The PENGUIN approach to reconstruct protein interactions at enhancer-promoter regions and its application to prostate cancer

Here we introduce Promoter-ENhancer-GUided Interaction Networks (PENGUIN), a method to uncover protein-protein interaction (PPI) networks at enhancer-promoter contacts. By integrating H3K27ac-HiChIP data and tissue-specific PPI information, PENGUIN enables cluster enhancers-promoter PPI networks (EPINs) and pinpoint actionable factors. Validating PENGUIN in cancer (LNCaP) and benign (LHSAR) prostate cell lines, we observed distinct CTCF-enriched clusters, which identifies diverse chromatin conformations. In LNCaP, we found an EPIN cluster enriched with oncogenes and prostate cancer-associated SNPs. We uncovered a total of 208 SNPs in LNCaP EPINs and used CRISPR/Cas9 knockout and RNAi screens to confirm their relevance. PENGUINs application in prostate cancer demonstrates its potential for studying human diseases. The approach allows exploration in different cell types and combinations of GWAS data, offering promising avenues for future investigations. In conclusion, PENGUIN provides valuable insights into the interplay between enhancer-promoter interactions and PPI networks, facilitating the identification of relevant genes and potential intervention targets.