Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 113, Issue 11, Pages 3018-3023Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1521827113
Keywords
chromatin; Ewing sarcoma; high throughput screening; FAIRE; histone deacetylase inhibitor
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Funding
- Wide Open Charitable Foundation
- V Foundation for Cancer Research
- National Institutes of Health (NIH) [R01CA166447, RC1GM090732, R01GM100919]
- Carolina Partnership
- University Cancer Research Fund, University of North Carolina at Chapel Hill
- NIH [T32CA071341, T32GM007092]
- Reelin' for Research
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Mutations in chromatin-modifying proteins and transcription factors are commonly associated with a wide variety of cancers. Through gain-or loss-of-function, these mutations may result in characteristic alterations of accessible chromatin, indicative of shifts in the landscape of regulatory elements genome-wide. The identification of compounds that reverse a specific chromatin signature could lead to chemical probes or potential therapies. To explore whether chromatin accessibility could serve as a platform for small molecule screening, we adapted formaldehyde-assisted isolation of regulatory elements (FAIRE), a chemical method to enrich for nucleosome-depleted genomic regions, as a high-throughput, automated assay. After demonstrating the validity and robustness of this approach, we applied this method to screen an epigenetically targeted small molecule library by evaluating regions of aberrant nucleosome depletion mediated by EWSR1-FLI1, the chimeric transcription factor critical for the bone and soft tissue tumor Ewing sarcoma. As a class, histone deacetylase inhibitors were greatly overrepresented among active compounds. These compounds resulted in diminished accessibility at targeted sites by disrupting transcription of EWSR1-FLI1. Capitalizing on precise differences in chromatin accessibility for drug discovery efforts offers significant advantages because it does not depend on the a priori selection of a single molecular target and may detect novel biologically relevant pathways.
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