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 limits the development of new diagnostic and therapeutic approaches. We suggest that endometriosis is a uniquely epigenetic disease, with symptoms that manifest due to the acquisition or inheritance of abnormal DNA methylation. We recently profiled genome-wide differences in endometriotic cell DNA methylation, and uncovered an epigenetic switch in GATA isoform expression. This switch replaces the transcription factor GATA2 in normal healthy endometrium with GATA6 in endometriotic cells, and appears to 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 epigenetic and gene expression changes functionally defining 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 project assesses the mechanism and pathological effects of this switch. In our first aim we will identify the physical targets and th functional roles the GATAs in normal and diseased cells. We will use ChIP-seq to define the endogenous binding sites of GATA2 and GATA6 in healthy and diseased cells, and how manipulating GATA expression affects this binding pattern. Then using RNA-seq, we will evaluate gene expression profiles resulting from these treatments. Pathways significantly altered by this switch are likely to identify previously overlooked mediators of disease initiation Moreover, this data can be immediately joined with our genome-wide methylation profile to interpolate where GATA2 and GATA6 may serve as cofactors of epigenetic change.
Our second aim i s designed to define how DNA methylation affects the early stages of endometriosis, and what role the GATAs serve in this process. Using methylation arrays, we will define the methylome in freshly sorted cells from eutopic endometrium from subjects with or without endometriosis. Methylation differences between these populations are likely to identify the early events or defects in the pathogenesis of the disease. In parallel, we will use the same methylation arrays to determine the effects of exogenous GATA6 expression on the methylome of healthy endometrial cells. Differentially methylated targets identified either in vivo or in vito represent targets with the highest potential yield for developing new therapies, and will be verified by targeted resequencing. Moreover, we anticipate that determining the source of epigenetic change will allow the development of novel nonsurgical techniques for diagnosing endometriosis using DNA methylation as a biomarker.
Endometriosis causes severe pain and infertility 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 discovered an epigenetic 'switch' that occurs in healthy endometrial tissue compared with endometriotic tissue, and which appears to cause the expression of genes associated with endometriosis symptoms. By characterizing this switch, our project will provide novel, unifying insights into the molecular cause of endometriosis, and will inform the development of new tools for detecting and treating the disease.
| Miyazaki, Kaoru; Dyson, Matthew T; Coon V, John S et al. (2018) Generation of Progesterone-Responsive Endometrial Stromal Fibroblasts from Human Induced Pluripotent Stem Cells: Role of the WNT/CTNNB1 Pathway. Stem Cell Reports 11:1136-1155 |
| Monsivais, Diana; Dyson, Matthew T; Yin, Ping et al. (2016) Estrogen receptor ? regulates endometriotic cell survival through serum and glucocorticoid-regulated kinase activation. Fertil Steril 105:1266-1273 |
| Bulun, Serdar E; Monsivais, Diana; Kakinuma, Toshiyuki et al. (2015) Molecular biology of endometriosis: from aromatase to genomic abnormalities. Semin Reprod Med 33:220-4 |
| Dyson, Matthew T; Kakinuma, Toshiyuki; Pavone, Mary Ellen et al. (2015) Aberrant expression and localization of deoxyribonucleic acid methyltransferase 3B in endometriotic stromal cells. Fertil Steril 104:953-963.e2 |
