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性炎症性疾病，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重要作用。我们发现，细胞质ER β与 凋亡机制和炎性体复合物，以防止凋亡和刺激 细胞增殖活性。然而，核ER β在子宫内膜异位症发病机制中的作用 还没有被阐明。为了填补这一科学知识的空白，我们确定了 利用子宫内膜特异性ER β基因构建组织特异性ER β调控转录组和ER β顺式组 过表达小鼠模型我们新的组学数据提供了细胞核ER β功能的三个独特方面， 促使子宫内膜异位症的进展。1)子宫内膜中抗凋亡信号的增加是子宫内膜癌的一个重要原因。 子宫内膜异位症的治疗方法有哪些我们的组学数据显示ER β/Nuclear 活化T细胞因子5（NFAT 5）复合物直接下调N-Myc和STAT的表达 相互作用子（NMI），其刺激干扰素（IFN）α诱导的细胞死亡信号传导。在目标1中，我们将研究 NMI在IFN α诱导的正常子宫内膜细胞死亡信号传导中的作用，然后确定NMI是否 ER β/NFAT 5复合物下调子宫内膜异位症病灶中NMI的表达，促进子宫内膜异位症的发生。 由于表皮生长因子受体（EGFR）信号在增生组织中升高，并参与抗肿瘤作用， 我们还将研究EGFR在ER β/NFAT 5介导的NMI表达抑制中的作用。 组织中的细胞。2)上皮-间质转化（EMT）是子宫内膜异位症的关键步骤。我们 组学数据显示，ER β/早期生长反应蛋白1（EGR1）轴直接增加表达， 原纤维蛋白1（FBN1），这是一个激活剂的EMT，在异位病变。在目标2中，我们将定义FBN1在以下方面的作用： 异位病灶中子宫内膜异位症相关的EMT，然后确定ER β/EGR1轴是否上调 FBN1基因在异位病灶中的表达以刺激异位病灶中的EMT。由于EGFR信号也起着 EGFR在EMT中的重要作用，将研究EGFR在ER β/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- 异位病变中诱导的血管生成尚未阐明。我们的数据显示，ER β升高了 表达结缔组织生长因子（CTGF），其是缺氧诱导因子1a的激活剂 （HIF 1A）介导的血管生成，在异位病变。在目标3中，我们将定义CTGF在子宫内膜异位症中的作用- 相关血管生成，然后确定ER β/HIF 1A轴是否上调CTGF基因表达 刺激血管生成。由于EGFR信号传导在血管生成中也起重要作用， EGFR在ER β/HIF 1A轴介导的血管生成中的作用将被研究。总的来说，这三个ER β 基因网络将在概念上推进我们对子宫内膜异位症分子病因的理解， 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.