Understanding the Collaboration between the Androgen Receptor and ERG in Prostate Cancer
Annual summary rept. 15 Jul 2011-14 Jul 2012
DUKE UNIV MEDICAL CENTER DURHAM NC
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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 the male phenotype and prostate cancer pathogenesis, acts primarily through ligand-activated transcription of target genes. Our purpose is to explore how the ERG transcription factor impacts AR function by focusing on chromatin accessibility, AR binding and transcription. The first year of this award has been spent focusing on developing and optimizing the molecular biology techniques, computational tools and analyses to understand the chromatin dynamics of AR activation. This work lays a critical groundwork for understanding how perturbations to prostate cancer cells, such as ERG over-expression, impacts chromatin structure, AR binding to DNA, and transcription. Our analysis of AR activation in prostate cancer cells revealed both qualitative and quantitative differences in chromatin accessibility that largely correspond to AR binding and AR-regulated RNA transcription across the genome and underscores the importance of analyzing chromatin data as continuous signal rather than discrete binary peaks. Intriguingly, base pair resolution of the DNaseI cleavage profile revealed distinct footprinting patterns associated with the AR-DNA interaction, suggesting multiple modes of AR-DNA interactions. These analyses suggest a dynamic and novel quantitative relationship between chromatin structure and AR-DNA binding which impacts AR transcriptional specificity. The results from this year of work have been presented at national meetings are under review for publication.
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