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The FLI portion of EWS/FLI contributes a transcriptional regulatory function that is distinct from its DNA-binding function in Ewing sarcoma [CUT&RUN]

ABSTRACT: The purpose of this study was to compare the relevance of the FLI portion for genomic localization of the EWS/FLI protein in Ewing sarcoma cells. EWS/FLI cDNA constructs including various deletions of the FLI portion were virally transduced into cells and we sought to determine the ATAC profile of each.

ORGANISM(S): Homo sapiens

PROVIDER: GSE160896 | GEO | 2021/06/15

REPOSITORIES: GEO

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The FLI portion of EWS/FLI contributes a transcriptional regulatory function that is distinct from its DNA-binding function in Ewing sarcoma [ATAC-seq]

Project description:The purpose of this study was to compare the relevance of the FLI portion of EWS/FLI in the ability of the protein to act as a pioneer factor in Ewing sarcoma cells. EWS/FLI cDNA constructs including various deletions of the FLI portion were virally transduced into cells and we sought to determine the ATAC profile of each.

2021-06-15 | GSE160895 | GEO

The FLI portion of EWS/FLI contributes a transcriptional regulatory function that is distinct from its DNA-binding function in Ewing sarcoma [RNA-seq II]

Project description:The purpose of this study was to determine the roles of the alpha-helical region just downstream of the FLI ETS DNA-binding domain in EWS/FLI-driven gene regulation of Ewing sarcoma cells. EWS/FLI cDNA constructs including various deletions of the FLI portion were virally transduced into cells and we sought to determine the transcriptional profile of each.

2021-06-15 | GSE173376 | GEO

The FLI portion of EWS/FLI contributes a transcriptional regulatory function that is distinct from its DNA-binding function in Ewing sarcoma [RNA-seq]

Project description:The purpose of this study was to determine the roles of the flanking regions of the FLI ETS DNA-binding domain in gene regulation of Ewing sarcoma cells. EWS/FLI cDNA constructs including various deletions of the FLI portion were virally transduced into cells and we sought to determine the transcriptional profile of each.

2021-06-15 | GSE160897 | GEO

The FLI portion of EWS/FLI contributes a transcriptional regulatory function that is distinct from its DNA-binding function in Ewing sarcoma [RNA-seq III]

Project description:The purpose of this study was to determine transcriptional regulatory activity of EWS/FLI mutants in an alternative, non-Ewing sarcoma cell line. EWS/FLI cDNA constructs including various deletions of the FLI portion were transfected in HEK-293EBNA cells and we sought to determine the transcriptional profile of each through RNA-sequencing.

2021-06-15 | GSE173414 | GEO

A novel role for the EWS portion of EWS/FLI in binding GGAA-microsatellites required for oncogenic transformation in Ewing sarcoma [RNA-Seq]

Project description:Ewing sarcoma usually expresses the EWS/FLI fusion transcription factor oncoprotein. EWS/FLI regulates myriad genes required for Ewing sarcoma development. EWS/FLI binds GGAA-microsatellite sequences in vivo and in vitro, and these sequences provide EWS/FLI-mediated activation to reporter constructs, suggesting that they function as EWS/FLI-response elements. Genomic GGAA-microsatellites are highly variable and polymorphic. Current data suggest that there is an optimal “sweet-spot” GGAA-microsatellite length (of 18-26 GGAA repeats) that confers maximal EWS/FLI-responsiveness to target genes, but the mechanistic basis for this was not known. We now demonstrate the absolute necessity of an EWS/FLI-bound GGAA-microsatellite in regulation of the NR0B1 gene, as well as for Ewing sarcoma proliferation and oncogenic transformation. Biochemical studies, using recombinant Δ22 (a version of EWS/FLI containing only the FLI portion) demonstrated a stoichiometry of one Δ22-monomer binding to every two consecutive GGAA-repeats on shorter GGAA-microsatellite sequences. Surprisingly, the affinity for Δ22 binding to GGAA-microsatellites significantly decreased, and ultimately became unmeasureable, when the size of the GGAA-microsatellite was increased to the “sweet-spot” length. In contrast, a fully-functional EWS/FLI mutant (Mut9) that retains approximately half of the EWS portion of the fusion showed low affinity for smaller GGAA-microsatellites, but instead significantly increased its affinity at “sweet-spot” microsatellite lengths. Single-gene ChIP and genome-wide ChIP-seq and RNA-seq studies extended these findings to the in vivo setting. Taken together, these data demonstrate the absolute requirement of GGAA-microsatellites as EWS/FLI activating response elements in vivo and reveal an unsuspected novel role for the EWS portion of the EWS/FLI fusion in binding to optimal-length GGAA-microsatellites.

