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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 [RNA-seq II]

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE173376 | 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 [CUT&RUN]

Project description: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.

2021-06-15 | GSE160896 | GEO

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]

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

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 (RNA-Seq)

2022-08-15 | GSE185130 | GEO

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

2022-08-15 | GSE185125 | GEO