Estrogen and mTORC1 dependent genes in the uterus of uterine-specific Tsc2-null mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE78701 | GEO | 2016/02/26
SECONDARY ACCESSION(S): PRJNA313264
REPOSITORIES: GEO
Similar Datasets
Project description:To uncover genes regulated by mTORC1 and estradiol in uterine Tsc2-null LAM like cells, we performed RNAseq on uteri from 12-week old wild-type (WT) and uterine-specific Tsc2-null (KO) mice that were either untreated (intact), oopherectomized (ovx) or oopherectomized + treated with 17β-estradiol pellets (E2) for 8 weeks. We identified genes that were both estradiol- and TSC2-mediated. Uterine mRNA profiles of 12 week old wild type (WT) and uterine-specific Tsc2-null (KO) mice in the presence or absence of estradiol were generated using Illumina HiSeq2500
2016-02-26 | E-GEOD-78701 | biostudies-arrayexpress
Project description:Pulmonary Lymphangioleiomyomatosis (LAM), a rare lung disease that affects predominantly women, is characterized by proliferation of smooth muscle-like cells in the lungs, destruction of lung tissue, upregulation of VEGF-D, and growth of lymphatic vessels inducing a loss of pulmonary function. TSC2 gene mutations that render TSC2 inactive are a common finding associated with LAM. To better understand the function of the TSC2 gene in LAM , we sought to characterize differences in the transcriptome of cells where TSC2 is inactivated. RNA-Seq was used to measure transcript expression differences between a human TSC2-null angiolipoma cell line derived from an individual with LAM, and the same cell line with re-expressed TSC2 to serve as a control. The Illumina TruSeq method was used to prepare poly(A)-selected stranded RNA-Seq libraries, and 100bp paired-end reads were generated with an Illumina Hi-Seq 2500 instrument in high output mode. RNA-Seq data was analyzed using kallisto (http://pachterlab.github.io/kallisto/) and R.
2018-05-23 | GSE84476 | GEO
Project description:Pulmonary Lymphangioleiomyomatosis (LAM), a rare lung disease that affects predominantly women, is characterized by proliferation of smooth muscle-like cells in the lungs, destruction of lung tissue, upregulation of VEGF-D, and growth of lymphatic vessels inducing a loss of pulmonary function. TSC2 gene mutations that render TSC2 inactive are a common finding associated with LAM. To better understand the function of the TSC2 gene, we sought to characterize differences in the transcriptome of cells where TSC2 is inactivated. RNA-Seq was used to measure transcript expression differences between TSC2-null mouse embryonic fibroblasts and TSC2-expressed mouse embryonic fibroblasts. The Illumina TruSeq method was used to prepare stranded poly(A)-selected RNA-Seq libraries, and 100bp paired-end reads were generated with an Illumina Hi-Seq 2500 instrument in high output mode. RNA-Seq data was analyzed using kallisto (http://pachterlab.github.io/kallisto/) and R.
2018-05-23 | GSE84477 | GEO
Project description:Tuberous Sclerosis Complex (TSC) and Lymphangioleiomyomatosis (LAM) are caused by inactivating mutations in TSC1 or TSC2, leading to mTORC1 hyperactivation. The mTORC1 inhibitors rapamycin and analogs (rapalogs) are approved for treating of TSC and LAM. Due to their cytostatic and not cytocidal action, discontinuation of treatment leads to tumor regrowth and decline in pulmonary function. Therefore, life-long rapalog treatment is proposed for the control of TSC and LAM lesions, which increases the chances for the development of acquired drug resistance. Understanding the signaling perturbations leading to rapalog resistance is critical for the development of better therapeutic strategies. We developed the first Tsc2-null rapamycin-resistant cell line, ELT3-245, which is highly tumorigenic in mice, and refractory to rapamycin treatment. In vitro ELT3-245 cells exhibit enhanced anchorage-independent cell survival, resistance to anoikis, and loss of epithelial markers. A key alteration in ELT3-245 is increased β-catenin signaling. We propose that a subset of cells in TSC and LAM lesions have additional signaling aberrations, thus possess the potential to become resistant to rapalogs. Alternatively, when challenged with rapalogs TSC-null cells are reprogrammed to express mesenchymal-like markers. These signaling changes could be further exploited to induce clinically-relevant long-term remissions.
