Abstract 2923: Androgen receptor activation changes chromatin structure and transcriptional activation

Abstract

Abstract Epigenetic mechanisms such as chromatin accessibility and histone modifications impact transcription factor binding to DNA and transcriptional specificity. The androgen receptor (AR), a master regulator of prostate cancer initiation and progression, acts primarily through ligand-activated transcription of target genes. By combining deep sequencing with DNase I hypersensitivity analysis (DNase-seq) and RNA analysis (RNA-seq) we assessed genome-wide chromatin structure and transcription and combined this data with publicly available AR chromatin immunoprecipitation data (AR Chip-seq). We find that 64% of DNase I hypersensitive sites (DHS) overlap each other before and after androgen in LNCaP cells. Interestingly, in regions with increased chromatin accessibility following androgen induction, the canonical AR DNA recognition motif is enriched. Comparing identified DHS to AR binding sites from three different data sets consistently reveals that 50% of AR binding overlaps a DHS in induced cells. Of those sites with both DHS and AR binding, approximately half are available prior to androgen induction (i.e. “primed”) and half open in response to androgen stimulation. This contrasts with the glucocorticoid receptor (GR), which was recently reported to bind to DNA primarily in regions that are accessible to nuclease cleavage prior to ligand activation. Our RNA-seq analysis discovered 367 genes regulated by AR activation (FDR < 0.05), including 16 of the 19 most commonly identified AR-mediated genes in several other studies. Importantly, we find that regions of increased chromatin accessibility are significantly associated with genes identified as AR-regulated by RNA-seq. Finally, base pair resolution of the DNase-seq signal reveals distinct footprinting patterns associated with the AR-DNA interaction. Analysis of chromatin structure, AR binding, and transcription prior to and following androgen induction demonstrates that AR activation by ligand induces genome-wide changes in chromatin accessibility, these changes correspond to AR binding to the genome, and they impact AR-mediated transcriptional response. These findings suggest that interaction between the AR and DNA alters chromatin structure and transcriptional specificity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2923. doi:1538-7445.AM2012-2923