Chromatin accessibility reveals insights into androgen receptor activation and transcriptional specificity Public Deposited

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Creator
  • Furey, Terrence
    • Affiliation: School of Medicine, Department of Genetics, College of Arts and Sciences, Department of Biology, Carolina Center for Genome Sciences, N.C. Cancer Hospital, UNC Lineberger Comprehensive Cancer Center
  • Taylor, Barry S
    • Other Affiliation: Computational Biology Center, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
  • Febbo, Phillip G
    • Other Affiliation: Helen Diller Family Comprehensive Cancer Center, Department of Medicine, Department of Urology, University of California at San Francisco School of Medicine, San Francisco, CA 94115, USA
  • Crawford, Gregory E
    • Other Affiliation: Institute for Genome Sciences & Policy, Department of Pediatrics, Division of Medical Genetics, Duke University, Durham, NC 27708, USA
  • Ohler, Uwe
    • Other Affiliation: Institute for Genome Sciences & Policy, Department of Biostatistics and Bioinformatics, Department of Computer Science, Duke University, Durham, NC 27708, USA
  • Sheffield, Nathan C
    • Other Affiliation: Institute for Genome Sciences & Policy, Duke University, Durham, NC 27708, USA
  • Shibata, Yoichiro
    • Other Affiliation: Institute for Genome Sciences & Policy, Duke University, Durham, NC 27708, USA
  • Tewari, Alok K
    • Other Affiliation: Institute for Genome Sciences & Policy, Duke University, Durham, NC 27708, USA
  • Yardimci, Galip
    • Other Affiliation: Institute for Genome Sciences & Policy, Duke University, Durham, NC 27708, USA
  • Coetzee, Gerhard A
    • Other Affiliation: Department of Preventive Medicine, Department of Urology, Norris Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
  • Song, Lingyun
    • Other Affiliation: Institute for Genome Sciences & Policy, Duke University, Durham, NC 27708, USA
  • Georgiev, Stoyan G
    • Other Affiliation: Institute for Genome Sciences & Policy, Duke University, Durham, NC 27708, USA
Abstract
  • 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.
Date of publication
Identifier
  • doi:10.1186/gb-2012-13-10-r88
Resource type
  • Article
Rights statement
  • In Copyright
Rights holder
  • Alok K Tewari et al.; licensee BioMed Central Ltd.
License
Journal title
  • Genome Biology
Journal volume
  • 13
Journal issue
  • 10
Page start
  • R88
Language
  • English
Is the article or chapter peer-reviewed?
  • Yes
ISSN
  • 1465-6906
Bibliographic citation
  • Genome Biology. 2012 Oct 03;13(10):R88
Access
  • Open Access
Publisher
  • BioMed Central Ltd
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