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The Ewing sarcoma cell line atlas (ESCLA) - The relevance of the transcription factors GATA2 and E2F2 in a Ewing sarcoma cell line model

ABSTRACT: Cell lines have been essential for major discoveries in cancer including Ewing sarcoma (EwS). EwS is a highly aggressive pediatric bone or soft-tissue cancer characterized by oncogenic EWSR1-ETS fusion transcription factors converting polymorphic GGAA-microsatellites (mSats) into neo-enhancers. However, further detailed mechanistic evaluation of gene regulation in EwS have been hindered by the limited number of well-characterized cell line models. Here, we present the Ewing Sarcoma Cell Line Atlas (ESCLA) comprising 18 EwS cell lines with inducible EWSR1-ETS knockdown that were profiled by whole-genome-sequencing, DNA methylation arrays, gene expression and splicing arrays, mass spectrometry, and ChIP-seq for EWSR1-ETS and histone marks. Systematic analysis of these multi-dimensional data identified GATA2 and E2F2 as EWSR1-ETS-driven putative co-regulatory transcription factors. To evaluate the relevance of these transcrition factors, RNA interference in a Ewing sarcoma cell line was employed with subsequent Affymetrix Exon array profiling. The expression data were analysed in synopsis with the effects of EWSR1-FLI1 in the same cell line.

ORGANISM(S): Homo sapiens

PROVIDER: GSE212063 | GEO | 2022/08/26

REPOSITORIES: GEO

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Systematic multi-omics cell line profiling uncovers principles of Ewing sarcoma fusion oncogene-mediated gene regulation

Project description:Ewing sarcoma (EwS) is characterized by EWSR1-ETS fusion transcription factors converting polymorphic GGAA microsatellites (mSats) into potent neo-enhancers. Although the paucity of additional mutations makes EwS a genuine model to study principles of cooperation between dominant fusion oncogenes and neo-enhancers, this is impeded by the limited number of well-characterized models. Here we present the Ewing Sarcoma Cell Line Atlas (ESCLA), comprising whole-genome, DNA methylation, transcriptome, proteome, and chromatin immunoprecipitation sequencing (ChIP-seq) data of 18 cell lines with inducible EWSR1-ETS knockdown. The ESCLA shows hundreds of EWSR1-ETS-targets, the nature of EWSR1-ETS-preferred GGAA mSats, and putative indirect modes of EWSR1-ETS-mediated gene regulation, converging in the duality of a specific but plastic EwS signature. We identify heterogeneously regulated EWSR1-ETS-targets as potential prognostic EwS biomarkers. Our freely available ESCLA (http://r2platform.com/escla/) is a rich resource for EwS research and highlights the power of comprehensive datasets to unravel principles of heterogeneous gene regulation by chimeric transcription factors.

2024-06-18 | PXD052856 | Pride

The Ewing Sarcoma Cell Line Atlas (ESCLA) - methylation profiling of 18 Ewing sarcoma cell lines in EWSR1-ETS-high versus -low condition

Project description:Cell lines have been essential for major discoveries in cancer including Ewing sarcoma (EwS). EwS is a highly aggressive pediatric bone or soft-tissue cancer characterized by oncogenic EWSR1-ETS fusion transcription factors converting polymorphic GGAA-microsatellites (mSats) into neo-enhancers. However, further detailed mechanistic evaluation of gene regulation in EwS have been hindered by the limited number of well-characterized cell line models. Here, we present the Ewing Sarcoma Cell Line Atlas (ESCLA) comprising 18 EwS cell lines with inducible EWSR1-ETS knockdown that were profiled by whole-genome-sequencing, DNA methylation arrays, gene expression and splicing arrays, mass spectrometry, and ChIP-seq for EWSR1-ETS and histone marks. Systematic analysis of these multi-dimensional data illuminated hundreds of new potential EWSR1-ETS target genes, the nature of EWSR1-ETS-preferred GGAA-mSats, and potential indirect modes of EWSR1-ETS-mediated gene regulation. Moreover, we identified putative co-regulatory transcription factors and heterogeneously regulated EWSR1-ETS target genes that may have implications for the clinical heterogeneity of EwS. Collectively, our freely available ESCLA constitutes an extremely rich resource for EwS research and highlights the power of leveraging multidimensional and comprehensive datasets to unravel principles of heterogeneous gene regulation by dominant fusion oncogenes.

