GATA6 confers an immunologic phenotype in endometriosis

Endometriosis is an estrogen-dependent, gynecological disease that affects 5–10% of reproductive-age women. The main symptoms are severely painful menses, chronic pelvic pain, painful intercourse, and more commonly, infertility. The mechanism through which normally-located eutopic endometrial cells (NoEM) are associated with endometriotic cells (OSIS) remains unknown. Recent genome-wide methylation analyses from our lab have pinpointed a unique epigenetic fingerprint in endometriosis, suggesting DNA methylation is an integral component of the disease. We observed significant differences between NoEM and OSIS in DNA methylation of the GATA family of transcription factors, suggesting a novel role for the GATA family as key regulators of uterine physiology. When GATA6 is expressed in NoEM, there is a lack of developmental plasticity, a block in hormone sensitivity, and an induction of endometriosis markers. We developed three groups consisting of primary cells for RNA-Seq and ChIP-Seq: 1) NoEM control, 2) NoEM AdGATA6, and 3) OSIS control. By conducting gene ontology analyses on our data, we were able to determine that GATA6 modulates many immune genes and pathways. Our RNA-Seq results indicated differential expression of many immune-related genes. Concurrently, we observed GATA6 was highly enriched at the promoters of immunomodulatory genes via ChIP-Seq. Examples of these genes include complement factors (e.g., C3 and CFB), chemokines (e.g., RANTES and CCL2), and interleukins (e.g., IL6). Our results coincide with several observations of inflammation and pain in patients with endometriosis and apoptotic resistance in OSIS. Overall, endometriotic cells possess a unique immunoregulatory, anti-apoptotic, and steroidogenic phenotype that directly contributes to the survival and persistence of diseased tissue. Our data suggest that differential DNA methylation directing the expression of GATA6 contribute to this diseased phenotype. This study uncovers a potential epigenetic and immunologic basis for GATA6 action in endometriosis, proposing a usefulness for the development of targeted and effective therapies for this disease.