2018-09-06 | GSE119524 | GEO
Project description:Rationale: Increased matrix metalloproteinase (MMP) activity has been implicated in the pathogenesis of lymphangioleiomyomatosis (LAM). Objectives: To investigate how TSC1 or TSC2 deficiency alters MMP expression and regulation. Methods: We studied immortalized cells that lack TSC2 derived from an angiomyolipoma (AML) of a LAM patient, and a TSC2 add back derivative; and murine embryonic fibroblast cells that lack Tsc1 or Tsc2 and respective controls. Global gene expression analysis was carried out in the AML and derivative cell lines. MMP levels in the conditioned media from these cells were analyzed by zymography and ELISA. Measurements and Main Results: We found increased MMP-2 expression in cells lacking TSC1/TSC2 compared to their respective controls by zymography. MMP-2 overproduction by these cells was not affected by rapamycin treatment. Gene expression analysis confirmed increased MMP-2 gene expression that was not affected by rapamycin. Furthermore, multiple other genes were found to be over-expressed in rapamycin-treated TSC2-deficient cells compared to TSC2+ cells. Conclusions: We conclude that TSC1/TSC2 deficiency leads to MMP-2 overproduction that is rapamycin insensitive, and that several genes exhibit similar patterns suggesting TSC1/TSC2 dependent but mTOR independent pathways may be involved in the pathogenesis of LAM.
2009-10-21 | GSE16944 | GEO
Project description:Patients with Lymphangioleiomyomatosis (LAM) develop nodules of cells within the lung parenchyma. These lesions contain both TSC2-/- LAM cells, and wild type fibroblasts. We investigated the effect of TSC2-/- cells on the transcriptional profile of both normal fibroblasts and fibroblasts isolated from LAM patient tissue (LAFs) using Affymetrix Gene Chip arrays, to identify upregulated pathways which could contribute to LAM pathology. We used Affymetrix microarrays to detail the changes in the global profile of gene expression in fibroblasts following co-culture with 621-101 cells, and identified upregulation of several chemokines, indicating that the fibroblasts had adopted an inflammatory phenotype.
2021-12-31 | GSE160618 | GEO
Project description:There are concerns regarding possible reproductive toxicity from consumption of soy including an increased risk of endometriosis and endometrial cancer. We used global uterine gene expression profiles in adult ovariectomized (OVX) female rats assessed by RNAseq to examine the estrogenicity of soy protein isolate (SPI) and the potential for feeding SPI to alter estrogen signaling in the uterus. Rats were fed AIN93G diets made with casein (CAS) or SPI from postnatal day (PND) 30. Rats were OVX on PND 50 and infused with 17 beta-estradiol (E2) or vehicle. E2 increased uterine wet weight (P<0.05) and significantly altered expression of 2084 uterine genes. In contrast, SPI feeding had no effect on uterine weight and only altered expression of 177 genes. Overlap between E2 and SPI genes was limited to 69 genes (3%). GO analysis indicated significant differences in uterine biological processes affected by E2 and SPI and little evidence for recruitment of ER alpha to the promoters of ER-responsive genes after SPI feeding. The major E2 up-regulated uterine pathways were cancer pathways and extracellular organization. SPI feeding up-regulated uterine PPAR signaling and fatty acid metabolism. The combination of E2 and SPI feeding resulted in significant regulation of 715 fewer genes relative to E2 alone. In a separate experiment, the combination of E2 and SPI reversed the ability of E2 to induce uterine proliferation in response to the carcinogen dimethybenz(a)anthracene (DMBA). These data suggest SPI does not act as a weak estrogen in the uterus but appears to be a selective estrogen receptor modulator (SERM) interacting with a small sub-set of E2-regulated genes and to be anti-estrogenic in the presence of endogenous estrogens. Rat uterus mRNA of ovariectomized adult female rats subject to four different diets (Caseine, Caseine + E2, Soy and Soy+E2 ) were sequenced, in triplicate, in an Illumina GAIIx sequencer.
