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Status |
Public on Nov 09, 2017 |
Title |
Identification of two types of GGAA microsatellites and their roles in EWS/FLI binding and gene regulation in Ewing sarcoma |
Organism |
Homo sapiens |
Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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Summary |
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.
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Overall design |
Examination of EWS/FLI binding in A673 cells.
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Contributor(s) |
Johnson KM, Taslim C, Saund RS, Lessnick SL |
Citation(s) |
29091716 |
Submission date |
Jun 12, 2017 |
Last update date |
May 15, 2019 |
Contact name |
Cenny Taslim |
E-mail(s) |
cenny.taslim@nationwidechildrens.org
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Organization name |
Nationwide Children's Hospital
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Street address |
700 Children's Drive
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City |
Columbus |
ZIP/Postal code |
43205 |
Country |
USA |
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Platforms (1) |
GPL16791 |
Illumina HiSeq 2500 (Homo sapiens) |
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Samples (8)
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Relations |
BioProject |
PRJNA390192 |
SRA |
SRP109046 |