2017-10-22 | GSE94502 | GEO

A novel role for the EWS portion of EWS/FLI in binding GGAA-microsatellites required for oncogenic transformation in Ewing sarcoma [ChIP-Seq]

2017-10-22 | GSE94480 | GEO

Human A673 Ewing sarcoma secretome - effect of EWS-FLI-1 silencing

Project description:EWS-FLI-1 was silenced by an shRNA in A673 Ewing sarcoma cells and the resulting alterations in the secretome was analyzed by GeLC-MS/MS approach (six gel slices for each sample, luciferase shRNA-expressing cell secretome as control)

2021-07-06 | PXD016052 | Pride

Transcription profiling of human Ewing sarcoma samples and EWS-FLI-1 inhibited Ewing sarcoma cell lines

Project description:The cellular origin of Ewing tumor (ET), a tumor of bone or soft tissues characterized by specific fusions between EWS and ETS genes, is highly debated. Through gene expression analysis comparing ETs with a variety of normal tissues, we show that the profiles of different EWS-FLI1-silenced Ewing cell lines converge toward that of mesenchymal stem cells (MSC). Moreover, upon EWS-FLI1 silencing, two different Ewing cell lines can differentiate along the adipogenic lineage when incubated in appropriate differentiation cocktails. In addition, Ewing cells can also differentiate along the osteogenic lineage upon long-term inhibition of EWS-FLI1. These in silico and experimental data strongly suggest that the inhibition of EWS-FLI1 may allow Ewing cells to recover the phenotype of their MSC progenitor. Experiment Overall Design: Ewing tumors and EWS-FLI-1 inhibited cell lines were profiled on Affymetrix U133A (GPL96) arrays.

2008-06-15 | E-GEOD-7007 | biostudies-arrayexpress

EWS/FLI mediated reprogramming of 3D chromatin promotes an altered transcriptional state in Ewing sarcoma (4C)

Project description:Ewing sarcoma is a prototypical fusion transcription factor-associated pediatric cancer that expresses EWS/FLI or highly related fusions. EWS/FLI dysregulates transcription to induce and maintain sarcomagenesis, but the mechanisms utilized are not fully understood. We therefore sought to define the global effects of EWS/FLI on chromatin conformation and transcription in Ewing sarcoma. We found that EWS/FLI (and EWS/ERG) genomic localization is largely conserved across multiple patient-derived Ewing sarcoma cell lines. EWS/FLI binding is primarily associated with compartment activation, establishment of topologically-associated domain (TAD) boundaries, enhancer-promoter looping that involve both intra- and inter-TAD interactions, and gene activation. Importantly, local chromatin features provide the basis for transcriptional heterogeneity in regulation of direct EWS/FLI target genes across different Ewing sarcoma cell lines. These data demonstrate a key role of EWS/FLI in mediating genome-wide changes in chromatin configuration and support the notion that fusion transcription factors serve as master regulators through three-dimensional reprogramming of chromatin.

2022-08-15 | GSE185131 | GEO

EWS/FLI mediated reprogramming of 3D chromatin promotes an altered transcriptional state in Ewing sarcoma (Hi-C)

2022-08-15 | GSE185125 | GEO