2021-06-09 | GSE176334 | GEO

The Ewing Sarcoma Cell Line Atlas (ESCLA) - expression profiling of 18 Ewing sarcoma cell lines in EWSR1-ETS-high versus -low condition

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The Ewing Sarcoma Cell Line Atlas - Systematic analysis of genome-wide EWSR1-ETS binding and histone marks in 18 Ewing sarcoma cell lines by ChIP-seq

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Genome-wide chromatin analysis of Ewing sarcoma (ChIP-seq)

Project description:We show that EWS-FLI1, an aberrant transcription factor responsible for the pathogenesis of Ewing sarcoma, reprograms gene regulatory circuits by directly inducing or directly repressing enhancers. At GGAA repeats, which lack regulatory potential in other cell types and are not evolutionarily conserved, EWS- FLI1 multimers potently induce chromatin opening, recruit p300 and WDR5, and create de novo enhancers. GGAA repeat enhancers can loop to physically interact with target promoters, as demonstrated by chromosome conformation capture assays. Conversely, EWS-FLI1 inactivates conserved enhancers containing canonical ETS motifs by displacing wild-type ETS transcription factors and abrogating p300 recruitment. ChIP-seq for of 4 histone modifications (H3K27ac, H3K4me1, H3K4me3 and H3K27me3), FLI1, p300, WDR5, ELF1 and GABPA in primary Ewing sarcomas, Ewing sarcoma cell lines (A673 and SKMNC cells), and mesenchymal stem cells (MSC). EWS-FLI1 was knocked down in Ewing sarcoma cell lines with lentiviral shRNAs (shFLI1 and shGFP control). EWS-FLI1 was expressed in MSCs with lentiviral expression vectors (pLIV EWSFLI1 or pLIV empty vector control). * Raw data not provided for the MSC and Primary Ewing sarcoma samples. *

2014-10-30 | E-GEOD-61944 | biostudies-arrayexpress

Genome-wide chromatin analysis of Ewing sarcoma (ATAC-seq)

Project description:We show that EWS-FLI1, an aberrant transcription factor responsible for the pathogenesis of Ewing sarcoma, reprograms gene regulatory circuits by directly inducing or directly repressing enhancers. At GGAA repeats, which lack regulatory potential in other cell types and are not evolutionarily conserved, EWS- FLI1 multimers potently induce chromatin opening, recruit p300 and WDR5, and create de novo enhancers. GGAA repeat enhancers can loop to physically interact with target promoters, as demonstrated by chromosome conformation capture assays. Conversely, EWS-FLI1 inactivates conserved enhancers containing canonical ETS motifs by displacing wild-type ETS transcription factors and abrogating p300 recruitment. Mesenchymal stem cells (MSCs) and a Ewing sarcoma cell line (SKNMC) were analyzed by ATAC-seq. EWS-FLI1 was expressed in MSCs using a lentiviral vector (pLIV EWSFLI1 or pLIV empty vector control). * Raw data not provided for the MSC samples. *

2014-10-30 | E-GEOD-61951 | biostudies-arrayexpress

Neo-peptides identification in Ewing sarcoma cell lines using proteomics approach

Project description:Ewing sarcoma (EwS) is an adolescent and young adult sarcoma characterized by chromosome translocations between members of the FET family of RNA binding proteins and members of the ETS family of transcription factors, the most frequent fusion being EWS-FLI1. EWS-FLI1 acts as a pioneer factor, creating de novo enhancers and activating genes located in the vicinity of EWS-FLI1-bound microsatellite sequences. recent results from our lab indicate that EWS-FLI1, which activates transcription through binding to the DNA at specific sites, can generate fully novel, unconventional transcription units in regions of the genome that are fully quiescent in normal cells (manuscript in preparation). The hypothesis of the project is that the open reading frames (ORFs) of these transcripts may encode peptides presented at the cell surface by HLA class I molecules and hence be recognized as non-self by the immune system. The aim of this study is to detect Ewing-specific neo-peptides/proteins using proteomics approach.

