The PENGUIN approach to reconstruct  protein interactions at enhancer-promoter regions and its application to prostate cancer
We introduce the Promoter-ENhancer-GUided Interaction Networks (PENGUIN) approach to identify protein-protein interactions (PPI) within enhancer-promoter (E-P) interactions. By integrating high-coverage H3K27ac-HiChIP data and tissue-specific PPI networks, PENGUIN identifies functional clusters in E-P networks. Here, we applied PENGUIN to E-P networks of  prostate cancer (PrCa) cell line LNCaP. We validated PENGUIN's structural classification by observing clear differential enrichment of the architectural protein CTCF. One of our 8 main clusters, comprising 273 promoters, showed significant enrichment for PrCa-associated single nucleotide polymorphisms (SNPs) and oncogenes. Our approach provides a mechanistic explanation for 208 PrCa SNPs located within DNA-binding protein (DBP) binding sites or intermediate protein-encoding genes involved in E-P contacts. CRISPR analysis in the LNCaP cell line confirmed the relevance of these SNPs in PrCa. PENGUIN confirms the importance of key regulators in PrCa and identifies new intervention candidates, offering new directions for identifying molecular targets in disease treatment. Data was generated in the Matthew L. Freedman lab. Overall design: H3K27ac HiChIP in LNCaP. Chromatin digested with MboI restriction enzyme. H3K27ac ChIP-seq ??