Expression and regulation of histone deacetylases in human endometrium during the menstrual cycle

Abstract

Histone acetylation is a critical epigenetic modification that changes chromatin architecture and regulates gene expression by opening or closing the chromatin structure. It plays an essential role in cell cycle progression and differentiation. The human endometrium goes through cycles of proliferation, differentiation, and degradation each month requiring strict epigenetic regulation for the proper functioning of the endometrium. Histone acetylation is generally associated with gene activation. It is regulated by histone acetyl transferases (HATs) and histone deacetylases (HDACs), which include sirtuins (SIRTs). Previous study from our lab has demonstrated that global histone acetylation changes in the endometrium correlate with the expected transcriptional activity during the menstrual cycle. However, the expression and regulation of HDACs in the endometrium have not been elucidated. The aim of this master’s project is to characterize the gene and protein expressions, and hormonal regulation of HDACs in human endometrium during the menstrual cycle. Normal endometrial tissues were obtained from cycling pre-menopausal women. Gene and protein expression patterns for the 18 HDACs were determined across the menstrual cycle stages. The analysis established the profile for HDAC expression in human endometrium during the menstrual cycle. In addition, effects of steroid hormone and HDAC inhibitor TSA were studied in three endometrial cell lines. The AN3 cells were used as a model for non-receptive endometrium epithelium, while RL95- 2 cells were used as a model for receptive epithelium. Human endometrial stromal cells (HESCs) were used as stromal cell models. The mRNA data showed that many of the HDACs were upregulated during the early secretory and mid secretory stages. The protein expression profiles matched the gene expression patterns in the endometrial tissues. The steroid hormone treatment showed that the gene expression of HDACs vary widely in the different cell lines in response to hormones. The effects of TSA on different HDACs also produced cell line specific effects. The results imply that there is temporal regulation of HDACs in endometrium during the menstrual cycle and is influenced by steroid hormones. Further functional studies to investigate the roles of specific HDACs will lead to better understanding of the regulation of histone acetylation in endometrium.