The many faces of estrogen signaling

Abstract

Estrogens have long been known as important regulators of the female reproductive functions; however, our understanding of the role estrogens play in the human body has changed significantly over the past years. It is now commonly accepted that estrogens and androgens have important functions in both female and male physiology and pathology. This is in part due to the local synthesis and action of estrogens that broadens the role of estrogen signaling beyond that of the endocrine system. Furthermore, there are several different mechanisms through which the three estrogen receptors (ERs), ERα, ERβ and G protein-coupled estrogen receptor 1 (GPER1) are able to regulate target gene transcription. ERα and ERβ are mostly associated with the direct and indirect genomic signaling pathways that result in target gene expression. Membrane-bound GPER1 is on the other hand responsible for the rapid non-genomic actions of estrogens that activate various protein-kinase cascades. Estrogen signaling is also tightly connected with another important regulatory entity, i.e. epigenetic mechanisms. Posttranslational histone modifications, microRNAs (miRNAs) and DNA methylation have been shown to influence gene expression of ERs as well as being regulated by estrogen signaling. Moreover, several coregulators of estrogen signaling also exhibit chromatin-modifying activities further underlining the importance of epigenetic mechanisms in estrogen signaling. This review wishes to highlight the newer aspects of estrogen signaling that exceed its classical endocrine regulatory role, especially emphasizing its tight intertwinement with epigenetic mechanisms.

Keywords: DNA methylation; epigenetic mechanisms; estrogen signaling; extragonadal synthesis; miRNA.

Figure 1.

Schematic representation of estrogen synthesis in extragonadal tissues. Estrogens and androgens are produced from C₁₉ steroid precursors through several enzymatic conversions. Testosterone can be converted to the most active ligand on the androgen receptor, i.e. DHT, or the most active ligand on the estrogen receptor, i.e. 17β-estradiol, in a single reaction. 3β-HSD – 3β-hydroxysteroid dehydrogenase; 17β-HSD – 17β-hydroxysteroid dehydrogenas; DHEA – dehydroepiandrosterone; DHEAS – dehydroepiandrosterone sulfate; DHT – 5α-dihydrotestosterone.

Figure 2.

The representation of different mechanisms of estrogen signaling. (I.) Direct genomic signaling pathway, considered the classical mechanism of estrogen signaling, promotes target gene expression by binding the E2-ER complex directly to the ERE. (II.) In the case of indirect genomic signaling pathway, E2-activated ERs bind DNA through protein-protein interactions with other classes of transcription factors at their respective response elements. (III.) Non-genomic signaling pathway starts with the binding of E2 to the ERs located at the plasma membrane resulting in the activation of various protein-kinase cascades. These can eventually lead to changes in gene expression due to phosphorylation of transcription factors. (IV). Ligand-independent signaling pathway causes ER activation and target gene transcription through phosphorylation of ERs or their associated coregulators. E2 – 17β-estradiol; ER – estrogen receptor; ERE – estrogen response element; P – phosphate group; TF – transcription factor; TF RE – transcription factor response element.