Laboratory of Neurobiology and Behaviour, The Rockefeller University, New York, NY, USA.
J Neuroendocrinol. 2013 Oct;25(10):939-55. doi: 10.1111/jne.12085.
Expression of the primary female sex behaviour, lordosis, in laboratory animals depends on oestrogen-induced expression of progesterone receptor (PgR) within a defined cell group in the ventrolateral portion of the ventromedial nucleus of the hypothalamus (VMH). The minimal latency from oestradiol administration to lordosis is 18 h. During that time, ligand-bound oestrogen receptors (ER), members of a nuclear receptor superfamily, recruit transcriptional coregulators, which induce covalent modifications of histone proteins, thus leading to transcriptional activation or repression of target genes. The present study aimed to investigate the early molecular epigenetic events underlying oestrogen-regulated transcriptional activation of the Pgr gene in the VMH of female mice. Oestradiol (E₂) administration induced rapid and transient global histone modifications in the VMH of ovariectomised female mice. Histone H3 N-terminus phosphorylation (H3S10phK14Ac), acetylation (H3Ac) and methylation (H3K4me3) exhibited distinct temporal patterns facilitative to the induction of transcription. A transcriptional repressive (H3K9me3) modification showed a different temporal pattern. Collectively, this should create a permissive environment for the transcriptional activity necessary for lordosis, within 3-6 h after E₂ treatment. In the VMH, changes in the H3Ac and H3K4me3 levels of histone H3 were also detected at the promoter region of the Pgr gene within the same time window, although they were delayed in the preoptic area. Moreover, examination of histone modifications associated with the promoter of another ER-target gene, oxytocin receptor (Oxtr), revealed gene- and brain-region specific effects of E₂ treatment. In the VMH of female mice, E₂ treatment resulted in the recruitment of ERα to the oestrogen-response-elements-containing putative enhancer site of Pgr gene, approximately 200 kb upstream of the transcription start site, although it failed to increase ERα association with the more proximal promoter region. Finally, E₂ administration led to significant changes in the mRNA expression of several ER coregulators in a brain-region dependent manner. Taken together, these data indicate that, in the hypothalamus and preoptic area of female mice, early responses to E₂ treatment involve highly specific changes in chromatin structure, dependent on cell group, gene, histone modification studied, promoter/enhancer site and time following E₂.
实验室动物的主要雌性性行为表现，即发情，取决于雌激素诱导的孕激素受体（PgR）在下丘脑腹内侧核腹外侧部的特定细胞群中的表达。从给予雌二醇到发情的最短潜伏期为 18 小时。在此期间，配体结合的雌激素受体（ER），核受体超家族的成员，募集转录共调节剂，诱导组蛋白蛋白的共价修饰，从而导致靶基因的转录激活或抑制。本研究旨在探讨雌激素调节 VMH 中 Pgr 基因转录激活的早期分子表观遗传事件。雌二醇（E₂）给药诱导去卵巢雌性小鼠 VMH 中快速而短暂的全局组蛋白修饰。组蛋白 H3 N 末端磷酸化（H3S10phK14Ac）、乙酰化（H3Ac）和甲基化（H3K4me3）表现出有利于转录诱导的不同时间模式。转录抑制（H3K9me3）修饰表现出不同的时间模式。总的来说，这应该在 E₂ 处理后 3-6 小时内为发情所需的转录活性创造一个允许的环境。在 VMH 中，在同一时间窗口内还检测到 Pgr 基因启动子区域组蛋白 H3 的 H3Ac 和 H3K4me3 水平的变化，尽管它们在视前区延迟。此外，检查与 ER 靶基因之一催产素受体（Oxtr）启动子相关的组蛋白修饰，揭示了 E₂ 处理的基因和脑区特异性效应。在雌性小鼠的 VMH 中，E₂ 处理导致 ERα 募集到 Pgr 基因转录起始位点上游约 200kb 的雌激素反应元件包含的推定增强子位点，尽管它未能增加 ERα 与更近端启动子区域的关联。最后，E₂ 给药以依赖于脑区的方式导致几种 ER 共调节剂的 mRNA 表达发生显著变化。总之，这些数据表明，在雌性小鼠的下丘脑和视前区，对 E₂ 处理的早期反应涉及高度特异的染色质结构变化，依赖于细胞群、研究的基因、组蛋白修饰、启动子/增强子位点和 E₂ 后的时间。