2022-05-12 | PXD027309 | Pride

Genome-wide chromatin analysis of Ewing sarcoma (RNA-seq)

Project description:We show that EWS-FLI1, an aberrant transcription factor responsible for the pathogenesis of Ewing sarcoma, reprograms gene regulatory circuits by directly inducing or directly repressing enhancers. At GGAA repeats, which lack regulatory potential in other cell types and are not evolutionarily conserved, EWS- FLI1 multimers potently induce chromatin opening, recruit p300 and WDR5, and create de novo enhancers. GGAA repeat enhancers can loop to physically interact with target promoters, as demonstrated by chromosome conformation capture assays. Conversely, EWS-FLI1 inactivates conserved enhancers containing canonical ETS motifs by displacing wild-type ETS transcription factors and abrogating p300 recruitment. Ewing sarcoma cell lines (A673 and SKNMC) were analyzed by RNA-seq. EWS-FLI1 was depleted by infection with lentiviral shRNAs (shFLI1 and shGFP control).

2014-10-30 | E-GEOD-61950 | biostudies-arrayexpress

Expression profiling of Ewing sarcoma samples

Project description:Expression profiling of Ewing sarcoma samples in the frame of the CIT program from the french Ligue Nationale Contre le Cancer (http://cit.ligue-cancer.net). Ewing sarcoma a rare pediatric tumor characterized by EWSR1-ETS fusions, is predominantly observed in populations of European ancestry. A genome-wide association study of at least 401 French ES patients compared to either 684 French or 3668 US self-described Caucasian controls consistently revealed candidate loci at chromosomes 1 and 10 (p<10-6). These loci were further replicated in two independent sets of cases and controls. Joint analysis identified rs9430161 (p=1.4x10-20; OR=2.2, CI99=1.8-2.7) 25kb upstream to TARDBP (1p36.22) and rs224278 (p=4.0x10-17 OR=1.7, CI99=1.4-1.9) 5kb upstream to EGR2 (10q21). The frequency of the major risk haplotypes in the European population were observed to be less prevalent in the African population, suggesting that variants at these loci could contribute to the differences in ES incidence observed between continents. TARDBP shares structural similarities with EWSR1 and FUS (TLS) EGR2 is an EWSR1-ETS target gene. Variants at both loci were associated with expression levels of TARDBP, ADO and EGR2. 117 Ewing sarcoma samples were profiled using affymetrix hgu133Plus2 arrays.

2012-02-11 | E-GEOD-34620 | biostudies-arrayexpress

Oncofusion driven de novo enhancer assembly promotes malignancy in Ewing sarcoma via aberrant expression of the stereociliary protein LOXHD1 [hypoxia]

Project description:Ewing Sarcoma (EwS) is a highly aggressive tumor of bone and soft tissues that mostly affects children and adolescents. The pathognomonic oncofusion EWSR1-ETS (EWS-FLI1/EWSR1-ERG) transcription factors drive EwS by orchestrating an oncogenic transcription program through de novo enhancers. Pharmacological targeting of these oncofusions has been challenged by unstructured prion-like domains and common DNA binding motifs in the EWSR1 and ETS protein, respectively. Alternatively, identification and characterization of mediators and downstream targets of EWS-FLI1 dependent or independent function could offer novel therapeutic options. By integrative analysis of thousands of transcriptome datasets representing pan-cancer cell lines, primary cancer, metastasis, and normal tissues, we have identified a 32 gene signature (ESS32) that could stratify EwS from pan-cancer. Of the ESS32 (Ewing Sarcoma Specific 32), LOXHD1 - coding for a stereociliary protein was the most exquisite gene expressed in EwS. CRISPR-Cas9 mediated deletion or silencing of EWS-FLI1 bound upstream de novo enhancer elements in EwS cells led to the loss of LOXHD1 expression and altered the EWS-FLI1, MYC, and HIF1 pathway genes, resulting in decreased proliferation and invasion in vitro and in vivo. These observations open up new avenues for developing LOXHD1-targeted drugs or cellular therapies for this deadly disease.

2022-06-04 | GSE163333 | GEO

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