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Nucleic Acids Research Advance Access originally published online on May 11, 2009
Nucleic Acids Research 2009 37(12):4135-4148; doi:10.1093/nar/gkp352
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Nucleic Acids Research, 2009, Vol. 37, No. 12 4135-4148
© 2009 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Gene Regulation, Chromatin and Epigenetics

Long-range activation of FKBP51 transcription by the androgen receptor via distal intronic enhancers

Harri Makkonen, Miia Kauhanen, Ville Paakinaho, Tiina Jääskeläinen and Jorma J. Palvimo*

Institute of Biomedicine/Medical Biochemistry, University of Kuopio, P.O. Box 1627, FI-70211 Kuopio, Finland

*To whom correspondence should be addressed. Tel: +358 40 591 0693; Fax: +358 17 16 2889; Email: jorma.palvimo{at}uku.fi

Received January 26, 2009. Revised April 2, 2009. Accepted April 23, 2009.

Androgen receptor (AR) is a ligand-controlled transcription factor frequently deregulated in prostate carcinomas. Since there is scarce information on the action of AR on the chromatin level, we have elucidated the molecular mechanisms underlying the androgen-dependent regulation of immunophilin FKBP51 in prostate cancer cells. In comparison to the canonical AR target PSA, FKBP51 is more rapidly and strongly induced by androgen, with the regulation occurring merely at the transcriptional level. FKBP51 locus harbors 13 in silico-predicted androgen response elements (AREs), with most of them located downstream from transcription start site (TSS) and capable of binding AR in vitro. Chromatin immunoprecipitation assays in VCaP and LNCaP prostate cancer cells indicate that activation of the locus by the AR relies on four major intronic sites, with the compound ARE-containing sites ≥90 kb downstream from the TSS playing critical roles. Binding of agonist-loaded AR onto these sites in vivo was accompanied with significant recruitment of RNA polymerase II and BRM-containing chromatin remodeling complexes to the FKBP51 locus, which resulted in changes in the histone density of the locus. Our results indicate that very distal AREs act as genuine and robust enhancers, highlighting the importance of long-range regulation of transcription by the AR.


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