title: Chromatin accessibility reveals insights into androgen receptor activation and transcriptional specificity.
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.
authors.forename: Alok K
authors.initials: AK
authors.lastname: Tewari
authors.forename: Galip Gürkan
authors.initials: GG
authors.lastname: Yardimci
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Shibata
authors.forename: Nathan C
authors.initials: NC
authors.lastname: Sheffield
authors.forename: Lingyun
authors.initials: L
authors.lastname: Song
authors.forename: Barry S
authors.initials: BS
authors.lastname: Taylor
authors.forename: Stoyan G
authors.initials: SG
authors.lastname: Georgiev
authors.forename: Gerhard A
authors.initials: GA
authors.lastname: Coetzee
authors.forename: Uwe
authors.initials: U
authors.lastname: Ohler
authors.forename: Terrence S
authors.initials: TS
authors.lastname: Furey
authors.forename: Gregory E
authors.initials: GE
authors.lastname: Crawford
authors.forename: Phillip G
authors.initials: PG
authors.lastname: Febbo
mesh_terms: D001665:Binding Sites; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D008297:Male; D015741:Metribolone / Q000494:pharmacology*; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism*; D017422:Sequence Analysis, DNA / Q000379:methods; D016329:Sp1 Transcription Factor / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: C410798:AR protein, human; D002843:Chromatin; D011944:Receptors, Androgen; D016329:Sp1 Transcription Factor; C108209:SP1 protein, human; D015741:Metribolone