Impact of Thyroid Hormones on Estrogen Receptor α-Dependent Transcriptional Mechanisms in Ventromedial Hypothalamus and Preoptic Area.

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 (T-3) 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 alpha (ER alpha) and TH receptor alpha (TR alpha) on the putative regulatory sequences of Pgr and Oxtr. Interestingly, T-3 inhibited E2-induced ER alpha binding to a specific Pgr enhancer site, whereas TR alpha binding was not affected, corroborating our theory that the competitive binding of TR alpha to an ER alpha binding site can inhibit ER alpha transactivation and the subsequent E2-responsive gene expression. On the Oxtr promoter, E2 and T-3 worked together to modulate ER alpha and TR alpha binding. Finally, the E2-dependent induction of cofactors was reduced by hypothyroidism and T-3. Thus, we determined that the Pgr and Oxtr promoter regions are responsive to E2 and that T-3 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. (C) 2015 S. Karger AG, Basel