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Cell- and gene-specific regulation of primary target genes by the androgen receptor

¹ Department of Cellular and Molecular Pharmacology, University of California, San Francisco, California 94143, USA; ² Department of Biochemistry and Biophysics, University of California, San Francisco, California 94143, USA; ³ Department of Urology, University of California, San Francisco, California 94143, USA; ⁴ California Institute for Quantitative Biomedical Research, University of California, San Francisco, California 94143, USA; ⁵ Chemistry and Chemical Biology Graduate Program, University of California, San Francisco, California 94143, USA; ⁶ Graduate Program in Biological and Medical Informatics, University of California, San Francisco, California 94143, USA

The androgen receptor (AR) mediates the physiologic and pathophysiologic effects of androgens including sexual differentiation, prostate development, and cancer progression by binding to genomic androgen response elements (AREs), which influence transcription of AR target genes. The composition and context of AREs differ between genes, thus enabling AR to confer multiple regulatory functions within a single nucleus. We used expression profiling of an immortalized human prostate epithelial cell line to identify 205 androgen-responsive genes (ARGs), most of them novel. In addition, we performed chromatin immunoprecipitation to identify 524 AR binding regions and validated in reporter assays the ARE activities of several such regions. Interestingly, 67% of our AREs resided within 50 kb of the transcription start sites of 84% of our ARGs. Indeed, most ARGs were associated with two or more AREs, and ARGs were sometimes themselves linked in gene clusters containing up to 13 AREs and 12 ARGs. AREs appeared typically to be composite elements, containing AR binding sequences adjacent to binding motifs for other transcriptional regulators. Functionally, ARGs were commonly involved in prostate cell proliferation, communication, differentiation, and possibly cancer progression. Our results provide new insights into cell- and gene-specific mechanisms of transcriptional regulation of androgen-responsive gene networks.

[Keywords: Androgen receptor (AR); androgen response element (ARE); transcription; steroid receptor; chromatin immunoprecipitation (ChIP); prostate cancer]

Received April 23, 2007; revised version accepted July 6, 2007.

E-MAIL yamamoto{at}cmp.ucsf.edu; FAX (415) 476-6129.

Supplemental material is available at http://www.genesdev.org.

Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1564207

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