The role of epigenetic mechanisms in the regulation of gene expression in the cyclical endometrium

Abstract

Background The human endometrium is a highly dynamic tissue whose function is mainly regulated by the ovarian steroid hormones estradiol and progesterone. The serum levels of these and other hormones are associated with three specific phases that compose the endometrial cycle: menstrual, proliferative, and secretory. Throughout this cycle, the endometrium exhibits different transcriptional networks according to the genes expressed in each phase. Epigenetic mechanisms are crucial in the fine-tuning of gene expression to generate such transcriptional networks. The present review aims to provide an overview of current research focused on the epigenetic mechanisms that regulate gene expression in the cyclical endometrium and discuss the technical and clinical perspectives regarding this topic. Main body The main epigenetic mechanisms reported are DNA methylation, histone post-translational modifications, and non-coding RNAs. These epigenetic mechanisms induce the expression of genes associated with transcriptional regulation, endometrial epithelial growth, angiogenesis, and stromal cell proliferation during the proliferative phase. During the secretory phase, epigenetic mechanisms promote the expression of genes associated with hormone response, insulin signaling, decidualization, and embryo implantation. Furthermore, the global content of specific epigenetic modifications and the gene expression of non-coding RNAs and epigenetic modifiers vary according to the menstrual cycle phase. In vitro and cell type-specific studies have demonstrated that epithelial and stromal cells undergo particular epigenetic changes that modulate their transcriptional networks to accomplish their function during decidualization and implantation. Conclusion and perspectives Epigenetic mechanisms are emerging as key players in regulating transcriptional networks associated with key processes and functions of the cyclical endometrium. Further studies using next-generation sequencing and single-cell technology are warranted to explore the role of other epigenetic mechanisms in each cell type that composes the endometrium throughout the menstrual cycle. The application of this knowledge will definitively provide essential information to understand the pathological mechanisms of endometrial diseases, such as endometriosis and endometrial cancer, and to identify potential therapeutic targets and improve women’s health.

Characterization of Epigenetic and Molecular Factors in Endometrium of Females with Infertility

“…Mechanisms of epigenetic regulation, such as DNA methylation, noncoding RNAs and histone post-translational modifications induce the expression of genes associated with stromal cell proliferation, endometrial epithelial growth, transcriptional regulation, and angiogenesis. During decidualization and implantation, epigenetic remodeling occurs in epithelial and stromal cells, leading to rearrangement of gene expression and cell function [ 42 ]. In this study, we showed that expression of miR-34a, miRNA-223, and miRNA-125b is significantly lower in endometrial tissue of patients with reproductive pathologies compared to endometrial tissue from control females.…”

Advancing understanding of maternal age: correlating epigenetic clocks in blood and myometrium

“…The stroma retains clonogenic properties of mesenchymal stem cells [ 35 , 36 ]. Cyclic modulation of endometrium may be controlled in part by epigenetic mechanisms [ 37 ]. With aging, the function of endometrium is affected by the loss of stem cells [ 38 ] as well as by decreased proliferation necessary for establishing implantation, driven by lower estrogen production.…”

Epigenetics of pregnancy: looking beyond the DNA code

“…High levels of progesterone in the post-ovulatory phase modulate the endometrial gene expression required for implantation by regulating DNA methylation [75][76][77], and alterations in the DNA methylation of 448 sites have been associated with defective endometrial receptivity and consequently in recurrent pregnancy failure [75,78]. Moreover, different non-coding transcripts like lncRNAs and miRNAs are involved in endometrial receptivity regulation [79].…”