The Genomic Function of Estrogen Receptor Beta in Endometriosis

由于子宫内膜异位症是一种雌激素依赖的炎症性疾病，雌激素/雌激素受体(ER)信号转导 在子宫内膜异位症的发病机制中起着重要作用。我们发现细胞质中的ERβ与 子宫内膜异位症组织中的细胞凋亡机制和炎性小体复合体对细胞凋亡的预防和刺激作用 细胞增殖活性分别为。核ERβ在子宫内膜异位症发病机制中的作用 尚未得到澄清。为了填补这一科学知识的空白，我们确定了子宫内膜异位症 利用一种新的子宫内膜特异性ERβ调节组织特异性ERβ转录组和ERβ-cstrome 过度表达的小鼠模型。我们的新组学数据提供了核ERβ功能的三个独特方面 推动子宫内膜异位症的进展。1)子宫内膜中抗细胞凋亡信号的增加是 促进子宫内膜异位症进展的关键驱动因素。我们的组学数据显示，ERβ/核 活化T细胞5因子(NFAT5)直接下调N-Myc和STAT的表达 干扰素α诱导的细胞死亡信号转导通路。在目标1中，我们将调查 Nmi在干扰素α诱导的正常子宫内膜细胞死亡信号转导中的作用 ERβ/NFAT5复合体下调子宫内膜异位症病变组织中NMI的表达，从而促进子宫内膜异位症的发生。 由于表皮生长因子受体(EGFR)信号在子宫内膜异位症组织中升高，并参与抗子宫内膜异位症 我们还将研究表皮生长因子受体在ERβ/NFAT5介导的抑制Nmi表达中的作用 在子宫内膜异位症组织中。2)上皮-间充质转化(EMT)是子宫内膜异位症发生的关键步骤。我们的 组学数据显示，ERβ/早期生长反应蛋白1(EGR1)轴直接增加了该基因的表达 纤维蛋白1(FBN1)，它是EMT的激活剂，在异位病变中的表达。在目标2中，我们将定义FBN1在 异位病变的子宫内膜异位症相关EMT，然后确定ERβ/EGR1轴是否上调 FBN1基因在异位病变中的表达刺激异位病变中的EMT。因为EGFR信号也在发挥作用 作为EMT中的一个重要角色，我们将研究EGFR在ERβ/EGR1轴介导的EMT中的作用。3)建立 子宫内膜异位症，血管生成在异位病变中被激活。然而，雌激素的分子机制-- 异位病变中诱导血管生成的机制尚不清楚。我们的数据显示，ERβ升高了 缺氧诱导因子1a激活剂结缔组织生长因子的表达 (HIF1a)介导的血管生成，在异位病变中。在目标3中，我们将定义CTGF在子宫内膜异位症中的作用- 相关的血管生成，然后确定ERβ/HIF1a轴是否上调CTGF基因的表达 在异位病变中刺激血管生成。由于EGFR信号在血管生成中也起着至关重要的作用， 我们将研究表皮生长因子受体在ERβ/HIF1a轴介导的血管生成中的作用。总而言之，这三个ERβ 基因网络将从概念上促进我们对子宫内膜异位症的分子病因学和 为子宫内膜异位症的替代治疗提供新的分子治疗靶点。

As endometriosis is an estrogen-dependent inflammatory disease, estrogen/estrogen receptor (ER) signaling has an essential role in the pathogenesis of endometriosis. We revealed that cytoplasmic ERβ interacts with the apoptosis machinery and inflammasome complex in endometriotic tissues to prevent apoptosis and stimulate cell proliferation activity, respectively. However, the function of nuclear ERβ in the pathogenesis of endometriosis has not yet been elucidated. To fill this gap in the scientific knowledge, we have determined the endometriotic tissue-specific ERβ-regulated transcriptome and ERβ-cistrome by using a novel endometrium-specific ERβ overexpression mouse model. Our new omics data provided three unique aspects of nuclear ERβ function that drive endometriosis progression. 1) The increases in anti-apoptosis signaling in the endometrium is one of the critical drivers that promote the progression of endometriosis. Our omics data revealed that the ERβ/Nuclear Factor of Activated T-cell 5 (NFAT5) complex directly downregulates the expression of N-Myc and STAT Interactor (NMI), which stimulates interferon (IFN)α-induced cell death signaling. In Aim 1, we will investigate the role of NMI in IFNα-induced cell death signaling in the normal endometrium and then identify whether the ERβ/NFAT5 complex downregulates the expression of NMI in endometriotic lesions to enhance endometriosis. Since epidermal growth factor receptor (EGFR) signaling is elevated in endometriotic tissue and involved in anti- apoptosis, we will also investigate the role of EGFR in the ERβ/NFAT5-mediated suppression of NMI expression in endometriotic tissues. 2) The epithelial-mesenchymal transition (EMT) is a critical step for endometriosis. Our omics data showed that the ERβ/Early Growth Response Protein 1 (EGR1) axis directly increased the expression of Fibrillin1 (FBN1), which is an activator of EMT, in ectopic lesions. In Aim 2, we will define the role of FBN1 in endometriosis-associated EMT in ectopic lesions and then determine whether the ERβ/EGR1 axis upregulates FBN1 gene expression in ectopic lesions to stimulate EMT in ectopic lesions. Since EGFR signaling also plays an essential role in EMT, the role of EGFR in ERβ/EGR1 axis-mediated EMT will be investigated. 3) To establish endometriosis, angiogenesis is activated in ectopic lesions. However, the molecular mechanism of estrogen- induced angiogenesis in ectopic lesions has not been elucidated. Our data revealed that ERβ elevated the expression of connective tissue growth factor (CTGF), which is the activator of hypoxia inducible factor 1a (HIF1A)-mediated angiogenesis, in ectopic lesions. In Aim 3, we will define the role of CTGF in endometriosis- associated angiogenesis and then determine whether the ERβ/HIF1A axis upregulates CTGF gene expression in ectopic lesions to stimulate angiogenesis. Since EGFR signaling also plays an essential role in angiogenesis, the role of EGFR in ERβ/HIF1A axis-mediated angiogenesis will be investigated. Collectively, these three ERβ gene networks will conceptionally advance our understanding of the molecular etiology of endometriosis and should provide new molecular therapeutic targets for alternative endometriosis therapies.