Estrogen-mediated Regulation of Igf1 Transcription and Uterine Growth Involves Direct Binding of Estrogen Receptor to Estrogen-responsive Elements
ABSTRACT Estrogen enables uterine proliferation, which depends on synthesis of the IGF1 growth factor. This proliferation and IGF1 synthesis requires the estrogen receptor (ER), which binds directly to target DNA sequences (estrogen-responsive elements or EREs), or interacts with other transcription factors, such as AP1, to impact transcription. We observe neither uterine growth nor an increase in Igf1 transcript in a mouse with a DNA-binding mutated ER alpha (KIKO), indicating that both Igf1 regulation and uterine proliferation require the DNA binding function of the ER. We identified several potential EREs in the Igf1 gene, and chromatin immunoprecipitation analysis revealed ER alpha binding to these EREs in wild type but not KIKO chromatin. STAT5 is also reported to regulate Igf1; uterine Stat5a transcript is increased by estradiol (E(2)), but not in KIKO or alpha ERKO uteri, indicating ER alpha- and ERE-dependent regulation. ER alpha binds to a potential Stat5a ERE. We hypothesize that E(2) increases Stat5a transcript through ERE binding; that ER alpha, either alone or together with STAT5, then acts to increase Igf1 transcription; and that the resulting lack of IGF1 impairs KIKO uterine growth. Treatment with exogenous IGF1, alone or in combination with E(2), induces proliferation in wild type but not KIKO uteri, indicating that IGF1 replacement does not rescue the KIKO proliferative response. Together, these observations suggest in contrast to previous in vitro studies of IGF-1 regulation involving AP1 motifs that direct ER alpha-DNA interaction is required to increase Igf1 transcription. Additionally, full ER alpha function is needed to mediate other cellular signals of the growth factor for uterine growth.
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- "This regional difference in the hormonal responsiveness of H1R between the vl VMN and dm VMN may be due to differential distribution of ERα in the two VMN subregions. ERα is a potent gene transcription factor that acts through genomic and non-genomic pathways upon ligand binding and is often coexpressed in neurons in which sex steroids cause changes in expression of a particular gene , . Regulation of receptor protein expression by ligand-bound ERα has been well characterized for the progesterone receptor (PR) ,  and oxytocin receptor ,  in the VMN, and for vasopressin receptors , mu-opioid receptors –, and cholecystokinin receptors . "
ABSTRACT: Female sexual behavior is controlled by central estrogenic action in the ventromedial nucleus of the hypothalamus (VMN). This region plays a pivotal role in facilitating sex-related behavior in response to estrogen stimulation via neural activation by several neurotransmitters, including histamine, which participates in this mechanism through its strong neural potentiating action. However, the mechanism through which estrogen signaling is linked to the histamine system in the VMN is unclear. This study was undertaken to investigate the relationship between estrogen and histamine receptor subtype H1 (H1R), which is a potent subtype among histamine receptors in the brain. We show localization of H1R exclusively in the ventrolateral subregion of the female VMN (vl VMN), and not in the dorsomedial subregion. In the vl VMN, abundantly expressed H1R were mostly colocalized with estrogen receptor α. Intriguingly, H1R mRNA levels in the vl VMN were significantly elevated in ovariectomized female rats treated with estrogen benzoate. These data suggest that estrogen can amplify histamine signaling by enhancing H1R expression in the vl VMN. This enhancement of histamine signaling might be functionally important for allowing neural excitation in response to estrogen stimulation of the neural circuit and may serve as an accelerator of female sexual arousal.PLoS ONE 05/2014; 9(5):e96232. DOI:10.1371/journal.pone.0096232 · 3.23 Impact Factor
