Regulation of gene expression by 17β-estradiol in the arcuate nucleus of the mouse through ERE-dependent and ERE-independent mechanisms.
Regulation of gene expression by 17β-estradiol in the arcuate nucleus of the mouse through ERE-dependent and ERE-independent mechanisms.
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DOI：
10.1016/j.steroids.2016.01.003
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发表时间：
2016-03
期刊：
影响因子：
2.7
通讯作者：
Roepke TA
中科院分区：
文献类型：
--
作者：
Yang JA;Mamounis KJ;Yasrebi A;Roepke TA
17β-雌二醇（E2）调节下丘脑弓状核（ARC）的基因表达以控制稳态功能。在ARC中，雌激素受体（ER）α高度表达，并且是E2作用的重要贡献者，通过雌激素反应元件（ERE）依赖性和非依赖性机制控制基因表达。本研究的目的是确定是否已知的E2调节基因通过这些机制进行调节。所选的基因已被证明可以调节体内平衡，并被分为三个部分：通道，受体和神经肽。为了确定是依赖于ERE还是不依赖于ERE的机制调节基因表达，除了野生型同窝小鼠外，还使用了两种转基因小鼠模型，ERα敲除（ERKO）和ERα敲入/敲除（KIKO），其缺乏功能性ERE结合结构域。所有基因型的雌性动物均切除卵巢，并注射油或苯甲酸雌二醇（E2 B）。我们的研究结果表明，E2 B通过这些机制调节多个基因。值得注意的是，Cacna 1g和Kcnmb 1通道表达仅在WT雌性中通过E2 B增加，表明具有ERE依赖性调节。此外，NKB受体Tac 3r在WT和KIKO雌性动物中受到E2 B抑制，但在ERKO雌性动物中不受抑制，表明ERα依赖性、ER非依赖性信号传导对于Tac 3r调节是必要的。肾上腺素能受体Adra 1b在所有基因型中被E2 B抑制，表明ERα不是E2 B作用的主要受体。E2 B通过依赖于ERE的机制抑制神经肽Tac 2。这些结果表明，E2 B通过ERE依赖性和ERE非依赖性机制激活ARC中的ERα依赖性和非依赖性信号传导以控制基因表达。
17β-estradiol (E2) modulates gene expression in the hypothalamic arcuate nucleus (ARC) to control homeostatic functions. In the ARC, estrogen receptor (ER) α is highly expressed and is an important contributor to E2’s actions, controlling gene expression through estrogen response element (ERE)-dependent and -independent mechanisms. The objective of this study was to determine if known E2-regulated genes are regulated through these mechanisms. The selected genes have been shown to regulate homeostasis and have been separated into three subsections: channels, receptors, and neuropeptides. To determine if ERE-dependent or ERE-independent mechanisms regulate gene expression, two transgenic mouse models, an ERα knock-out (ERKO) and an ERα knock-in/knock-out (KIKO), which lacks a functional ERE binding domain, were used in addition to their wild-type littermates. Females of all genotypes were ovariectomized and injected with oil or estradiol benzoate (E2B). Our results suggest that E2B regulates multiple genes through these mechanisms. Of note, Cacna1g and Kcnmb1 channel expression was increased by E2B in WT females only, suggesting an ERE-dependent regulation. Furthermore, the NKB receptor, Tac3r, was suppressed by E2B in WT and KIKO females but not ERKO females, suggesting that ERα-dependent, ERE-independent signaling is necessary for Tac3r regulation. The adrenergic receptor Adra1b was suppressed by E2B in all genotypes indicating that ERα is not the primary receptor for E2B’s actions. The neuropeptide Tac2 was suppressed by E2B through ERE-dependent mechanisms. These results indicate that E2B activates both ERα-dependent and independent signaling in the ARC through ERE-dependent and ERE-independent mechanisms to control gene expression.