Refinement of the androgen response element based on ChIP-Seq in androgen-insensitive and androgen-responsive prostate cancer cell lines.
Sequence motifs are short, recurring patterns in DNA that can mediate sequence-specific binding for proteins such as transcription factors or DNA modifying enzymes. The androgen response element (ARE) is a palindromic, dihexameric motif present in promoters or enhancers of genes targeted by the androgen receptor (AR). Using chromatin immunoprecipitation sequencing (ChIP-Seq) we refined AR-binding and AREs at a genome-scale in androgen-insensitive and androgen-responsive prostate cancer cell lines. Model-based searches identified more than 120,000 ChIP-Seq motifs allowing for expansion and refinement of the ARE. We classified AREs according to their degeneracy and their transcriptional involvement. Additionally, we quantified ARE utilization in response to somatic copy number amplifications, AR splice-variants, and steroid treatment. Although imperfect AREs make up 99.9% of the motifs, the degree of degeneracy correlates negatively with validated transcriptional outcome. Weaker AREs, particularly ARE half sites, benefit from neighboring motifs or cooperating transcription factors in regulating gene expression. Taken together, ARE full sites generate a reliable transcriptional outcome in AR positive cells, despite their low genome-wide abundance. In contrast, the transcriptional influence of ARE half sites can be modulated by cooperating factors.
Systems Biology and Cancer Metabolism, Program for Quantitative Systems Biology, University of California Merced, 2500 North Lake Road, Merced, CA 95343, USA.
Stephen
S
Wilson
Marlene and Stewart Greenebaum Cancer Center, Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, 655 West Baltimore Street, Baltimore MD 21201, USA.
Jianfei
J
Qi
Systems Biology and Cancer Metabolism, Program for Quantitative Systems Biology, University of California Merced, 2500 North Lake Road, Merced, CA 95343, USA.
Fabian V
FV
Filipp
D000728:Androgens / Q000378:metabolism; D001665:Binding Sites / Q000235:genetics; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins / Q000235:genetics; D006801:Humans; D008297:Male; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000473:pathology; D059372:Nucleotide Motifs / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D011485:Protein Binding; D011944:Receptors, Androgen / Q000235:genetics*; D020218:Response Elements / Q000235:genetics*
C410798:AR protein, human; D000728:Androgens; D004268:DNA-Binding Proteins; D011944:Receptors, Androgen