Project description:In this study we functionally quantified the enhancer activity of all clinical ARBS. We demonstrated that only 7% of ARBS demonstrate androgen-dependent enhancer activation, while 11% have enhancer activity independent of AR binding. Almost all of these AR enhancers have not been previously studied. Surprisingly the vast majority of ARBS (81%) do not have significant enhancer activity. This in vitro annotation strongly correlated to clinical PCa samples. Integrating long-range chromatin interactome and transcriptomic data, we found androgen inducible enhancers were significantly more enriched to serve as anchors for gene looping and acted as a ?hub? to activate AR-regulated genes. To characterize the mechanism of AR enhancers we developed a deep neural network that can successfully predict active enhancers and identify key features for active enhancers. Finally, combining these results with whole genome sequencing of primary and metastatic PCa, we identified and characterized non-coding somatic SNVs that significantly impacted AR enhancer activity of a critical tumour suppressor.
Project description:In this study we functionally quantified the enhancer activity of all clinical ARBS. We demonstrated that only 7% of ARBS demonstrate androgen-dependent enhancer activation, while 11% have enhancer activity independent of AR binding. Almost all of these AR enhancers have not been previously studied. Surprisingly the vast majority of ARBS (81%) do not have significant enhancer activity. This in vitro annotation strongly correlated to clinical PCa samples. Integrating long-range chromatin interactome and transcriptomic data, we found androgen inducible enhancers were significantly more enriched to serve as anchors for gene looping and acted as a ‘hub’ to activate AR-regulated genes. To characterize the mechanism of AR enhancers we developed a deep neural network that can successfully predict active enhancers and identify key features for active enhancers. Finally, combining these results with whole genome sequencing of primary and metastatic PCa, we identified and characterized non-coding somatic SNVs that significantly impacted AR enhancer activity of a critical tumour suppressor.