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- "ERα is reported to be necessary for the IGF-1 signaling cascade controlling endometrial epithelial cell proliferation [16, 17]. It was recently reported that ERα–DNA interaction is necessary for E2-mediated regulation of Igf1 transcription in the mouse uterus , and ERα binds to several ERE sites located in the mouse Igf1. On the other hand, Weihua et al. reported the elevation of IGF-1 gene expression in the uterus of ERβ knockout mice, but quantitative analysis of IGF-1 gene expression was not performed in their study . "
ABSTRACT: Insulin-like growth factor 1 (IGF-1) is involved in regulations of reproductive functions in rats and mice. IGF-1 expression is regulated by estrogen in several reproductive organs including the uterus and ovary. Two types of estrogen receptor (ERα and ERβ) are expressed in mouse uteri and ovaries, and it is unclear whether they differently mediate IGF-1 gene transcription. To clarify the roles of ERα and ERβ, mouse endometrial stromal cells and ovarian granulosa cells were treated with ligands specific for individual estrogen receptors. In endometrial stromal cells, propyl-pyrazole-triol (PPT; ERα-selective agonist) increased Igf1 mRNA expression, which was suppressed by methyl-piperidino-pyrazole (MPP, ERα-selective antagonist), while diarylpropionitrile (DPN, ERβ-potency selective agonist) increased Igf1 mRNA expression, which was inhibited by MPP but not by 4-[2-phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-α]pyrimidin-3-yl]phenol (PHTPP; ERβ antagonist). PHTPP enhanced the DPN-induced increase in Igf1 mRNA expression. In ovarian granulosa cells, E2 and DPN decreased Igf1 mRNA expression, whereas PPT did not affect Igf1 mRNA levels. In these cells, PHTPP inhibited the DPN-induced decrease in Igf1 mRNA expression. These results suggest that ERα facilitates Igf1 transcription, whereas ERβ appears to inhibit Igf1 gene transcription in mouse endometrial stromal cells and ovarian granulosa cells.Journal of Reproduction and Development 03/2014; 60(3). DOI:10.1262/jrd.2013-085 · 1.64 Impact Factor
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- "E2 increases Ltf expression through a well-characterized ERE (–324) located upstream from the Ltf promoter transcription start site (Liu and Teng 1992; Liu et al. 1993). Using chromatin immunoprecipitation (ChIP) quantitative PCR (Hewitt et al. 2010), we confirmed that ERα is bound to this ERE site (–324) in the Ltf gene promoter in SVs from 10-week-old WT mice with or without neonatal DES exposure. However, DES enhances the enrichment of ERα binding (data not shown). "
ABSTRACT: Diethylstilbestrol (DES) is a synthetic estrogen that is associated with adverse effects on reproductive organs. DES-induced toxicity of the mouse seminal vesicle (SV) is mediated by ERα with altered expression of seminal vesicle secretory protein IV (Svs4) and lactoferrin (Ltf) genes. We examined a role for nuclear receptor activity in association with DNA methylation and altered gene expression. We used the neonatal DES exposure mouse model to examine DNA methylation patterns via bisulfite conversion sequencing in WT and αERKO SVs. DNA methylation status at 4 specific CpGs (-160, -237, -306 and -367) in the Svs4 gene promoter changes during mouse development from methylated to un-methylated, and DES prevents this change at 10-weeks of age in WT SV. DES alters the methylation status from methylated to un-methylated at 2 specific CpGs (-449 and -459) of the Ltf gene promoter. Alterations in DNA methylation of Svs4 and Ltf were not observed in αERKO SV, suggesting that changes of methylation status at these CpGs are ERα dependent. The methylation status associates with the level of gene expression. In addition, gene expression of three epigenetic modifiers, including DNMT3A, MBD2, and HDAC2 increased after DES exposure in WT SV. DES-induced hormonal toxicity results from altered gene expression of Svs4 and Ltf associated with changes in DNA methylation that are mediated by ERα. Alterations in gene expression of DNMT3A, MBD2 and HDAC2 after DES exposure may be involved in mediating the changes in methylation status in the SVs of male mice.Environmental Health Perspectives 12/2013; 122(3). DOI:10.1289/ehp.1307351 · 7.98 Impact Factor