A distal super enhancer mediates estrogen-dependent mouse uterine–specific gene transcription of Insulin-like growth factor 1 (Igf1)
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PROVIDER: PRJNA518135 | ENA |
REPOSITORIES: ENA
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Project description:Insulin-like growth factor 1 (IGF1) is primarily synthesized in and secreted from the liver; however, estrogen (E2), through E2 receptor α (ERα), increases uterine Igf1 mRNA levels. Previous ChIP-Seq analyses of the murine uterus have revealed a potential enhancer region distal from the Igf1 transcription start site (TSS) with multiple E2-dependent ERα-binding regions. Here, we show E2-dependent super enhancer–associated characteristics and suggest contact between the distal enhancer and the Igf1 TSS. We hypothesized that this distal super-enhancer region controls E2-responsive induction of uterine Igf1 transcripts. We deleted 430 bp, encompassing one of the ERα-binding sites, thereby disrupting interactions of the enhancer with gene-regulatory factors. As a result, E2-mediated induction of mouse uterine Igf1 mRNA is completely eliminated, whereas hepatic Igf1 expression remains unaffected. This highlights the central role of a distal enhancer in the assembly of the factors necessary for E2-dependent interaction with the Igf1 TSS and induction of uterus-specific Igf1 transcription. Of note, loss of the enhancer did not affect fertility or uterine growth responses. Deletion of uterine Igf1 in a PgrCre;Igf1f/f model decreased female fertility, but did not impact the E2-induced uterine growth response. Moreover, E2-dependent activation of uterine IGF1 signaling was not impaired by disrupting the distal enhancer or by deleting the coding transcript. This indicated a role for systemic IGF1, suggested that other growth mediators drive uterine response to E2, and that uterine-derived IGF1 is essential for reproductive success. Our findings elucidate the role of a super enhancer in Igf1 regulation and uterine growth.
2019-05-08 | GSE125972 | GEO
Project description: Not available
| S-EPMC6597841 | biostudies-literature
Project description:Estrogen (E2) signaling through its nuclear receptor, estrogen receptor α (ERα) increases insulin-like growth factor 1 (IGF1) in the rodent uterus, which then initiates further signals via the IGF1 receptor (IGF1R). Directly administering IGF1 results in similar biological and transcriptional uterine responses. Our studies using global ERα-null mice demonstrated a loss of uterine biological responses of the uterus to E2 or IGF1 treatment, while maintaining transcriptional responses to IGF1. To address this discrepancy in the need for uterine ERα in mediating the IGF1 transcriptional vs. growth responses, we assessed the IGF1 transcriptional responses in PgrCre+Esr1f/f (called ERαUtcKO) mice, which selectively lack ERα in progesterone receptor (PGR) expressing cells, including all uterine cells, while maintaining ERα expression in other tissues and cells that do not express Pgr. Additionally, we profiled IGF1-induced ERα binding sites in uterine chromatin using ChIP-seq. Herein, we explore the transcriptional and molecular signaling that underlies our findings to refine our understanding of uterine IGF1 signaling and identify ERα-mediated and ERα-independent uterine transcriptional responses. Defining these mechanisms in vivo in whole tissue and animal contexts provides details of nuclear receptor mediated mechanisms that impact biological systems and have potential applicability to reproductive processes of humans, livestock and wildlife.
2017-06-17 | GSE100131 | GEO
Project description:Estrogen (E2) signaling through its nuclear receptor, estrogen receptor α (ERα) increases insulin-like growth factor 1 (IGF1) in the rodent uterus, which then initiates further signals via the IGF1 receptor (IGF1R). Directly administering IGF1 results in similar biological and transcriptional uterine responses. Our studies using global ERα-null mice demonstrated a loss of uterine biological responses of the uterus to E2 or IGF1 treatment, while maintaining transcriptional responses to IGF1. To address this discrepancy in the need for uterine ERα in mediating the IGF1 transcriptional vs. growth responses, we assessed the IGF1 transcriptional responses in PgrCre+Esr1f/f (called ERαUtcKO) mice, which selectively lack ERα in progesterone receptor (PGR) expressing cells, including all uterine cells, while maintaining ERα expression in other tissues and cells that do not express Pgr. Additionally, we profiled IGF1-induced ERα binding sites in uterine chromatin using ChIP-seq. Herein, we explore the transcriptional and molecular signaling that underlies our findings to refine our understanding of uterine IGF1 signaling and identify ERα-mediated and ERα-independent uterine transcriptional responses. Defining these mechanisms in vivo in whole tissue and animal contexts provides details of nuclear receptor mediated mechanisms that impact biological systems and have potential applicability to reproductive processes of humans, livestock and wildlife.
