Yang Jennifer A, Stires Hillary, Belden William J, Roepke Troy A
Department of Animal Sciences and Program in Endocrinology and Animal Biosciences, Rutgers, The State University of New Jersey, New Brunswick, New Jersey.
Endocrinology. 2017 Mar 1;158(3):612-626. doi: 10.1210/en.2016-1663.
To influence energy homeostasis and reproduction, 17β-estradiol (E2) controls the arcuate nucleus (ARC) through multiple receptor-mediated mechanisms, but primarily via estrogen receptor (ER) α, which signals through both estrogen response element (ERE)-dependent and -independent mechanisms. To determine ERα-mediated, ERE-dependent, and ERE-independent E2 signaling in the ARC, we examined the differential regulation of the mouse arcuate transcriptome by E2 using three mice genotypes: (1) wild-type, (2) ERα knock-in/knockout (ERE-independent mechanisms), and (3) total ERα knockout (ERα-independent mechanisms). Females were ovariectomized and injected with oil or E2, and RNA sequencing on the ARC was used to identify E2-regulated genes in each genotype. Our results show that E2 regulates numerous genes involved in cell signaling, cytoskeleton structure, inflammation, neurotransmission, neuropeptide production, and transcription. Furthermore, ERE-independent signaling regulates ARC genes expressed in kisspeptin neurons and transcription factors that control the hypothalamic/pituitary/gonadal axis. Interestingly, a few genes involved in mitochondrial oxidative respiration were regulated by E2 through ERα-independent signaling. A comparison within oil- and E2-treated females across the three genotypes suggests that genes involved in cell growth and proliferation, extracellular matrices, neuropeptides, receptors, and transcription are differentially expressed across the genotypes. Comparing with previously published chromatin immunoprecipitation sequencing analysis, we found that ERE-independent regulation in the ARC is mainly mediated by tethering of ERα, which is consistent with previous findings. We conclude that the mouse arcuate estrogen-regulated transcriptome is regulated by multiple receptor-mediated mechanisms to modulate the central control of energy homeostasis and reproduction, including novel E2-responsive pathways.
为了影响能量平衡和生殖，17β-雌二醇（E2）通过多种受体介导机制控制弓状核（ARC），但主要是通过雌激素受体（ER）α，其通过雌激素反应元件（ERE）依赖性和非依赖性机制进行信号传导。为了确定ARC中ERα介导的、ERE依赖性和ERE非依赖性的E2信号传导，我们使用三种小鼠基因型研究了E2对小鼠弓状转录组的差异调节：（1）野生型，（2）ERα敲入/敲除（ERE非依赖性机制），以及（3）总ERα敲除（ERα非依赖性机制）。对雌性小鼠进行卵巢切除并注射油或E2，然后对ARC进行RNA测序，以鉴定每种基因型中E2调节的基因。我们的结果表明，E2调节许多参与细胞信号传导、细胞骨架结构、炎症、神经传递、神经肽产生和转录的基因。此外，ERE非依赖性信号传导调节在 kisspeptin 神经元中表达的ARC基因以及控制下丘脑/垂体/性腺轴的转录因子。有趣的是，一些参与线粒体氧化呼吸的基因通过ERα非依赖性信号传导受E2调节。在三种基因型的油处理和E2处理的雌性小鼠之间进行比较表明，参与细胞生长和增殖、细胞外基质、神经肽、受体和转录的基因在不同基因型中差异表达。与先前发表的染色质免疫沉淀测序分析相比，我们发现ARC中的ERE非依赖性调节主要由ERα的拴系介导，这与先前的发现一致。我们得出结论，小鼠弓状雌激素调节的转录组由多种受体介导机制调节，以调节能量平衡和生殖的中枢控制，包括新的E2反应途径。
