Epigenetic regulation of Kiss1 gene expression mediating estrogen-positive feedback action in the mouse brain-猫眼课题宝

DOI：

10.1073/pnas.1114245109

发表时间：

2012-04

期刊：

Proceedings of the National Academy of Sciences

影响因子：

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通讯作者：

中科院分区：

其他

文献类型：

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作者：

Junko Tomikawa;Y. Uenoyama;M. Ozawa;Tatsuya Fukanuma;Kenji Takase;Teppei Goto;Hitomi Abe;Nahoko Ieda;Shiori Minabe;Chikaya Deura;Naoko Inoue;M. Sanbo;Koichi Tomita;M. Hirabayashi;Satoshi Tanaka;T. Imamura;H. Okamura;K. Maeda;H. Tsukamura

本研究旨在探讨Kiss1基因在前腹侧脑室周围核(AVPV)表达的表观遗传学机制，以了解雌激素对促性腺激素释放激素/促性腺激素峰的正反馈作用机制。我们研究了雌激素对小鼠AVPV Kiss1基因座表观遗传状态的调控，并与弓状核(ARC)进行了比较，在ARC中，Kiss1的表达被雌激素下调。AVPV Kiss1启动子区域的组蛋白高度乙酰化，雌激素在该区域高度募集雌激素受体α。相反，ARC Kiss1启动子区的组蛋白被雌激素去乙酰化。抑制组蛋白去乙酰化在体外上调下丘脑非Kiss1表达细胞系中Kiss1的表达。基因构象分析表明，雌激素诱导的Kiss1启动子和3‘端基因间隔区之间形成染色质环，提示该基因间隔区在AVPV中促进雌激素依赖的Kiss1的表达。这一观点得到了证实，因为具有完整Kiss1基因座序列的转基因报告鼠在AVPV和ARC中都显示了Kisspeptin神经元特异性GFP的表达，但3‘区的缺失导致仅在AVPV中GFP的表达大大降低。综上所述，这些结果表明，雌激素诱导动植物病毒Kiss1启动子区域雌激素受体α的募集和组蛋白乙酰化，从而促进Kiss1启动子和Kiss1基因增强子染色质环的形成，从而增加动植物病毒特异性Kiss1基因的表达。这些结果表明，Kiss1基因的表观遗传调控参与了雌激素正反馈，以产生促性腺激素释放激素/促性腺激素峰。

This study aims to determine the epigenetic mechanism regulating Kiss1 gene expression in the anteroventral periventricular nucleus (AVPV) to understand the mechanism underlying estrogen-positive feedback action on gonadotropin-releasing hormone/gonadotropin surge. We investigated estrogen regulation of the epigenetic status of the mouse AVPV Kiss1 gene locus in comparison with the arcuate nucleus (ARC), in which Kiss1 expression is down-regulated by estrogen. Histone of AVPV Kiss1 promoter region was highly acetylated, and estrogen receptor α was highly recruited at the region by estrogen. In contrast, the histone of ARC Kiss1 promoter region was deacetylated by estrogen. Inhibition of histone deacetylation up-regulated in vitro Kiss1 expression in a hypothalamic non–Kiss1-expressing cell line. Gene conformation analysis indicated that estrogen induced formation of a chromatin loop between Kiss1 promoter and the 3′ intergenic region, suggesting that the intergenic region serves to enhance estrogen-dependent Kiss1 expression in the AVPV. This notion was proved, because transgenic reporter mice with a complete Kiss1 locus sequence showed kisspeptin neuron-specific GFP expression in both the AVPV and ARC, but the deletion of the 3′ region resulted in greatly reduced GFP expression only in the AVPV. Taken together, these results demonstrate that estrogen induces recruitment of estrogen receptor α and histone acetylation in the Kiss1 promoter region of the AVPV and consequently enhances chromatin loop formation of Kiss1 promoter and Kiss1 gene enhancer, resulting in an increase in AVPV-specific Kiss1 gene expression. These results indicate that epigenetic regulation of the Kiss1 gene is involved in estrogen-positive feedback to generate the gonadotropin-releasing hormone/gonadotropin surge.