RNA-seq analysis of FET cells treated with RSPO1 or TGFβ1
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE103650 | GEO | 2017/09/09
SECONDARY ACCESSION(S): PRJNA403844
REPOSITORIES: GEO
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Project description:RNA-seq analysis of FET cells treated with RSPO1 or TGFβ1
| PRJNA403844 | ENA
Project description:R-spondin1 (Rspo1) is a member of a secreted protein family which has pleiotropic functions in development and stem cell growth. Rspo1 knock-out mice are sex-reversed, but some remain sub-fertile, so, they are unable to nurse their pups. A lack of Rspo1 expression in mammary epithelial cells results in an absence of duct side-branching development and defective alveolar formation. In this study we propose to characterize the molecular functions involved to mammary gland phenotype due to Rspo1 knock out. By transcriptional profiling, we have identified gene misregulated in mammary gland of Rspo1 knock-out mice during pregnancy. A stronger expression of genes characterising mesenchymal tissue was observed in the absence of alterations to the structure of mammary epithelial tissue. Mammary epithelial cell characterization, by immunohistochemistry approach, revealed a persistence of virgin markers which sign a delay in their differentiation. Moreover serial transplantation experiments show that Rspo1 is associated with a regenerative potential of mammary epithelial cell control. Our data have also highlighted that in mammary gland during pregnancy the expression of Rspo1’s partners, Lgr4 and RNF43, are negatively regulated and Tgf-β signaling is modified in the absence of Rspo1. Taken together, our results show an abrupt halt in mammary development at mid-pregnancy due to loss of further differentiated function.
2017-02-09 | GSE81244 | GEO
Project description:Frozen-thawed embryo transfer (FET) is increasingly available for the improvement of the success rate of assisted reproductive technologies other than fresh embryo transfer (ET). There have been numerous findings that FET provides better obstetric and perinatal outcomes. However, the birth weight of infants conceived using FET is heavier than that of those conceived via ET. In addition, some reports have suggested that FET is associated with perinatal diseases such as placenta accreta and pregnancy-induced hypertension and a decrease in the sex ratio of male infants. These phenotypic alterations are caused by epigenetic alterations. MicroRNAs (miRNAs) are one of epigenetic modifications and dysregulation of miRNAs due to the environment in utero leads to placenta-associated diseases in infants and subsequently chronic diseases later in life. In this study, we compared miRNA expression profiles in the placentas originated from intracytoplasmic sperm injection and FET (ICSI-FET), intracytoplasmic sperm injection and ET (ICSI-ET) and from intracytoplasmic sperm injection and FET (ICSI-FET), intracytoplasmic sperm injection and ET (ICSI-ET) and spontaneous pregnancies (SP).
2017-08-16 | GSE85270 | GEO
Project description:Genome-wide DNA methylation profiling of 20 intracranial mesenchymal tumors with FET-CREB fusions encompassing both intracranial myxoid mesenchymal tumors and intracranial angiomatoid fibrous histiocytoma-like neoplasms. The Illumina Infinium EPIC 850k Human DNA Methylation Beadchip was used to obtain DNA methylation profiles across approximately 850,000 CpG sites of genomic DNA extracted from formalin-fixed, paraffin-embedded tumor tissue of 20 intracranial mesenchymal tumors with FET-CREB fusions.
2021-11-18 | GSE164994 | GEO
Project description:FET fusion oncoprotein-regulated genes in HT1080 cell line
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Project description:4 replicates were prepared from A2058 melanoma cells [transfected with 10ng of empty vector (pcDNA3.1+)] and treated with 5ng/ml TGFβ1 or vehicle control for 24hrs This is the control arm of a larger experiment where cells transfected with a particular expression plasmid were treated with TGFβ1 or control vehicle. The transfection with the expresion plasmid was unsucessful so this empty vector data has been used alone to simply examine the effect of TGFβ1 treatment on A2058 cells.
