Expression of the SS18/SYT-SSX fusion protein is believed to underlie the pathogenesis of synovial sarcoma (SS). Recent evidence suggests that deregulation of the Wnt pathway may play an important role in SS but the mechanisms whereby SS18-SSX might affect Wnt signaling remain to be elucidated. Here, we show that SS18/SSX tightly regulates the elevated expression of the key Wnt target AXIN2 in primary SS. SS18-SSX is shown to interact with TCF/LEF, TLE and HDAC but not -catenin in vivo and to induce Wnt target gene expression by forming a complex containing promoter-bound TCF/LEF and HDAC but lacking -catenin. Our observations provide a tumor-specific mechanistic basis for Wnt target gene induction in SS that can occur in the absence of Wnt ligand stimulation.
The fusion protein SS18-SSX1 employs core Wnt pathway transcription factors to induce a partial Wnt signature in synovial sarcoma.
Cell line
View SamplesCancer stem cells (CSCs) display plasticity and self-renewal properties reminiscent of normal tissue stem cells, but the events responsible for their emergence remain obscure. We recently identified CSCs in Ewing sarcoma family tumors (ESFTs) and showed that they retain mesenchymal stem cell (MSC) plasticity. In the present study, we addressed the mechanisms that underlie ESFT CSC development. We show that the EWS-FLI-1 fusion gene, associated with 85%-90% of ESFTs and believed to initiate their pathogenesis, induces expression of the embryonic stem cell (ESC) genes OCT4, SOX2, and NANOG in human pediatric MSCs (hpMSCs) but not in their adult counterparts. Moreover, under appropriate culture conditions, hpMSCs expressing EWS-FLI-1 generate a cell subpopulation displaying ESFT CSC features in vitro. We further demonstrate that induction of the ESFT CSC phenotype is the result of the combined effect of EWS-FLI-1 on its target gene expression and repression of microRNA-145 (miRNA145) promoter activity. Finally, we provide evidence that EWS-FLI-1 and miRNA-145 function in a mutually repressive feedback loop and identify their common target gene, SOX2, in addition to miRNA145 itself, as key players in ESFT cell differentiation and tumorigenicity. Our observations provide insight for the first time into the mechanisms whereby a single oncogene can reprogram primary cells to display a CSC phenotype.
EWS-FLI-1 modulates miRNA145 and SOX2 expression to initiate mesenchymal stem cell reprogramming toward Ewing sarcoma cancer stem cells.
Specimen part
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Cell identity regulators link development and stress responses in the Arabidopsis root.
Age, Specimen part, Treatment
View SamplesCell-type specific transcriptional profiles were generated by FACS (Fluorescence Activated Cell Sorting) sorting of roots that express cell-type specific GFP-reporters. Five different GFP-reporter lines were used. FACS cell populations were isolated from roots grown under standard pH (pH 5.7) or roots that had been transfered to low pH (pH 4.6) media for 24 hours.
Cell identity regulators link development and stress responses in the Arabidopsis root.
Specimen part
View SamplesTo understand the effect of low pH on developmental stages in the root, we dissected the root into four developmental zones after exposure to low pH and expression profiled each zone.
Cell identity regulators link development and stress responses in the Arabidopsis root.
Age
View SamplesCell-type specific transcriptional profiles were generated by FACS (Fluorescence Activated Cell Sorting) sorting of roots that express cell-type specific GFP-reporters. Five different GFP-reporter lines were used. FACS cell populations were isolated from roots grown under sulfur deficient conditions for 3 hours.
Cell identity regulators link development and stress responses in the Arabidopsis root.
Specimen part
View SamplesWe preformed at time-course of the expression of whole Arabidopsis roots for 3H, 12H, 24H, 48H and 72H after transfer to media lacking sulfur. We combined these data with 13 other datasests and performed a meta-analysis to ask whether a universal stress response exists in Arabidopsis roots.
Cell identity regulators link development and stress responses in the Arabidopsis root.
No sample metadata fields
View SamplesTo understand the effect of sulfur deficiency on developmental stages in the root, we dissected the root into four developmental zones after exposure to sulfur deficiency and expression profiled each zone.
Cell identity regulators link development and stress responses in the Arabidopsis root.
No sample metadata fields
View SamplesTo estimate the effect of protoplasting and sorting on low pH-regulated gene expression, we generated expression profiles for whole roots treated with low pH for 24 hours and whole roots that had been protoplasted and FACS sorted after 24 hours of exposure to low pH.
Cell identity regulators link development and stress responses in the Arabidopsis root.
Treatment
View SamplesThe molecular mechanisms of neurogenic fate determination are of particular importance in light of the need to regenerate neurons. However the molecular logic of neurogenic fate determination is still ill understood, even though some key transcription factors have been implicated. Here we describe how one of these, the transcription factor Pax6, regulates adult neurogenesis by initiating a cross-regulatory network of 3 transcription factors executing neuronal fate and regulating genes required for neuronal differentiation. This network is initiated and driven to sufficiently high expression levels by the transcription factor Pax6 in close interaction with Brg1-containing SWI/SNF chromatin remodeling factors.
The BAF complex interacts with Pax6 in adult neural progenitors to establish a neurogenic cross-regulatory transcriptional network.
Sex, Age, Specimen part
View Samples