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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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE94503 | GEO | 2017/10/22

SECONDARY ACCESSION(S): PRJNA374494

REPOSITORIES: GEO

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Role for the EWS domain of EWS/FLI in binding GGAA-microsatellites required for Ewing sarcoma anchorage independent growth.

Project description: Not available

| S-EPMC5603999 | biostudies-literature

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

Emergent Properties of EWS/FLI Regulation via GGAA Microsatellites in Ewing's Sarcoma.

Project description: Not available

| S-EPMC2935179 | biostudies-literature

Identification of two types of GGAA-microsatellites and their roles in EWS/FLI binding and gene regulation in Ewing sarcoma.

Project description: Not available

| S-EPMC5665490 | biostudies-literature

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

Project description:A novel role for the EWS portion of EWS/FLI in binding GGAA-microsatellites required for oncogenic transformation in Ewing sarcoma

| PRJNA374494 | ENA

Microsatellites as EWS/FLI response elements in Ewing's sarcoma.

Project description: Not available

| S-EPMC2481306 | biostudies-literature

EWS/FLI mediates transcriptional repression via NKX2.2 during oncogenic transformation in Ewing's sarcoma.

Project description: Not available

| S-EPMC2291578 | biostudies-literature

The role of FLI-1-EWS, a fusion gene reciprocal to EWS-FLI-1, in Ewing sarcoma.

Project description: Not available

| S-EPMC4701224 | biostudies-literature

Identification of two types of GGAA microsatellites and their roles in EWS/FLI binding and gene regulation in Ewing sarcoma

Project description:Ewing sarcoma is a bone malignancy of children and young adults, frequently harboring the EWS/FLI t(11;22)(q24;q12) chromosomal translocation. The resulting fusion protein is an aberrant transcription factor that uses highly repetitive GGAA-containing elements (microsatellites) to activate and repress thousands of target genes mediating oncogenesis. However, the mechanisms of EWS/FLI interaction with microsatellites and regulation of target genes expression is not clearly understood. Here, we profile genome-wide protein binding and gene expression. Using a combination of unbiased genome-wide computational and experimental analysis, we define GGAA-microsatellites in a Ewing sarcoma context. Our study identifies two distinct classes of GGAA-microsatellites and demonstrates that EWS/FLI responsiveness is dependent on microsatellite length. At close range (within 5 kb) “promoter-like” microsatellites, EWS/FLI binding and subsequent target genes activation is highly dependent on the number of GGAA-motifs. “Enhancer-like” microsatellites demonstrate a positive correlation with length-dependent EWS/FLI binding, but minimal correlation for activated and none for repressed target genes. Our data suggest that EWS/FLI binds to “promoter-like” and “enhancer-like” microsatellites to mediate activation and repression of target genes through different regulatory mechanisms. Such characterization contributes valuable insight to EWS/FLI transcription factor biology and clarifies the role of GGAA-microsatellites on a global genomic scale. This may provide a unique perspective on the role of non-coding DNA in cancer susceptibility and therapeutic development.

2017-11-09 | GSE99959 | GEO

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