Genomic profiling of H3K27ac and transcription factor binding in ERG-overexpressing prostate cancer

Structural rearrangements leading to the TMPRSS2:ERG (T2E) fusion typify ~50% of prostate tumors and result in overexpression of the ERG transcription factor. Using T2E and non-T2E primary prostate tumors, we assessed the impact of ERG overexpression on chromatin by integrating ChIP-seq against H3K27ac, a chromatin modification found at active cis-regulatory elements, with paired genomic and expression data. We show that T2E tumors have a consistent and distinct cis-regulatory landscape to non-T2E tumors which drives their unique transcriptional profile. The T2E-specific cis-regulatory landscape is driven by ERG-mediated co-option of prostate master transcription factors HOXB13 and FOXA1 and is typified by Cluster Of Regulatory Elements (COREs)  including one spreading into the ERG locus of the structurally rearranged allele. This gives rise to a cis-regulatory element within the rearranged ERG gene that contributes to ERG overexpression. The unique cis-regulatory landscape in T2E primary prostate tumors also reveals the activation of the NOTCH signalling pathway. Accordingly, chemical NOTCH pathway inhibition limited the invasive nature of T2E prostate cancer cells, revealing an actionable vulnerability against T2E prostate tumors. Taken together, our work delineates the role of ERG over-expression in co-opting master transcription factors to deploy a unique cis-regulatory landscape inducing a dependency on NOTCH signaling in T2E prostate tumors. Overall design: Genomic profiles of H3K27ac in ERG overexpressing prostate cancer and prostate cancer without ERG overexpression. Genomic binding of AR, FOXA1, HOXB13 in 22Rv1 prostate cells and of HOXB13 in LNCaP prostate cells. Genomic binding of FOXA1 and HOXB13, as well as H3K27ac profiles, upon knockdown of ERG in VCaP prostate cells.