ReviewDynamic regulation of estrogen receptor-alpha gene expression in the brain: A role for promoter methylation?
Introduction
Estrogens, and in particular, 17β-estradiol (E2), the primary biologically active form of estrogen, have long been known to play a crucial role in coordinating the neuroendocrine events that control sexual development, sexual behavior and reproduction. In rodents, E2 is critical for sexual differentiation of the brain (see review by Gore in this issue and [63]. Generation of the differences between the male and female brain results from the exposure of the male brain to E2 [62]. During early postnatal development, the female brain is believed to be isolated from E2 by the presence of alpha-fetoprotein that prevents circulating E2 from crossing the blood brain barrier [5]. The effects of E2 on neural circuits and apoptosis of neurons lead to long-term differences in the male and female brain [2], [99], [121]. In addition to its role in development, E2 modulates numerous facets of brain function in the adult brain (for review see [64]). Such actions include protection against neuronal injury, involvement in learning and memory as well as promoting the formation of synapses [59], [106], [114], [134], [136].
The majority of these crucial and diverse actions of E2 require the action of an estrogen receptor, whether it be in a classical nuclear manner or mediated by cytoplasmic or membrane mechanisms. Indeed, E2 binding studies have shown a unique binding pattern in non-reproductive brain areas such as the cortex and hippocampus [32], [109]. Furthermore, these binding patterns change during postnatal development and decrease dramatically as the animal approaches puberty [122]. While the molecular actions of steroid hormones mediated through their receptors have been extensively studied in the brain and in peripheral tissues, considerably less is known about the molecular mechanisms that regulate the expression of steroid hormone receptors themselves. Because of the dramatic and dynamic regulation of estrogen receptor-alpha (ERα) mRNA described below, and its important role in numerous neuronal processes, this review will focus on the regulation of expression of the ERα gene in several brain regions and present potential molecular mechanisms that control its expression.
Section snippets
Estrogen receptor expression
The physiological effects resulting from E2 actions in target tissues are mediated by changes in the expression patterns of specific target genes. Many of these actions are mediated by intracellular receptors, and to date, two nuclear estrogen receptors have been well characterized, ERα and ERβ [38], [50], [55], [70], [131]. Additionally, membrane receptors are believed to mediate rapid actions of estrogens under certain physiological conditions [23], [98], [123], [137]. Both ERα and ERβ have
Developmental regulation of estrogen receptor-alpha
Dynamic changes take place throughout development in ERα protein levels that are also reflected by changes in ERα mRNA expression [111], [113], [122]. Autoradiographic studies first demonstrated high levels of estradiol binding in non-hypothalamic regions such as the cortex and hippocampus during the first two weeks of life [89], [105], [109]. Interestingly, this expression declines as animals approach puberty. In rats, ERα mRNA expression was also shown to correlate with the changes in
Epigenetic regulation of estrogen receptor-alpha gene expression
At the molecular level, epigenetic modification of chromatin involves chemical changes to the DNA and associated proteins (for review see [135] and [49]). These modifications are heritable and can be passed to daughter cells during mitosis or meiosis [96]. Epigenetic modifications include DNA methylation, histone methylation and histone acetylation [9], [16]. Histones can also be ubiquitinated and phosphorylated leading to epigenetic regulation of gene expression where methylated DNA and
Learning and memory
Epigenetic regulation of gene expression in neurons is associated with long-term memory formation and synaptic plasticity [3], [58]. In the rodent hippocampus fear conditioning has been shown to induce DNA methyltransferase 3A (Dnmt3A) and Dnmt3B expression [66]. Additionally, fear conditioning in rats resulted in the rapid methylation of the protein phosphatase 1 gene promoter, a gene known to be involved with LTP and memory formation [58]. E2 has long been thought to influence specific types
Summary
Estrogens mediate numerous effects on the brain, and most require the presence of the estrogen receptor. Regulation of the ERα gene is critical for mediating these responses in an age, gender, and brain region-specific manner. Alterations in this regulation either during development, disease or aging could potentially interfere with estrogen action. We propose that numerous physiological influences can potentially regulate ERα gene expression using reversible epigenetic mechanisms. An
Acknowledgments
This work cited from our laboratory was supported by a COBRE Grant P20 RR15592 from the National Center for Research Resources (NCRR), R01 HL073693 (M.E.W.) and American Heart Association Predoctoral Fellowship 0615231B (A.K.P.).
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2019, Molecular and Cellular EndocrinologyCitation Excerpt :Many microRNAs (miRNAs - miR) have been discovered to interfere with ERα mRNA. miR-18a, miR-18b, miR-193b, miR-302c, miR-22, miR-201, miR-221, and miR-222, miR-206, miR-222-3p, miR-4728-3p, miR-373, miR-9-5p,let-7a, let-7b, and let-7i pair with the 3’-untranslated region (3’-UTR) of ERα mRNA and activate the cleavage processes for this ribonucleic acid (Wilson et al., 2008; Tubel et al., 2016; Zhao et al., 2008; Adams et al., 2007; Pandey and Picard, 2009; Liu et al., 2009; Klinge, 2015). Therefore, at least three different genomic mechanisms (i.e., genetic/epigenetic) exist for the regulation of the receptor mRNA intracellular concentration, with the genetic ones being involved in the accumulation processes while epigenetic ones are implicated in the reduction of ERα mRNA levels (Fig. 2).
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2017, Molecular and Cellular EndocrinologyCitation Excerpt :DNA methylation, in turn, dampens promoter activity and receptor mRNA synthesis. However, the molecular mechanism of ERα gene regulation by methylation is not completely understood and requires further investigation (Wilson et al., 2008; Tubel et al., 2016). Once synthesized, ERα mRNA is the target of a number of miRNA (miR) molecules that finely tune its intracellular abundance.
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2013, Brain ResearchCitation Excerpt :However, in a series of pioneering experiments, Kangaspeska et al. have described a mechanism of cyclic methylation and demethylation in CpG dinucleotides of gene promoters that encode pS2 (also known as TFF1 Trefoil Factor 1), thus demonstrating that methylation can in fact be a dynamic process (Kangaspeska et al., 2008). Additionally, the expression of estrogen receptor α (ERα) changes according to different methylation modifications; both pS2 and ERα genes respond to estrogens, and display epigenetic regulation (Wilson et al., 2008). It is unknown if these mechanisms can be involved in the dynamic regulation of PR isoforms during various physiological processes, such as neuroprotection, sexual behavior, maternal behavior, and multiple functions which have been described in the Central Nervous System (CNS).
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2013, Pharmacological ReportsCitation Excerpt :A decline in ERα mRNAexpression has been reported in the hippocampus of individuals with schizophrenia and Alzheimer's disease [54]. There are also data implicating ERs in modulating symptoms of major mental illnesses, including depression and schizophrenia [9, 71]. ERs can bind to EDCs including PCBs, pesticides and compounds derived from plastics, such as bisphenol A and 4-nonylphenol.