Transcriptional regulation in the ovary of estrogen-deficient mouse
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE73529 | GEO | 2015/09/29
SECONDARY ACCESSION(S): PRJNA297228
REPOSITORIES: GEO
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Project description:At birth, all female mice, including those that either lack estrogen receptor α (ERα-knockout) or that express mutated forms of ERα (AF2ERKI), have a hypoplastic uterus. However, uterine growth and development that normally accompanies pubertal maturation does not occur in ERα-knockout or AF2ERKI mice, indicating ERα mediated estrogen signaling is essential for this process. Mice that lack Cyp19 (aromatase, ArKO mice), an enzyme critical for estrogen (E2) synthesis, are unable to make E2, and lack pubertal uterine development. A single injection of E2 into ovariectomized adult (10 weeks old) females normally results in uterine epithelial cell proliferation, however, we observe that, although ERα is present in the ArKO uterine cells, no proliferative response is seen. We assessed the impact of exposing ArKO mice to E2 during pubertal and post-pubertal windows and observed that E2 exposed ArKO mice acquired growth responsiveness. Analysis of differential gene expression between unexposed ArKO samples and samples from animals exhibiting the ability to mount an E2-induced uterine growth response (WT or E2 exposed ArKO) revealed activation of EZH2 and HAND2 signaling and inhibition of GLI1 responses. EZH2 and HAND2 are known inhibit uterine growth, and GLI1 is involved in IHH signaling, which is a positive mediator of uterine response. Finally, we show that exposure of ArKO females to dietary phytoestrogens results in their acquisition of uterine growth competence. Altogether our findings suggest that pubertal levels of endogenous and exogenous estrogens impact biological function of uterine cells later in life via ERα-dependent mechanisms. We compared uterine RNA from ovariectomized adult aromatase knockout mice (ARKO) mice that were untreated to WT mice and to ARKO that were administered estradiol benzoate (EB) to induce uterine epithelial cell growth competence
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Project description:In this study, we have utilized wild-type (WT) and aromatase knockout (ArKO; estrogen free) mouse ovaries as an in vivo model to profile estrogen dependent genes. RNA from each individual ovary (n=3) was analyzed by a microarray-based screen using Illumina Sentrix Mouse WG-6 BeadChip (45,281 transcripts).
2010-09-15 | E-MEXP-2824 | biostudies-arrayexpress
Project description:The role of reproductive hormones in lung cancer is controversial; obervations from epidemiological studies support the possibilities that estrogen either promotes or protects against the disease. In an earlier study we reported that estradiol (E2) stimulated tumorigenesis in a genetically defined mouse model based on the conditional expression of oncogenic Kras and concomitant deletion of p53. The present study was meant to further examine the effects of estrogens in this model. Instead we found that tumorigenesis was inhibited by the presence of the ovaries and that E2 proved protective against tumorigenesis in ovariectomized animals. Specifically, E2 and the Esr1-specific agonist PPT reduced the number and size of tumors that developed; furthermore, the protective effects of these two steroids were dose-dependent. However, the Esr2 agonist DPN produced no effect. Since Esr2 predominates in the lung, these results suggest that the E2 effect is indirect, perhaps being mediated by an endocrine factor from another organ. Furthermore, the fact that the E2 effect in this second iteration of the mouse model was diametrically opposed to our earlier results suggests that genetic background plays a critical role in determining the effect of estrogen.
2015-09-25 | GSE61837 | GEO
Project description:Estradiol-17β (E2) has been shown to promote primordial follicle (PF) formation and to involve BMP2 as a downstream effector to promote PF in the hamsters. However, the molecular mechanism whereby these factors regulate ovarian somatic cells to pre-granulosa cells (preGC) transition leading to PF formation remains unclear. The objective of this study was to determine whether BMP2 and/or E2 would regulate the expression of specific ovarian transcriptome during preGC transition and PF formation in the mouse ovary. BMP2 mRNA level increased during the period of PF formation with concurrent presence of BMP2 protein in ovarian somatic cells. E2 but not BMP2 exposure led to increased expression of ovarian BMP2 mRNA, and the effect of E2 could not be suppressed by LDN 193189 (LDN). Either BMP2 or E2 stimulated PF formation without inducing apoptosis. RNAseq analysis of ovaries exposed to exogenous BMP2 or E2 revealed differential expression of several thousand genes. Most of the differentially expressed genes (DEG), which were common between BMP2 or E2 treatment demonstrated concordant changes, reinforcing the idea of cooperativity between E2 and BMP2 during PF formation. Further, we have Identified E2, in cooperation with BMP2, could affect the expression of three major transcription factors GATA2, GATA4 and EGR2 and one serine protease, hepsin in preGC during PF formation. Taken together, results of this study suggest that E2 and BMP2 may regulate ovarian gene expression that promote somatic cells to preGC transition and PF formation in the mouse ovary.
