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Endogenous degron alleles enable tunable control of EWSR1-FLI1 oncoprotein expression

ABSTRACT: Endogenous degron alleles enable tunable control of EWSR1-FLI1 oncoprotein expression

PROVIDER: PRJNA1127516 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR29536477_1.fastq.gz	Fastqsanger.gz
	SRR29536477_2.fastq.gz	Fastqsanger.gz
	SRR29536478_1.fastq.gz	Fastqsanger.gz
	SRR29536478_2.fastq.gz	Fastqsanger.gz
	SRR29536479_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

Endogenous degron alleles enable tunable control of EWSR1-FLI1 oncoprotein expression

Project description:Pediatric malignancies frequently harbor chromosomal translocations that induce expression of fusion oncoproteins. The EWSR1-FLI1 fusion oncoprotein acts as a neomorphic transcription factor and is the dominant genetic driver of Ewing’s sarcoma. However, interrogation of the mechanisms by which EWSR1-FLI1 drives tumorigenesis has been limited by a lack of model systems to precisely and selectively control its expression in patient-derived cell lines and xenografts. Here, we report the generation of a panel of patient-derived EWS cell lines in which inducible protein degrons have been engineered into the endogenous EWSR1-FLI1 locus. These systems enable precise control of EWSR1-FLI1 expression and the timing of oncoprotein depletion. We establish that complete suppression of EWSR1-FLI1 leads to a reversible cell cycle arrest at the G1-S phase transition, and we identify a core set of transcripts downstream of EWSR1-FLI1 across multiple cell lines and degron systems. Additionally, depletion of EWSR1-FLI1 using this system potently suppresses tumor growth in xenograft models validating efforts to directly target EWSR1-FLI1 in Ewing’s sarcoma.

2025-01-20 | GSE270570 | GEO

Endogenous EWSR1-FLI1 degron alleles enable control of fusion oncoprotein expression in tumor cell lines and xenografts.

Project description:Pediatric malignancies frequently harbor chromosomal translocations that induce expression of fusion oncoproteins. The EWSR1-FLI1 fusion oncoprotein acts as a neomorphic transcription factor and is the dominant genetic driver of Ewing's sarcoma. Interrogation of the mechanisms by which EWSR1-FLI1 drives tumorigenesis has been limited by a lack of model systems to precisely and selectively control its expression in patient-derived cell lines and xenografts. Here, we report the generation of a panel of patient-derived EWS cell lines in which inducible protein degrons were engineered into the endogenous EWSR1-FLI1 locus. These alleles enabled rapid and efficient depletion of EWSR1-FLI1. Complete suppression of EWSR1-FLI1 induced a reversible cell cycle arrest at the G1-S checkpoint, and we identified a core set of transcripts downstream of EWSR1-FLI1 across multiple cell lines and degron systems. Additionally, depletion of EWSR1-FLI1 potently suppressed tumor growth in xenograft models validating efforts to directly target EWSR1-FLI1 in Ewing's sarcoma.

| S-EPMC11566046 | biostudies-literature

Rewiring the fusion oncoprotein EWSR1::FLI1 in Ewing scarcoma with bivalent small molecules [RNA-Seq]

Project description:Dysregulated transcription is a defining hallmark of cancer. Recently, novel chemically induced proximity approaches have enabled the rewiring of transcriptional machinery to drive expression of pro-apoptotic genes using bivalent small molecules. In this work, we demonstrate that this strategy is amenable to relocalizing DNA bound transcriptional machinery, such as fusion transcription factors that commonly drive pediatric malignancies. Targeting fusion transcription factors, such as EWSR1::FLI1 in Ewing sarcoma, with these bivalent compounds may open new therapeutic avenues. Here, we develop a small molecule, EB-TCIP, that recruits FKBP12F36V-tagged EWSR1::FLI1 to DNA sites bound by the transcriptional regulator BCL6, leading to rapid chromatin remodeling and expression of BCL6 target genes. This proof-of-concept study demonstrates that DNA binding proteins with pioneering transcription factor activity, such as EWSR1::FLI1, can be relocalized on chromatin to induce expression of repressed genes. Insights herein will guide the development of future bivalent molecules that rewire DNA binding transcriptional machinery.

