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Proc Natl Acad Sci U S A. 2016 Mar 15;113(11):3018-23. doi: 10.1073/pnas.1521827113. Epub 2016 Feb 29.

High-throughput small molecule screen identifies inhibitors of aberrant chromatin accessibility.

Author information

1
Center for Integrative Chemical Biology and Drug Discovery, University of North Carolina at Chapel Hill, Chapel Hill, NC 27302; Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27302;
2
Department of Genetics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599; Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599; Curriculum in Bioinformatics and Computational Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599;
3
Department of Genetics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599; Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599; Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599;
4
Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599; Department of Pediatrics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599;
5
Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599;
6
Department of Genetics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599; Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599; Department of Pediatrics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599; Carolina Center for Genome Sciences, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 ian_davis@med.unc.edu.

Abstract

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.

KEYWORDS:

Ewing sarcoma; FAIRE; chromatin; high throughput screening; histone deacetylase inhibitor

PMID:
26929321
PMCID:
PMC4801272
DOI:
10.1073/pnas.1521827113
[Indexed for MEDLINE]
Free PMC Article

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