Roles of GATA Transcription Factors in Endometriosis

ABSTRACT Endometriosis is associated with significant clinical, social, emotional, and financial burden on women and their families. Endometriosis is a complex gynecologic disease affecting about 10% of women but remains poorly understood at the molecular level. Endometriosis results from the establishment of ectopic islands of endometrial tissue/cells on pelvic organs via retrograde menstruation. Although eutopic endometrium consists of a mixture of stromal and epithelial cells, ectopic endometriotic tissue is comprised primarily of stromal cells that lack any mutations but with widespread transcriptional and epigenetic defects. The transcription factor GATA2 is physiologically expressed in normal endometrial cells, whereas GATA2 is deficient and replaced by GATA4 and GATA6 (GATA-switch) in endometriotic stromal cells. However, the role of this “GATA-switch” in establishment of transcriptomic, epigenomic, enhancer activity, and cellular states in normal endometrium and in endometriosis is mostly unknown. Using eutopic endometrial samples from endometriosis-free women and patients with endometriosis, and unique genetically altered human normal endometrial and endometriotic stromal cells, we will establish distinguishing epigenomic, transcriptomic, and 3-D chromatin organization features of the endometrium from endometriosis-free women, and endometriosis itself driven by GATA factor switch. Our study will also define, at the integrative epigenome and transcription factor level and with mechanistic depth, whether enhancer malfunction and the GATA transcription factor switch interact and whether this is a key contributor to the pathophysiology of endometriosis. Using clinically relevant human samples, and unique mouse endometriosis induction models, we will test our hypothesis in a setting that is closely related to the in vivo condition, thereby significantly enhancing the relevance, novelty, and significance of the proposed studies. The proposed studies are highly significant because they will also directly address the basic mechanism of endometriosis using clinically relevant human samples, thereby removing a key barrier to knowledge. Execution of the proposed research in an exceptional environment by scientific leaders with complementary expertise studying complex gynecologic diseases, and genome-wide analyses will further enhance the impact of the proposed work. This work is expected to reveal the common and distinguishing features of endometriosis with a strong disease predictive value. Finally, new results stemming from our studies will identify actionable epigenomic, and cellular features that can be targeted for future therapeutic interventions in endometriosis.