2015-02-20 | E-GEOD-66114 | biostudies-arrayexpress
Project description:Genes encoding the RNA-binding proteins FUS, EWSR1, and TAF15 (FET proteins) are involved in chromosomal translocations in several rare sarcomas. FET-rearranged sarcomas are often aggressive malignancies affecting pediatric, adolescent, and young and middle-aged adults, with prognosis depending on the fusion and whether the disease is localized, metastatic, or relapsed. New therapies are needed for these patients. These translocations fuse the 5’ portion of the FET family gene with a 3’ partner gene encoding a transcription factor. The resulting fusion proteins have the intrinsically disordered low complexity domain (LCD) of the FET protein paired with a DNA binding domain and these chimeras function as oncogenic transcription factors. FET fusion proteins have proven stubbornly difficult to target directly and promising new therapeutic strategies target the critical regulators and co-regulators of these proteins. One such protein is the histone lysine specific demethylase 1 (LSD1). LSD1 physically interacts with and is recruited by multiple FET fusions, including EWSR1::FLI1. LSD1 promotes EWSR1::FLI1 gene regulation and prior studies showed that treatment with the noncompetitive inhibitor SP-2509 blocked the transcriptional activity of the fusion. A similar molecule, seclidemstat (SP-2577), was identified as a promising lead for clinical development and is currently in clinical trials for FET-rearranged sarcomas (NCT03600649). However, whether seclidemstat has pharmacological activity against EWSR1::FLI1 or any other FET fusion protein has yet to be demonstrated. In this study, we sought to evaluate the in vitro potency of seclidemstat against multiple cell lines derived from different FET-rearranged sarcomas, including Ewing sarcoma, desmoplastic small round cell tumor, clear cell sarcoma, and myxoid liposarcoma. We also defined the transcriptomic effect of seclidemstat treatment in these diseases and evaluated the activity of seclidemstat against FET fusion transcriptional regulation in multiple cell lines. Seclidemstat showed potent activity in cell viability assays in all four FET-rearranged sarcomas and disrupted the transcriptional function of all the tested fusion proteins. Though epigenetic and targeted inhibitors are unlikely to be effective as a single agents in the clinic, these data suggest seclidemstat remains a promising new treatment strategy for patients with FET-rearranged sarcomas
2024-06-12 | GSE267611 | GEO
Project description:We constructed AAV-vectors for systemic expression of a soluble RSPO1 protein in ApcMin/+ mice. We found that the RSPO1-Fc fusion protein suppresses the Wnt/ß-catenin signaling activity in intestinal adenomas and in adenoma-derived intestinal organoids ex vivo, but not in normal intestinal epithelial cells. In the Apc mutant cells, the RSPO1-Fc fusion protein activated the TGFß/SMAD signaling pathway to suppress several Wnt target genes and adenoma growth, which effect was rescued suppressed by the TGFß receptor kinase inhibitor SB-431542. Simultaneously, RSPO1-Fc induced proliferation of the normal intestinal stem cells, giving them a growth advantage over the mutant cells, which enabled the intestinal epithelium to eventually outgrow the adenoma cells. Prolonged systemic expression of AAV-RSPO1-Fc decreased significantly the number of the intestinal adenomas and improved the overall survival of ApcMin/+ mice. Thus RSPO1-Fc provides the normal intestinal epithelial cells a growth advantage when compared to the adenoma cells, which eventually leads to the extrusion of the adenomatous tissue. An attractive idea now is to exploit such differential response of normal vs. cancer cells in cancer therapy.
2020-02-29 | GSE146099 | GEO
Project description:Purpose: Ectopic Rspo1 expression in the mouse adrenal gland (driven by Sf1-Cre) leads to a sexually dimorphic phenotype of adrenocortical hyperplasia and tissue degeneration. In order to gain a mechanistic understanding of the sexual dimorphism, we compared the gene expression profiles of Rspo1-overexpressing animals (Rspo1 GOF) with control littermates. Methods: Total RNA was extracted from whole adrenals of male and female, control and Rspo1GOF mice during puberty (4 weeks). mRNA sequencing and differential gene expression analysis was conducted by Novogene Co. Hierarchical clustering and principal component analysis were conducted using Phantasus. Gene set enrichment analysis was performed using Broad's institute GSEA and the Molecular Signatures database. Conclusions: After Rspo1 transgene expression, sex is the second most important component that explains variability among the experimental groups. Genes specifically upregulated in female Rspo1GOF adrenals vs all the other groups are enriched in DNA proliferation and cell cycle genes, targets of E2F transcription factros and the DREAM complex. Genes specifically upregulated in male Rspo1GOF adrenals are related to immune system regulation. Verification of the RNA Seq results by experimental methods has showed that ectopic proliferation in the mutant adrenals is female-specific and that androgen receptor signalling plays a role in proliferation arrest in male animals. Moreover, accumulation of abnormal foamy-like macrophages in the male adrenals leads to tissue degeneration.
2021-06-27 | GSE178958 | GEO
Project description:Purpose: The goal of this study was to compare the transcriptome profiling (RNAseq) of two cell populations (Axin2pos and Axin2neg) that in differentiated bile duct-derived organoids (Axin2CreERT2+/-; R26-LSL-tdTom+/-) that aroused following 24h Rspo1 treatment. The transcriptome of these two cell populations was additionally compared with cells isolated from differentiated control organoids, which were all negative for Axin2 expression. Methods: Single-end 75bp sequencing of Axin2pos and Axin2neg cells isolated by FACS from differentiated bile duct organoids (Axin2CreERT2+/-; R26-LSL-tdTom+/-) organoids at three different passages (P5, P6 and P10) based on tdTom expression levels was performed with 100ng of total RNA input. To label Axin2 expressing cells, organoids treated with 500nM of 4-OHT for the last 24h of culture. Rspo1-treated organoids were exposed to 100ng/ml of Rspo1 during the last 24h of culture. Results: The addition of Rspo1 to the cultures caused an overall decrease of BEC lineage markers (Hnf1b, Muc1, Krt19, Krt7) in both Axin2pos and Axin2neg cells when compared to untreated cells, indicating that exposure to Rspo1 promoted escape from biliary fate. Axin2pos isolated from Rspo1-treated organoids were enriched in proliferation and hepatic progenitor cell markers when compared to Axin2neg cells isolated from Rspo1 treated organoids Conclusions: Our study uncover a possible role for the Wnt signalling pathway in BEC regenerative biology and cellular plasticity.
2020-11-09 | GSE161039 | GEO