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Transcriptomic analysis to functionally map the intrinsically disordered domain of EWS/FLI

ABSTRACT: This SuperSeries is composed of the SubSeries listed below. The data represent functional transcriptomic profiles of the oncogenic fusion transcription factor EWS/FLI.

ORGANISM(S): Homo sapiens

PROVIDER: GSE122537 | GEO | 2019/02/21

REPOSITORIES: GEO

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Transcriptomic analysis to functionally map the intrinsically disordered domain of EWS/FLI [Experiment 2]

Project description:The purpose of this study was to define unique classes of EWS/FLI target genes and the distinct set of structural features present in the EWS domain required for target gene regulation at different EWS/FLI response elements. This study reports the first genome-wide transcriptomic description of a partially-functional EWS/FLI mutant . We report new structure-function dependencies across different classes of response element and tie these dependencies to the ability of EWS/FLI to transform cells.

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Transcriptomic analysis to functionally map the intrinsically disordered domain of EWS/FLI

Project description:Transcriptomic analysis to functionally map the intrinsically disordered domain of EWS/FLI

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Transcriptomic analysis to functionally map the intrinsically disordered domain of EWS/FLI [Experiment 2]

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

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Transcriptomic analysis functionally maps the intrinsically disordered domain of EWS/FLI and reveals novel transcriptional dependencies for oncogenesis.

Project description:EWS/FLI is the pathognomic fusion oncoprotein that drives Ewing sarcoma. The amino-terminal EWS portion coordinates transcriptional regulation and the carboxy-terminal FLI portion contains an ETS DNA-binding domain. EWS/FLI acts as an aberrant transcription factor, orchestrating a complex mix of gene activation and repression, from both high affinity ETS motifs and repetitive GGAA-microsatellites. Our overarching hypothesis is that executing multi-faceted transcriptional regulation requires EWS/FLI to use distinct molecular mechanisms at different loci. Many attempts have been made to map distinct functions to specific features of the EWS domain, but described deletion mutants are either fully active or completely "dead" and other approaches have been limited by the repetitive and disordered nature of the EWS domain. Here, we use transcriptomic approaches to show an EWS/FLI mutant, called DAF, previously thought to be nonfunctional, displays context-dependent and partial transcriptional activity but lacks transforming capacity. Using transcriptomic and phenotypic anchorage-independent growth profiles of other EWS/FLI mutants coupled with reported EWS/FLI localization data, we have mapped the critical structure-function requirements of the EWS domain for EWS/FLI-mediated oncogenesis. This approach defined unique classes of EWS/FLI response elements and revealed novel structure-function relationships required for EWS/FLI activation at these response elements.

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Chromatin profiling of the relationship between EWS/FLI, LSD1, and H3K27 acetylation

Project description:The purpose of this study was to define the genome-wide functional relationship between LSD1 and EWS/FLI in Ewing sarcoma cells. We found EWS/FLI and LSD1 co-localize throughout the genome and that EWS/FLI induces a large change in the genomic distribution of LSD1.

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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.

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

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