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| Status |
Public on Mar 09, 2018 |
| Title |
BRCA1/RNApII regulation in Ewing's sarcoma (ChIP-seq) |
| Organism |
Homo sapiens |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
|
| Summary |
Ewing sarcoma (EwS) is an aggressive pediatric bone and soft tissue cancer. It is driven by a fusion oncogene involving the EWSR1 gene, predominantly EWS-FLI1. EwS is exquisitely sensitive to genotoxic agents, but the molecular basis for this sensitivity is relatively underexplored. We have discovered that EwS displays alterations in damage-induced transcription regulation and an accumulation of R-loops. Consequently, we observe an increase in replication stress but impaired homologous recombination. We demonstrate an enriched interaction between BRCA1 and the elongating transcription machinery and suggest that this interaction may be the underlying cause for impaired recombination. Investigation into the unique transcription profile of EwS also revealed upregulated mechanisms (including RNASEH2, FEN1 and Fanconi Anemia pathway) to compensate for the increased EWS-FLI1 induced toxicity. Finally, we have uncovered a novel role for EWSR1 transcriptional response to damage, suppressing R-loops and promoting homologous recombination. Taken together, our findings improve the current understanding of wild-type EWSR1 function, elucidate the mechanistic basis for EwS chemosensitivity (including PARP1 inhibitors) and suggest potential targets for novel second-line therapy.
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| Overall design |
Four different cell lines, IMR90, U2OS, TC32 and EWS502 were profiled for RNAPII and BRCA1 via ChIP protocol. Samples treated with etoposide for 6 hours were profiled as well.
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| |
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| Contributor(s) |
Gorthi A, Yidong C, Bishop AJ |
| Citation(s) |
29513652 |
| |
| Submission date |
Sep 23, 2016 |
| Last update date |
Jul 25, 2021 |
| Contact name |
Yidong Chen |
| E-mail(s) |
[email protected]
|
| Phone |
2105629163
|
| Organization name |
UT Health Science Center at San Antonio
|
| Department |
Population Health Sciences
|
| Street address |
8403 Floyd Curl Drive, MSC 7784
|
| City |
San Antonio |
| State/province |
Texas |
| ZIP/Postal code |
78229 |
| Country |
USA |
| |
|
| Platforms (2) |
| GPL11154 |
Illumina HiSeq 2000 (Homo sapiens) |
| GPL21290 |
Illumina HiSeq 3000 (Homo sapiens) |
|
| Samples (26)
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| This SubSeries is part of SuperSeries: |
| GSE68847 |
BRCA1, R-loops and Recombination defects in Ewing's sarcoma |
|
| Relations |
| BioProject |
PRJNA344334 |
| SRA |
SRP090392 |
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