Song Anying, Jiang Shujun, Wang Qinghua, Zou Jianghuan, Lin Zhaoyu, Gao Xiang
State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing 210061, China.
Endocrinology. 2017 Jun 1;158(6):1798-1811. doi: 10.1210/en.2016-1750.
The hypothalamic-pituitary-gonadal axis controls development, reproduction, and metabolism. Although most studies have focused on the hierarchy from the brain to the gonad, many questions remain unresolved concerning the feedback from the gonad to the central nervous system, especially regarding the potential epigenetic modifications in hypothalamic neurons. In the present report, we generated genetically modified mice lacking histone H3 lysine 27 (H3K27) demethylase Jumonji domain-containing 3 (JMJD3) in hypothalamic rat-insulin-promoter-expressing neurons (RIP-Cre neurons). The female mutant mice displayed late-onset obesity owing to reduced locomotor activity and decreased energy expenditure. JMJD3 deficiency in RIP-Cre neurons also results in delayed pubertal onset, an irregular estrous cycle, impaired fertility, and accelerated ovarian failure in female mice owing to the dysregulation of the hypothalamic-ovarian axis. We found that JMJD3 directly regulates Kiss1 gene expression by binding to the Kiss1 promoter and triggering H3K27me3 demethylation in the anteroventral periventricular (AVPV) nucleus. Further study confirmed that the aberrations arose from impaired kisspeptin signaling in the hypothalamic AVPV nucleus and subsequent estrogen deficiency. Estrogen replacement therapy can reverse obesity in mutant mice. Moreover, we demonstrated that Jmjd3 is an estrogen target gene in the hypothalamus. These results provide direct genetic and molecular evidence that JMJD3 is a key mediator for the kisspeptin-estrogen feedback loop.
下丘脑-垂体-性腺轴控制着发育、生殖和新陈代谢。尽管大多数研究都集中在从大脑到性腺的层级关系上，但关于性腺向中枢神经系统的反馈，尤其是下丘脑神经元中潜在的表观遗传修饰，仍有许多问题尚未解决。在本报告中，我们构建了在表达大鼠胰岛素启动子的下丘脑神经元（RIP-Cre神经元）中缺乏组蛋白H3赖氨酸27（H3K27）去甲基化酶含Jumonji结构域3（JMJD3）的转基因小鼠。雌性突变小鼠由于运动活动减少和能量消耗降低而出现迟发性肥胖。RIP-Cre神经元中JMJD3的缺乏还导致雌性小鼠青春期启动延迟、发情周期不规律、生育能力受损以及卵巢早衰，这是由于下丘脑-卵巢轴失调所致。我们发现JMJD3通过与Kiss1启动子结合并触发室周前腹侧核（AVPV）中的H3K27me3去甲基化来直接调节Kiss1基因表达。进一步的研究证实，这些异常是由下丘脑AVPV核中促性腺激素释放激素信号受损以及随后的雌激素缺乏引起的。雌激素替代疗法可以逆转突变小鼠的肥胖。此外，我们证明Jmjd3是下丘脑中的一个雌激素靶基因。这些结果提供了直接的遗传和分子证据，表明JMJD3是促性腺激素释放激素-雌激素反馈回路的关键介质。
