Genomics

Dataset Information

168

EWS-FLI1 represses Rho-actin signaling via MRTFB/YAP-1/TEAD perturbation in Ewing Sarcoma [Chip-Seq]


ABSTRACT: Ewing Sarcoma (EwS) is a EWS-FLI1- fusion driven pediatric bone cancer with high metastatic potential. Cellular plasticity, typically regulated via the Rho-pathway, is a prerequisite for metastasis initiation. Here we interrogated the role of the Rho transcriptional effectors MRTFA/B in EwS. We find MRTFB transcriptional function strongly repressed by EWS-FLI1. Under EWS-FLI1-low (knock-down) conditions, MRTFB is activated and antagonizes global EWS-FLI1-dependent transcription. Furthermore, ChIP-Seq revealed strong overlaps in MRTFB and EWS-FLI1 chromatin occupation, especially for EWS-FLI1 suppressed-(anticorrelated) genes. Enrichment of TEAD binding motifs in these shared genomic binding regions, and overlapping transcriptional footprints of MRTFB and TEAD1-4 perturbation led us to propose synergy between MRTFB and TEAD in the regulation of EWS-FLI1 suppressed-anticorrelated genes. Finally, we find F-actin assembly to be already perturbed in our EwS model, F-actin polymerization is perturbed by EWS-FLI1 in our model cell line, however,but pharmacological inhibition of actin polymerization still reduced expression serum-induced expression of MRTFB/YAP-1/TEAD target genes. In summary our data support a model of indirect and direct EWS-FLI1-driven perturbation of MRTFB/YAP-1/TEAD target gene regulation . Overall design: Chromatin Immunoprecipitation coupled with Next-generation sequencing (ChIP-seq) of MRTFA, MRTFB, SRF and EWS-FLI1 (2 replicates each) under serum-induced conditions.

INSTRUMENT(S): Illumina HiSeq 2000 (Homo sapiens)

SUBMITTER: Maximilian Kauer  

PROVIDER: GSE92738 | GEO | 2017-07-06

SECONDARY ACCESSION(S): PRJNA358640

REPOSITORIES: GEO

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Publications

EWS-FLI1 perturbs MRTFB/YAP-1/TEAD target gene regulation inhibiting cytoskeletal autoregulatory feedback in Ewing sarcoma.

Katschnig A M AM   Kauer M O MO   Schwentner R R   Tomazou E M EM   Mutz C N CN   Linder M M   Sibilia M M   Alonso J J   Aryee D N T DNT   Kovar H H  

Oncogene 20170703 43


Ewing sarcoma (EWS) is a paediatric bone cancer with high metastatic potential. Cellular plasticity resulting from dynamic cytoskeletal reorganization, typically regulated via the Rho pathway, is a prerequisite for metastasis initiation. Here, we interrogated the role of the Ewing sarcoma driver oncogene EWS-FLI1 in cytoskeletal reprogramming. We report that EWS-FLI1 strongly represses the activity of the Rho-F-actin signal pathway transcriptional effector MRTFB, affecting the expression of a la  ...[more]

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