2015-06-13 | E-GEOD-69819 | biostudies-arrayexpress
Project description:There are concerns regarding possible reproductive toxicity from consumption of soy including an increased risk of endometriosis and endometrial cancer. We used global uterine gene expression profiles in adult ovariectomized (OVX) female rats assessed by RNAseq to examine the estrogenicity of soy protein isolate (SPI) and the potential for feeding SPI to alter estrogen signaling in the uterus. Rats were fed AIN93G diets made with casein (CAS) or SPI from postnatal day (PND) 30. Rats were OVX on PND 50 and infused with 17 beta-estradiol (E2) or vehicle. E2 increased uterine wet weight (P<0.05) and significantly altered expression of 2084 uterine genes. In contrast, SPI feeding had no effect on uterine weight and only altered expression of 177 genes. Overlap between E2 and SPI genes was limited to 69 genes (3%). GO analysis indicated significant differences in uterine biological processes affected by E2 and SPI and little evidence for recruitment of ER alpha to the promoters of ER-responsive genes after SPI feeding. The major E2 up-regulated uterine pathways were cancer pathways and extracellular organization. SPI feeding up-regulated uterine PPAR signaling and fatty acid metabolism. The combination of E2 and SPI feeding resulted in significant regulation of 715 fewer genes relative to E2 alone. In a separate experiment, the combination of E2 and SPI reversed the ability of E2 to induce uterine proliferation in response to the carcinogen dimethybenz(a)anthracene (DMBA). These data suggest SPI does not act as a weak estrogen in the uterus but appears to be a selective estrogen receptor modulator (SERM) interacting with a small sub-set of E2-regulated genes and to be anti-estrogenic in the presence of endogenous estrogens.
2015-06-13 | GSE69819 | GEO
Project description:ChIP-seq from mice with DNA binding mutations in Esr1 (KIKO mouse). Estrogen Receptor M-NM-1 (ERM-NM-1) interacts with DNA, directly, or indirectly via other transcription factors, referred to as M-bM-^@M-^\tetheringM-bM-^@M-^]. Evidence for tethering is based on in vitro studies and a widely used M-bM-^@M-^\KIKOM-bM-^@M-^] mouse model containing mutations that prevent direct estrogen response element (ERE) DNA-binding. KIKO mice are infertile, due in part to the inability of estrogen (E2) to induce uterine epithelial proliferation. To elucidate the molecular events that prevent KIKO uterine growth, regulation of the pro-proliferative E2 target gene Klf4, and of Klf15, a progesterone (P4) target gene that opposes KLF4M-bM-^@M-^Ys pro-proliferative activity, were evaluated. Klf4 induction was impaired in KIKO uteri; however, Klf15 was induced by E2 rather than by P4. Whole uterine ChIP-seq revealed enrichment of KIKO ERM-NM-1 binding to hormone response elements (HRE), motifs. KIKO binding to HRE motifs was verified using reporter gene and DNA-binding assays. Because the KIKO ERM-NM-1 has HRE DNA-binding activity, we evaluated the M-bM-^@M-^\EAAEM-bM-^@M-^] ERM-NM-1, which has more severe DBD mutations, and demonstrated lack of ERE or HRE reporter gene induction or DNA binding. The EAAE mouse has an ERM-NM-1-null like phenotype, with impaired uterine growth and transcriptional activity. Our findings demonstrate that the KIKO mouse model, which has been used by numerous investigators, cannot be used to establish biological functions for ERM-NM-1 tethering, as KIKO ERM-NM-1 effectively stimulates transcription using HRE motifs. The EAAE-ERM-NM-1 DBD mutant mouse demonstrates that ERM-NM-1 DNA-binding is crucial for biological and transcriptional processes in reproductive tissues, and that ERM-NM-1-tethering may not contribute to estrogen-responsiveness in vivo. one sample each, vehicle ER-alpha ChIP seq,1 hour estradiol ER-alpha ChIP seq, vehicle RNA polymerase II ChIP seq,1 hour estradiol RNA polymerase II ChIP seq, input DNA
2014-04-03 | E-GEOD-56466 | biostudies-arrayexpress
Project description:Lymphangioleiomyomatosis (LAM) is a rare, debilitating lung disease that predominantly affects women of reproductive age. LAM cells carry deleterious mutations of tuberous sclerosis complex (TSC1/TSC2) genes, resulting in hyperactivation of the mechanistic target of rapamycin complex 1 (mTORC1) and ultimately dysregulated cell growth. The integrative single cell omics data identified the activation of uterine specific HOX-PBX transcriptional programming in pulmonary LAMCORE cells. Network analysis predicted homeobox transcription factors including PBX1 and HOXD11 as key regulators controlling LAMCORE cell fate. Targeting the HOX-PBX network may have therapeutic value in LAM and TSC-related diseases, and possibly in other mTORC1-hyperactive neoplasms.
2023-04-03 | GSE217107 | GEO