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

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

PROVIDER: PRJNA985606 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR24968238_1.fastq.gz	Fastqsanger.gz
	SRR24968238_2.fastq.gz	Fastqsanger.gz
	SRR24968239_1.fastq.gz	Fastqsanger.gz
	SRR24968239_2.fastq.gz	Fastqsanger.gz
	SRR24968240_1.fastq.gz	Fastqsanger.gz

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

Project description: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.

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

Project description:We introduce Promoter-Enhancer-Guided Interaction Networks (PENGUIN), a method for studying protein-protein interaction (PPI) networks within enhancer-promoter interactions. PENGUIN integrates H3K27ac-HiChIP data with tissue-specific PPIs to define enhancer-promoter PPI networks (EPINs). We validated PENGUIN using cancer (LNCaP) and benign (LHSAR) prostate cell lines. Our analysis detected EPIN clusters enriched with the architectural protein CTCF, a regulator of enhancer-promoter interactions. CTCF presence was coupled with the prevalence of prostate cancer (PrCa) single nucleotide polymorphisms (SNPs) within the same EPIN clusters, suggesting functional implications in PrCa. Within the EPINs displaying enrichments in both CTCF and PrCa SNPs, we also show enrichment in oncogenes. We substantiated our identified SNPs through CRISPR/Cas9 knockout and RNAi screens experiments. Here we show that PENGUIN provides insights into the intricate interplay between enhancer-promoter interactions and PPI networks, which are crucial for identifying key genes and potential intervention targets. A dedicated server is available at https://penguin.life.bsc.es/ .

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