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 angiogenesi...