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 regeneration, proliferation, differentiation, and degradation each month; each phase requiring strict epigenetic regulation for the proper functioning of the endometrium. Aberrant histone acetylation and alterations in levels of two acetylation modulators-histone acetylases (HATs) and histone deacetylases (HDACs)-have been associated with endometrial pathologies such as endometrial cancer, implantation failures, and endometriosis. Thus, histone acetylation is likely to have an essential role in the regulation of endometrial remodelling throughout the menstrual cycle.

Cytokines are important regulators of pregnancy and parturition. Aberrant expression of proinflammatory cytokines during pregnancy contributes towards preterm labor, pre‐eclampsia, and gestational diabetes mellitus. The regulation of cytokine expression in human cells is highly complex, involving interactions between environment, transcription factors, and feedback mechanisms. Recent developments in epigenetic research have made tremendous advancements in exploring histone modifications as a key epigenetic regulator of cytokine expression and the effect of their signaling molecules on various organ systems in the human body. Histone acetylation and subsequent deacetylation by histone deacetylases (HDACs) are major epigenetic regulators of protein expression in the human body. The expression of various proinflammatory cytokines, their role in normal and abnormal pregnancy, and their epigenetic regulation via HDACs will be discussed in this review.

Steroid hormones govern the complex, cyclic changes of the endometrium, predominantly through their receptors. An interplay between steroid hormones and epigenetic mechanisms controls the dynamic endometrial gene regulation. Abnormalities in expression of genes and enzymes associated with steroid hormone signaling, contribute to a disturbed hormonal equilibrium. Limited evidence suggests the involvement of TET (Ten Eleven Translocation)-mediated DNA hydroxymethylation in endometrial cancer, with some data on the use of TET1 as a potential prognostic and diagnostic biomarker, however the mechanisms guiding it and its regulation remains unexplored. This study aims to explore the changes in the expressions of TETs and steroid hormone receptors in response to estrogen and progesterone in endometrial cancer cells. Gene expression was examined using real-time PCR and protein expression was quantified using fluorescent western blotting in endometrial cancer cell lines (AN3 and RL95-2). Results indicate that TET1 and TET3 gene and protein expression was cell-specific in cancer cell-lines. Protein expression of TET1 was downregulated in AN3 cells, while TET1 and TET3 expressions were both upregulated in RL95-2 cells in response to estrogen-progesterone. Further, a decreased AR expression in AN3 cells and an increased ERα and ERβ protein expressions in RL95-2 cells was seen in response to estrogen-progesterone. PR gene and protein expression was absent from both cancer cell-lines. Overall, results imply that expressions of steroid hormones, steroid-hormone receptors and TETs are co-regulated in endometrial cancer-cells. Further studies are needed to interpret how these mechanisms fit in with DNMTs and DNA methylation in regulating endometrial biology. Understanding the role of TETs and hydroxymethylation in steroid hormone receptor regulation is crucial to comprehend how these mechanisms work together in a broader context of epigenetics in the endometrium and its pathologies.

Background: Histone Deacetylases (HDACs) are a class of enzymes that deacetylate the lysine residues on the protruding histone tails, causing tightening of the chromatin structure and making genes inaccessible to be transcribed. Class I and II HDACs have been involved in cell cycle regulation and progression. Class 1 HDACs have been widely studied in endometrial pathologies and menstrual cycle regulation. Studies have shown that class IIa HDACs (4, 5, 7, and 9) regulate the cell cycle, proliferation, and differentiation. But any potential roles for class IIa HDACs in endometrial biology have not been explored. This study aims to characterise the temporal expression of class IIa HDACs in the endometrium and their regulation by steroid hormones in human endometrial stromal cells (HESCs). Methods: mRNA expression and protein expression of HDAC 4, 5, 7, and 9 were analyzed in endometrial tissue biopsies collected from premenopausal women throughout the menstrual cycle by real-time quantitative PCR and fluorescent western blot analysis, respectively. Effect of hormonal regulation on class IIa HDAC expression was studied in endometrial stromal cell line following treatments with estrogen (E2) and estrogen-progesterone combined (E2+P4) over 24hrs, 48hrs, and 72hrs period. The cells were also treated with HDAC inhibitor Trichostatin A (TSA) combined with the steroid hormones. Results: In endometrial tissue, mRNA expression of class IIa HDACs showed cyclic changes. HDACs 5 and 7 were significantly upregulated during the early secretory phase, while HDAC9 was upregulated during the mid-secretory phase, compared to other cycle stages. In addition, HDAC 5 and 9 proteins were significantly upregulated in the human endometrium during the secretory phase, compared to the proliferative stage. Protein expression levels of class IIa HDACs in HESCs were upregulated in response to the combined estrogen-progesterone treatment for 24 and 48 hrs, in vitro. While TSA mitigated these hormonal effects.. Conclusions: This study shows that class IIa HDACs are expressed in the human endometrium in a cyclic pattern and are influenced by steroid hormones. Suggesting their possible involvement in menstrual cycle regulation and endometrial pathologies.