Faustino Larissa C, Gagnidze Khatuna, Ortiga-Carvalho Tania M, Pfaff Donald W
Laboratory of Neurobiology and Behavior, The Rockefeller University, New York, N.Y., USA.
Neuroendocrinology. 2015;101(4):331-46. doi: 10.1159/000381459. Epub 2015 Mar 13.
Elevated levels of thyroid hormones (TH) reduce estradiol (E2)-dependent female sexual behavior. E2 stimulates progesterone receptor (Pgr) and oxytocin receptor (Oxtr) within the ventromedial hypothalamus and preoptic area, critical hypothalamic nuclei for sexual and maternal behavior, respectively. Here, we investigated the impact of TH on E2-dependent transcriptional mechanisms in female mice. First, we observed that triiodothyronine (T3) inhibited the E2 induction of Pgr and Oxtr. We hypothesized that differences in histone modifications and receptor recruitment could explain the influence of TH on E2-responsive Pgr and Oxtr expression. We observed that histone H3 acetylation (H3Ac) and methylation (H3K4me3) was gene and brain-region specific. We then analyzed the recruitment of estrogen receptor α (ERα) and TH receptor α (TRα) on the putative regulatory sequences of Pgr and Oxtr. Interestingly, T3 inhibited E2-induced ERα binding to a specific Pgr enhancer site, whereas TRα binding was not affected, corroborating our theory that the competitive binding of TRα to an ERα binding site can inhibit ERα transactivation and the subsequent E2-responsive gene expression. On the Oxtr promoter, E2 and T3 worked together to modulate ERα and TRα binding. Finally, the E2-dependent induction of cofactors was reduced by hypothyroidism and T3. Thus, we determined that the Pgr and Oxtr promoter regions are responsive to E2 and that T3 interferes with the E2 regulation of Pgr and Oxtr expression by altering the recruitment of receptors to DNA and changing the availability of cofactors. Collectively, our findings provide insights into molecular mechanisms of response to E2 and TH interactions controlling sex behavior in the hypothalamus.
甲状腺激素（TH）水平升高会降低雌二醇（E2）依赖性的雌性性行为。E2刺激腹内侧下丘脑和视前区的孕激素受体（Pgr）和催产素受体（Oxtr），这两个下丘脑核分别对性行为和母性行为至关重要。在此，我们研究了TH对雌性小鼠中E2依赖性转录机制的影响。首先，我们观察到三碘甲状腺原氨酸（T3）抑制了Pgr和Oxtr的E2诱导。我们推测组蛋白修饰和受体募集的差异可以解释TH对E2反应性Pgr和Oxtr表达的影响。我们观察到组蛋白H3乙酰化（H3Ac）和甲基化（H3K4me3）具有基因和脑区特异性。然后，我们分析了雌激素受体α（ERα）和甲状腺激素受体α（TRα）在Pgr和Oxtr假定调控序列上的募集情况。有趣的是，T3抑制了E2诱导的ERα与特定Pgr增强子位点的结合，而TRα的结合不受影响，这证实了我们的理论，即TRα与ERα结合位点的竞争性结合可抑制ERα的反式激活及随后的E2反应性基因表达。在Oxtr启动子上，E2和T3共同作用来调节ERα和TRα的结合。最后，甲状腺功能减退和T3降低了E2依赖性的辅因子诱导。因此，我们确定Pgr和Oxtr启动子区域对E2有反应，并且T3通过改变受体与DNA的募集以及改变辅因子的可用性来干扰E2对Pgr和Oxtr表达的调节。总的来说，我们的研究结果为下丘脑对E2和TH相互作用控制性行为的反应分子机制提供了见解。