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2010-12-13 | E-GEOD-25570 | biostudies-arrayexpress
Project description:Here we perform transcriptional profiling of late third instar larval ovaries and gonadal fatbody from Drosophila melanogaster w1118 flies. We designed this experiment to investigate the effect of protease treatment on dissected ovaries. We profiled ovaries without protease treatment with some fatbody still attached, fatbody alone dissected from around the ovaries, ovaries cleaned of fatbody using a papain/collagenase cocktail, and ovaries dissociated using a papain/collagenase cocktail. We then constructed polyA+ libraries and performed 50 bp stranded single end RNA-Seq.
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Project description:Inhibition of VE-PTP, an endothelial receptor type tyrosine phosphatase, triggers phosphorylation of the tyrosine kinase receptor Tie-2, which leads to the suppression of inflammation-induced vascular permeability. Analyzing the underlying mechanism, we show here that inhibition of VE-PTP and activation of Tie-2 induce tyrosine phosphorylation of FGD5, a GTPase exchange factor (GEF) for Cdc42, and stimulate translocation of this GEF to cell contacts. Interfering with the expression of FGD5 blocked the junction stabilizing effect of VE-PTP inhibition in vitro and in vivo. Likewise, FGD5 was required for strengthening of cortical actin bundles and inhibiting radial stress fiber formation, which were each stimulated by VE-PTP inhibition. We identified Y820 of FGD5 as the direct substrate for VE-PTP. Inhibition of VE-PTP could no longer stabilize endothelial junctions or activate Cdc42 if endothelial cells expressed a Y820F point mutated version of FGD5. In contrast, FGD5-Y820F was still recruited to endothelial cell contacts. Thus, activation of FGD5 is a two-step process that comprises membrane recruitment and phosphorylation of Y820. These steps are necessary for the junction stabilizing effect that is stimulated by VE-PTP inhibition and Tie-2 activation.
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Project description:The emergence of anti-estrogen resistance in breast cancer is an important clinical phenomenon affecting long-term survival in this disease. Identifying factors that convey cell survival in this setting may guide improvements in treatment. Estrogen (E2) can induce apoptosis in breast cancer cells that have been selected for survival after E2 deprivation for long periods (MCF-7:5C cells), but the mechanisms underlying E2-induced stress in this setting have not been elucidated. Here, we report that the c-Src kinase functions as a key adapter protein for the estrogen receptor (ER, ESR1) in its activation of stress responses induced by E2 in MCF-7:5C cells. E2 elevated phosphorylation of c-Src, which was blocked by 4-hydroxytamoxifen (4-OHT), suggesting that E2 activated c-Src through the ER. We found that E2 activated the sensors of the unfolded protein response (UPR), IRE1α (ERN1) and PERK kinase (EIF2AK3), the latter of which phosphorylates eukaryotic translation initiation factor-2α (eIF2α). E2 also dramatically increased reactive oxygen species production and upregulated expression of heme oxygenase HO-1 (HMOX1), an indicator of oxidative stress, along with the central energy sensor kinase AMPK (PRKAA2). Pharmacologic or RNA interference-mediated inhibition of c-Src abolished the phosphorylation of eIF2α and AMPK, blocked E2-induced ROS production, and inhibited E2-induced apoptosis. Together, our results establish that c-Src kinase mediates stresses generated by E2 in long-term E2-deprived cells that trigger apoptosis. This work offers a mechanistic rationale for a new approach in the treatment of endocrine-resistant breast cancer.
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Project description:We sequenced small RNA from total RNA samples in two siRNA-pathway mutants in fly ovaries. This submission comes from a modENCODE project. For data usage terms and conditions, please refer to http://www.genome.gov/27528022 and http://www.genome.gov/Pages/Research/ENCODE/ENCODEDataReleasePolicyFinal2008.pdf
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