Genomic Function of Estrogen Receptor ? in Endometriosis.

ABSTRACT: Estrogen receptor (ER) ? plays a critical role in endometriosis progression because cytoplasmic ER? stimulates proinflammatory signaling in ectopic lesions and prevents apoptosis to promote their survival. However, the role of "nuclear ER?" in endometriosis progression is not known. This critical knowledge gap obscures our understanding of the full molecular etiology of ER?-mediated endometriosis progression. To fill this void, we generated an ER?-regulated transcriptome and ER? cistrome in ectopic lesions and the eutopic endometrium of mice with endometriosis by using a new endometrium-specific FLAG-tagged human ER? overexpression mouse model. The integration of these omics data sets revealed that ER? stimulated the proliferation activities of ectopic lesions and the eutopic endometrium by directly upregulating MYC and E2 transcription factor target genes and genes associated with the G2/M transition. Additionally, ER? stimulated gene expression associated with TNF?/nuclear factor ?B (NF-?B) signaling, epithelial-mesenchymal transition, reactive oxygen species signaling, IL-6/Janus kinase (JAK)/signal transducer and activator of transcription (STAT)3 signaling, and hypoxia signaling and suppressed IFN? signaling in ectopic lesions to enhance endometriosis progression. ER? also stimulated gene expression associated with the unfolded protein response and IL-6/JAK/STAT3 inhibitory signaling and suppressed TNF?/NF-?B signaling in the eutopic endometrium to cause endometriosis-associated endometrial dysfunction. Therefore, nuclear ER?-regulated gene networks provide critical clues to understand the molecular etiology and complexity of endometriosis and endometriosis-associated endometrial dysfunction.

SUBMITTER: Han SJ 

PROVIDER: S-EPMC6773435 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature