受损和组蛋白去乙酰化异常。在本研究中，我们进一步分析了TRH基因的组蛋白修饰以及TR和RNA聚合酶II的动力学。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，TH的添加导致两个残基暂时脱乙酰。尽管在没有T（3）的情况下H3K4被二甲基化和三甲基化，但未检测到H3K9或K27的甲基化。与T（3）的长期孵育降低了三甲基化H3K4的水平，TR的量以及磷酸化RNA聚合酶II的水平，但没有二甲基化的H3K4。用H3K4甲基转移酶抑制剂5'-脱氧-5'-甲基硫代腺苷处理可降低基础启动子活性，但不影响TH抑制。相反，MLL（一种H3K4特异性甲基转移酶）的过表达导致基础活性增加。在F455S的存在下，H3K4的甲基化和TR的动力学是完整的，但H3K9和H3K14都被过度乙酰化，并且T（3）诱导的脱乙酰化受到损害，从而导致高转录水平。这些发现表明：1）TH对TRH基因的负调控涉及组蛋白尾巴特定残基的乙酰化和甲基化，并改变TR的量; 2）F455S对组蛋白修饰的主要损害是特定组蛋白的超乙酰化尾巴。

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