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Chromatin accessibility reveals insights into androgen receptor activation and transcriptional specificity

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Item Type:Article
Title:Chromatin accessibility reveals insights into androgen receptor activation and transcriptional specificity
Creators Name:Tewari, A.K. and Yardimci, G.G. and Shibata, Y. and Sheffield, N.C. and Song, L. and Taylor, B.S. and Georgiev, S.G. and Coetzee, GA. and Ohler, U. and Furey, T.S. and Crawford, G.E. and Febbo, P.G.
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.
Keywords:Androgen Receptors, Binding Sites, Chromatin, DNA Sequence Analysis, Genetic Transcription, Human Genome, High-Throughput Nucleotide Sequencing, Metribolone, Neoplastic Gene Expression Regulation, Sp1 Transcription Factor, Tumor Cell Line
Source:Genome Biology
Publisher:BioMed Central
Page Range:R88
Date:3 October 2012
Official Publication:https://doi.org/10.1186/gb-2012-13-10-r88
PubMed:View item in PubMed

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