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This article is part of a special issue on epigenomics.

Open Access Research

Chromatin accessibility reveals insights into androgen receptor activation and transcriptional specificity

Alok K Tewari1, Galip G├╝rkan Yardimci1, Yoichiro Shibata1, Nathan C Sheffield1, Lingyun Song1, Barry S Taylor3, Stoyan G Georgiev1, Gerhard A Coetzee45, Uwe Ohler167, Terrence S Furey8, Gregory E Crawford19 and Phillip G Febbo10112*

Author affiliations

1 Institute for Genome Sciences & Policy, Duke University, Durham, NC 27708, USA

2 Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, CA 94115, USA

3 Computational Biology Center, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA

4 Department of Preventive Medicine, Norris Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA

5 Department of Urology, Norris Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA

6 Department of Biostatistics and Bioinformatics, Duke University, Durham, NC 27708, USA

7 Department of Computer Science, Duke University, Durham, NC 27708, USA

8 Departments of Biology and Genetics, Carolina Center for Genome Sciences and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA

9 Department of Pediatrics, Division of Medical Genetics, Duke University, Durham, NC 27708, USA

10 Department of Medicine, University of California at San Francisco School of Medicine, San Francisco, CA 94115, USA

11 Department of Urology, University of California at San Francisco School of Medicine, San Francisco, CA 94115, USA

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Citation and License

Genome Biology 2012, 13:R88  doi:10.1186/gb-2012-13-10-r88

Published: 3 October 2012

Abstract

Background

Epigenetic mechanisms such as chromatin accessibility impact transcription factor binding to DNA and transcriptional specificity. The androgen receptor (AR), a master regulator of the male phenotype and prostate cancer pathogenesis, acts primarily through ligand-activated transcription of target genes. Although several determinants of AR transcriptional specificity have been elucidated, our understanding of the interplay between chromatin accessibility and AR function remains incomplete.

Results

We used deep sequencing to assess chromatin structure via DNase I hypersensitivity and mRNA abundance, and paired these datasets with three independent AR ChIP-seq datasets. Our analysis revealed qualitative and quantitative differences in chromatin accessibility that corresponded to both AR binding and an enrichment of motifs for potential collaborating factors, one of which was identified as SP1. These quantitative differences were significantly associated with AR-regulated mRNA transcription across the genome. Base-pair resolution of the DNase I cleavage profile revealed three distinct footprinting patterns associated with the AR-DNA interaction, suggesting multiple modes of AR interaction with the genome.

Conclusions

In contrast with other DNA-binding factors, AR binding to the genome does not only target regions that are accessible to DNase I cleavage prior to hormone induction. AR binding is invariably associated with an increase in chromatin accessibility and, consequently, changes in gene expression. Furthermore, we present the first in vivo evidence that a significant fraction of AR binds only to half of the full AR DNA motif. These findings indicate a dynamic quantitative relationship between chromatin structure and AR-DNA binding that impacts AR transcriptional specificity.