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首页> 外文期刊>European thyroid journal >Physiologic Significance of Epigenetic Regulation of Thyroid Hormone Target Gene Expression
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Physiologic Significance of Epigenetic Regulation of Thyroid Hormone Target Gene Expression

机译：甲状腺激素靶基因表达表观遗传调控的生理意义

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Background: In previous publications, we have reported our findings demonstrating that exposure to high maternal levels of thyroid hormones (TH) has life-long effects on the wild-type (WT, without THRB mutation) progeny of mothers with resistance to thyroid hormone beta (RTH beta). The mechanism of this epigenetic effect remains unclear. Objectives: We reviewed the mechanisms involved in the epigenetic regulation of TH target genes and understand how they may explain the reduced sensitivity to TH in the WT progeny of RTH beta mothers. Methods: The availability of a large, formerly genotyped Azorean population with many individuals harboring the THRB mutation, R243Q, provided us a model to study the influence of fetal exposure to high maternal TH levels. Results: The thyroid-stimulating hormone (TSH) response in WT adults was less suppressible following the administration of L-triiodothyronine (L-T-3). This finding suggests reduced sensitivity to TH that is induced by an epigenetic mechanism resulting from exposure to high maternal levels of TH during pregnancy. The persistence of this effect across 3 generations of WT subjects favors transgenerational epigenetic inheritance. Based on preliminary studies in mice, we identified the naturally imprinted gene encoding deiodinase type 3, i.e., DIO3, as a possible mediator of this epigenetic effect through increased inactivation of TH. Conclusion: Increased D3 expression and consequently increased T-3 degradation appear to be responsible for the reduced sensitivity of the anterior pituitary to administered L-T-3. The imprinted DIO3 gene may be a candidate gene that mediates the epigenetic effect induced by exposure to high maternal levels of TH. However, we cannot exclude the role of other TH-responsive genes.
机译：背景：在以前的出版物中，我们已经报告了我们的研究结果，证明了暴露于高母体水平的甲状腺激素（TH）对母亲的野生型（WT，没有THRB突变）母亲的终生效效应具有抗性甲状腺激素β的抗性（第一个Beta）。这种表观遗传效应的机制仍不清楚。目的：我们审查了参与靶基因的表观遗传调节的机制，并了解他们如何解释Rth Beta母亲的WT后代的敏感性降低。方法：具有含有THRB突变的许多人R243Q的许多人的含有大量基因分型的少数族裔人口的可用性为我们提供了一种研究胎儿暴露对高母体水平的影响。结果：在施用L-三碘甲酚（L-T-3）后，WT成人的甲状腺刺激激素（TSH）反应抑制不大。该发现表明对由妊娠期间暴露于高母体水平引起的表观遗传机制引起的敏感性。这种效果的持续存在于3代WT受试者的兴趣伴有转基因表观遗传遗传。基于小鼠的初步研究，我们确定了编码脱碘酶3型的天然印迹基因，即DIO3，作为这种表观遗传效果的可能介质通过增加的灭活。结论：增加D3表达并因此增加的T-3降解似乎负责脑前垂体对施用L-T-3的敏感性。印迹的DIO3基因可以是介导通过暴露于高母体水平诱导的表观遗传效应的候选基因。但是，我们不能排除其他TH响应基因的作用。

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