Identification of androgen receptor transcriptional complexes on distinct promoter targets


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Charlie Massie1, Falk Butter2, Andy Lynch1, Boris Adryan3, Nuno Barbosa-Morais1, Naomi Sharma1, Maxine Tran2, Matthias Mann1, David Neal1, Ian Mills1

1Cancer Research UK Cambridge Research Institute, University of Cambridge, UK, 2Max-Planck-Institute, Martinsried, Germany, 3Cambridge Systems Biology Centre, University of Cambridge, UK

Abstract

Transcriptional regulation by the androgen receptor (AR) is integral to male sexual development and the onset and progression of prostate cancer. Many studies have identified the transcriptional changes which follow androgen stimulation, as well as identifying proteins which can modulate AR function. However, direct target genes of the AR are poorly characterised and the cooperation of AR co-regulators in mediating AR target gene transcription remains obscure. Therefore, the key initiating signals mediated by the androgen signalling axis in prostate cancer and the coordinated mechanism behind these transcriptional progams remain undefined. We have attempted to address these shortfalls by using a combination of (1) chromatin immunoprecipitation with on array detection (ChIP-on-chip) to identify promoter binding sites of the AR, (2) detailed time-course analysis of the transcriptional changes in response to androgens and (3) a novel in vitro proteomics method to identify proteins which are co-recruited to AR bound DNA sequences. The integration of these approaches has provided insights into the preferred genomic binding sites of the AR, the dynamics of AR transcriptional targets and testable models for the dynamic regulation of AR target genes through recruitment of specific AR co-regulators to distinct sets of AR target genes.

Transcriptional regulation by the androgen receptor (AR) is integral to male sexual development and the onset and progression of prostate cancer. Many studies have identified the transcriptional changes which follow androgen stimulation, as well as identifying proteins which can modulate AR function. However, direct target genes of the AR are poorly characterised and the cooperation of AR co-regulators in mediating AR target gene transcription remains obscure. Therefore, the key initiating signals mediated by the androgen signalling axis in prostate cancer and the coordinated mechanism behind these transcriptional progams remain undefined. We have attempted to address these shortfalls by using a combination of (1) chromatin immunoprecipitation with on array detection (ChIP-on-chip) to identify promoter binding sites of the AR, (2) detailed time-course analysis of the transcriptional changes in response to androgens and (3) a novel in vitro proteomics method to identify proteins which are co-recruited to AR bound DNA sequences. The integration of these approaches has provided insights into the preferred genomic binding sites of the AR, the dynamics of AR transcriptional targets and testable models for the dynamic regulation of AR target genes through recruitment of specific AR co-regulators to distinct sets of AR target genes.

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