Endometriosis is a chronic gynecological disease causing severe pain and infertility when endometrium - like tissue persists outside the uterus. The disease affects up to 10% of reproductive age women, during what should be women’s peak years of health, but an insufficient understanding of the factors that cause the disease has limited the development of new diagnostic and therapeutic approaches. We suggest that endometriosis is a uniquely epigenetic disease, with symptoms that manifest due to the acquisi tion or inheritance of abnormal DNA methylation. W e recently discovered an epigenetic switch in GATA isoform expression that results in the replacement of GATA2 in normal healthy endometrium with GATA6 in endometriotic cells. Moreover this defect appears t o strongly contribute to the endometriotic phenotype. We hypothesize that inherited or acquired epigenetic defects alter GATA expression, and the switch from GATA2 to GATA6 represents a fundamental molecular abnormality that orchestrates the hallmark epige netic and gene expression changes that functionally define the disease . We posit that GATA isoform expression affects critical cell fate decisions in the steroid - hormone sensitive stromal cells of the endometrium, and that the targets of GATA transcription factors in these cells contribute to the pathogenesis of endometriosis. This p roject will determine the mechanism and pathological effects of this switch in GATA transcription factor expression . In our first aim we will demonstrate how the replacement of GATA2 with GATA6 causes pathological mRNA and protein expression , utilizing ChIP - seq and RNA - seq to identify the genomic targets of the GATAs in healthy and diseased cells. This comprehensive approach will provide a functional understan ding of where and why this GATA switch occurs . Analysis of the pathways significantly altered by this switch is likely to identify previously overlooked mediators of disease initiation. In our second aim we will define whether aberrant GATA isoform express ion alters the DNA methylation land scape in endometriosis , and the mechanism through which this occurs . By defining th e mechanism of the GATA switch we will provide a more unified understanding of t he disease’s origin, allowing for the development of targe ted prevention strategies. Our studies will identify the specific genes directly governed by GATA2 in healthy tissue and GATA6 in diseased tissue. These genes represent targets with the highest potential yield for developing new therapies. Moreover, we ant icipate that determining the source of epigenetic change will allow the development of novel nonsurgical techniques for diagnosing endometriosis using DNA methylation as a biomarker
|Effective start/end date||8/26/15 → 7/31/17|
- National Institute of Child Health and Human Development (5R03HD082558-02)
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