2025-03-17 | GSE290895 | GEO

Rewiring the fusion oncoprotein EWSR1::FLI1 in Ewing scarcoma with bivalent small molecules [ChIP-Seq]

2025-03-17 | GSE290894 | GEO

Rewiring the fusion oncoprotein EWSR1::FLI1 in Ewing scarcoma with bivalent small molecules [ATAC-seq]

2025-03-17 | GSE290893 | GEO

Rewiring the fusion oncoprotein EWSR1::FLI1 in Ewing scarcoma with bivalent small molecules [ChIP-Seq]

Project description:Rewiring the fusion oncoprotein EWSR1::FLI1 in Ewing scarcoma with bivalent small molecules [ChIP-Seq]

| PRJNA1230723 | ENA

Rewiring the fusion oncoprotein EWSR1::FLI1 in Ewing scarcoma with bivalent small molecules [RNA-Seq]

Project description:Rewiring the fusion oncoprotein EWSR1::FLI1 in Ewing scarcoma with bivalent small molecules [RNA-Seq]

| PRJNA1230725 | ENA

Rewiring the fusion oncoprotein EWSR1::FLI1 in Ewing scarcoma with bivalent small molecules [ATAC-seq]

Project description:Rewiring the fusion oncoprotein EWSR1::FLI1 in Ewing scarcoma with bivalent small molecules [ATAC-seq]

| PRJNA1230724 | ENA

KDM6A and B-mediated transcriptional activation of EWSR1-FLI1 targets coordinates demethylase dependent and independent mechanisms in Ewing sarcoma

Project description:Ewing Sarcoma (EwS) is a highly aggressive tumor arising in bones and soft tissues driven by the fusion oncoprotein EWSR1::FLI1. This aberrant transcription factor binds to GGAA microsatellites, causing epigenetic reprogramming through the formation of active neo-enhancers in a permissive cellular context. Inhibition of the oncogene remains challenging, and current efforts seek to exploit emergent epigenetic treatments targeting EWSR1::FLI1 cofactors. In EwS, neo-enhancers are characterized by strong enrichment of the active H3K27ac mark and concomitant lack of the repressive H3K27me3 mark. These regions are typically decorated with high levels of H3K27me3 prior to EWSR1::FLI1-activation. Here, upon expression of EWSR1::FLI1 in human pediatric mesenchymal stem cells, considered the putative cell of origin of EwS, we unraveled the genome-wide redistribution of H3K27me3. Stemming from these results, we elucidated the contribution of the H3K27me3 demethylases KDM6A/UTX and KDM6B/JMJD3 in the transcriptional activity of EWSR1::FLI1 induced enhancers. KDM6A had a demethylase-independent role in recruiting BRG1 at EWSR1::FLI1-primed enhancers containing single GGAA motifs, which was critical for EwS tumor growth. Conversely, KDM6B demethylated H3K27me3 at specific EWSR1::FLI1-active enhancers, co-localizing with BRG1 at GGAA repeats. Loss of KDM6B impaired the growth of EwS tumor xenografts. These results highlight KDM6 demethylases as EWSR1::FLI1 functional partners with potential as targets for treating EwS.

2025-08-18 | GSE211743 | GEO

Gene expression profiling of human Ewing sarcoma cells after knockdown of EGR2 or EWSR1-FLI1.

Project description:To get insight in the functional role of EGR2 for Ewing sarcoma, we performed a transcriptional profiling of Ewing sarcoma cells after knockdown of EGR2 and compared the resulting transcriptional signature with that of EWSR1-FLI1-silenced Ewing sarcoma cells. In accordance with the strong EGR2-induction by EWSR1-FLI1, both genes highly significantly overlap in their transcriptional signatures. Gene-set enrichment analyses (GSEA) and DAVID (Database for Annotation, Visualisation and Integrated Discovery) gene ontology analyses indicated a strong impact of EGR2 on cholesterol and lipid biosynthesis resembling its function in orchestrating lipid metabolism of myelinating Schwann cells. A673 and SK-N-MC Ewing sarcoma cells were transfected with specific siRNAs directed against EGR2 or EWSR1-FLI1 or non-targeting control siRNA. 48 h thereafter RNA was harvested and processed for microarray analysis.

2015-07-26 | E-GEOD-62090 | biostudies-arrayexpress

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