Although the etiology of endometriosis is not known, various theories attempt to explain the mechanisms whereby endometrial cells are able to survive and grow in the peritoneum and other ectopic sites, forming lesions that are hormone-dependent1. These theories include retrograde menstruation, genetic predisposition, immune system disturbances, and environmental exposures2. Dysregulation of gene expression is believed to play a major role in the ability if endometrial cells to survive and grow ectopically. The mechanisms at play have not been sufficiently studied, but epigenetic regulation of gene expression is emerging as a key player in endometriosis. Histone modification, including deacetylation by histone deacetylases or HDACs, has recently emerged as a key mechanism of gene expression regulation in cancer and other diseases6-8. HDACs are enzymes involved in cell cycle regulation, proliferation and cell differentiation that modify key residues in histones and change the chromatin conformation. Histone modification, like promoter methylation, result in gene silencing. Recently, it has been shown that histone deacetylase inhibitors (HDACi) reduce the invasion potential and induce cell cycle arrest of an endometriotic cell line. Albeit limited, these preliminary data indicate that methylation changes are probably not the only epigenetic mechanism involved in endometriosis. The main hypothesis of the present proposal is that histone modification is an important mechanism of gene regulation in endometriosis and therefore a potential target for therapy. In support of this hypothesis, preliminary studies in our laboratory showed that the levels of expression of HDAC isoforms belonging to the HDAC Class I family were higher in an endometriotic cell line as compared to normal endometrium cell lines. Also, while the level of gene expression of HDACs varied among human endometriotic lesions, a substantial number of tissues expressed higher levels of these enzymes than eutopic endometrium from controls. We propose that aberrant expression of Class I HDACs leads to dysregulations in gene expression that underlie the development of endometriosis. Therefore, the main goal of this proposal is to identify epigenetic correlates of endometriosis, by examining the role of histone acetylation/deacetylation in the pathophysiology of this disease. To test this hypothesis, we propose to 1) determine whether increased levels of HDACs promote increased migration and proliferation of human endometrial cell lines, 2) to assess the global histone acetylation profile of eutopic endometrium and endometriosis tissues, and 3) identify hyper/hypoacetylated promoter regions of candidate genes in endometriotic tissues and concomitant gene expression changes. The proposed studies are expected to significantly contribute to the current understanding of endometriosis by dissecting the epigenetic mechanisms underlying changes in gene expression. Also, this information may enable the design of more effective treatments and diagnostic assays for this incurable disease.
Endometriosis results when endometrial cells reaching the peritoneum through the fallopian tubes survive and grow in this new environment, causing inflammation, pain and infertility. It is believed that endometriosis tissues express different amounts of proteins than normal cells growing in the uterus, which may allow them to survive and grow causing this disease. The proposed studies will investigate the mechanisms (or how) this occurs and may help identify potential targets for new drugs to treat endometriosis.
|Monteiro, Janice B; ColÃ³n-DÃaz, Maricarmen; GarcÃa, Miosotis et al. (2014) Endometriosis is characterized by a distinct pattern of histone 3 and histone 4 lysine modifications. Reprod Sci 21:305-18|
|ColÃ³n-DÃaz, Maricarmen; BÃ¡ez-Vega, Perla; GarcÃa, Miosotis et al. (2012) HDAC1 and HDAC2 are differentially expressed in endometriosis. Reprod Sci 19:483-92|