2017-06-14 | GSE100023 | GEO
Project description:Project in which conditionally immortalised mouse podocytes had either their insulin, IGF1 or both receptors knocked down. 72 hours post receptor knock-down total proteomics was performed on 40 samples.
2024-04-04 | PXD051018 | Pride
Project description:IGF1 and IGF1 receptors (IGF1R) are present in the adult heart and have been shown to be essential for myocardial performance. Insulin-like growth factor 1 (IGF1) is produced in numerous tissues particularly by the liver in response to growth hormone stimulation and is an important factor in the regulation of post-natal growth and development. We have generated and characterized transgenic mice over-expressing the IGF1R. We crossed IGF1R transgenic mice with dominant negative (dn)PI3K (p110) and with constitutively active (ca)PI3K(p110) transgenic mice. Expression profiling was performed on the ventricles of IGF1R, IGF1R-caPI3K, IGF1R-dnPI3K, caPI3K, dnPI3K transgenic female mice at 3 months of age. Non-transgenic littermates were used as controls. Keywords = http://cardiogenomics.med.harvard.edu/groups/proj1/pages/igfr1_home.html Keywords: other
2004-03-24 | GSE1143 | GEO
Project description:Estrogen receptor α (ERα) modulates gene expression through interactions with enhancer regions of chromatin that are frequently distal from the promoters of estrogen regulated genes. Active chromatin enriched “super-enhancer” (SE) regions, mainly described in in vitro culture systems, often control production of key cell type determining transcription factors. Here, we define ERα binding super-enhancers in vivo within hormone responsive uterine tissue. SE are already formed prior to estrogen exposure at the onset of puberty. The SE encode critical developmental factors including Rara and Hoxd. Using chromosome conformation capture with high throughput sequencing (Hi-C) we demonstrate that most ERα-binding SE are located at a chromatin loop end and most uterine genes in loop ends associated with ERα-binding SEs are estrogen regulated. Although SE are formed prior to puberty, SE-associated genes acquire optimal ERα dependent expression after reproductive maturity, indicating estrogen impacts enhancer function subsequent to assembly. ERα-binding SE-associated genes impact key uterine functions mediated by estrogen, including TGFβ and LIF signaling pathways. This is the first identification of ERα-binding SE interactions underlying hormonal regulation of genes in uterine tissue and optimal development of estrogen response
2020-04-29 | GSE147843 | GEO
Project description:Temproral networks of (phospho)-proteins are constructed and analyzed to infer differential interactions under insulin and IGF1 stimulation. In total, 134 antibodies are tested in 21 breast cancer cell lines. The experiments are done in triplicate. Three serum-free-condition time points (5min, 24hr, 48hr) and six stimulation time points (5min, 10min, 30min, 6hr, 24hr, and 48hr) are obtained with either 10 nM IGF1 or 10 nM insulin stimulation.
2016-07-21 | E-GEOD-80233 | biostudies-arrayexpress
Project description:We examined the effect pg IGF1 actibation on cellular contractility and migration in SSC osteoblast cells. Based on microarray levels of IGF1 expression, we selected fifteen cases and nine controls spanning from the highest IGF1 expression to the lowest in cases and controls. Subsequently, the pattern of IGF1 expressions in these cells was assessed using high throughput RNA sequencing.
2016-11-29 | GSE75524 | GEO
Project description:Insight into the role of Insulin-like Growth Factor (IGF) in development of lungs has come from the study of genetically modified mice. IGF1 is a key factor during lung development. IGF1 deficiency in the neonatal mouse causes respiratory failure collapsed alveoli and altered alveolar septa. To further characterize IGF1 function during lung development we analyzed Igf1-/- mouse prenatal lungs in a C57Bl/6 genetic background. Mutant lungs showed disproportional hypoplasia, disorganized extracellular matrix and dilated alveolar capillaries. IGF1 target genes during lung maturation were identified by analyzing RNA differential expression in Igf1-/- lungs using microarrays. Lungs from E18.5 were isolated from both Igf1+/+ wild type and Igf1-/- null mice and pooled to obtain RNA. Heterozygous male and female with a genetic background C57BL/6J were mated to obtain embryos at embrionic (E) stage 18.5 days post coitum (E18.5). 3 biological replicates per genotype.
2014-03-31 | E-GEOD-17157 | biostudies-arrayexpress